mu p75-SAP References

mu p75-SAP (Cat. #IT-16)

68 entries found for : it-16

Stimulation of the muscarinic receptor M4 activates quiescent neural precursor cells and ameliorates medial septum cholinergic lesion-induced impairments in adult hippocampal neurogenesis

Madrid LI, Bandhavkar S, Hafey K, Jimenez-Martin J, Milne M, Coulson EJ, Jhaveri DJ (2022) Stimulation of the muscarinic receptor M4 activates quiescent neural precursor cells and ameliorates medial septum cholinergic lesion-induced impairments in adult hippocampal neurogenesis. bioRxiv 2022.08.25.505357. doi: 10.1101/2022.08.25.505357

Objective: To investigate the contribution of basal forebrain medial septum (MS) and diagonal band of Broca (DBB) cholinergic neurons that innervate the hippocampus and the identity of the cholinergic receptor(s) that regulate the production and maturation of new neurons.

Summary: This work reveals stage-specific roles of cholinergic signaling in regulating functionally relevant adult hippocampal neurogenesis.

Usage: Medial septum cholinergic lesion was achieved by infusion of mu p75-SAP (0.4 µg/µl). Rabbit IgG-SAP (0.4 µg/µl) was used as control.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Tart cherry extract and omega fatty acids reduce behavioral deficits, gliosis, and amyloid-beta deposition in the 5xFAD mouse model of Alzheimer’s disease

Bowers Z, Maiti P, Bourcier A, Morse J, Jenrow K, Rossignol J, Dunbar GL (2021) Tart cherry extract and omega fatty acids reduce behavioral deficits, gliosis, and amyloid-beta deposition in the 5xFAD mouse model of Alzheimer's disease. Brain Sci 11(11):1423. doi: 10.3390/brainsci11111423

Objective: To assess the efficacy of Total Body Rhythm (TBR) for treating behavioral and neuropathological deficits in the 5xFAD model of AD.

Summary: The combination of tart cherry extract and omega fatty acids in TBR can reduce AD-like deficits in 5xFAD mice.

Usage: Previous work demonstrated that TBR can prevent loss of body weight in a mu p75-SAP mouse model of AD.

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Engrafted stem cell therapy for Alzheimer’s disease: A promising treatment strategy with clinical outcome

Salwa, LK (2021) Engrafted stem cell therapy for Alzheimer's disease: A promising treatment strategy with clinical outcome. J Control Release 338:837-857. doi: 10.1016/j.jconrel.2021.09.007 Objective: This review provides a detailed update on stem cell therapy (SCT) for Alzheimer’s Disease (AD) Summary: What future holds for SCT in the treatment of AD is summarized Usage: Liu et al. injected 1.5 μg of mu p75-SAP into the medial septum. See: Liu Y et al. Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol 31(5):440-447, 2013. Read the featured article in Targeting Trends. Related Products: mu p75-SAP (Cat. #IT-16)

Cholinergic modulation of sensory processing in awake mouse cortex

Jimenez-Martin J, Potapov D, Potapov K, Knöpfel T, Empson RM (2021) Cholinergic modulation of sensory processing in awake mouse cortex. Sci Rep 11(1):17525. doi: 10.1038/s41598-021-96696-8

Objective: To decipher the timing and significance of acetylcholine actions.

Summary: Study provides new insights into how the cortex processes sensory information and how loss of acetylcholine, for example in Alzheimer’s Disease, disrupts sensory behaviours.

Usage: Focal cortical injection of mu p75-SAP or Rabbit IgG-SAP (1.7 mg/ml, 0.3 µl total volume, rate 0.075 µl/minute).

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

The medial septum as a potential target for treating brain disorders associated with oscillopathies

Takeuchi Y, Nagy AJ, Barcsai L, Li Q, Ohsawa M, Mizuseki K, Berényi A (2021) The medial septum as a potential target for treating brain disorders associated with oscillopathies. Front Neural Circuits 15:701080. doi: 10.3389/fncir.2021.701080

Summary: The medial septum (MS) may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders.

Usage: 192-IgG-SAP. The MS cholinergic neurons along with theta oscillations are known to be essential for memory because selective lesion of the cholinergic neurons resulted in spatial memory impairments (150 ng; Easton et al., 2011) (5.04 μg icv; Jeong et al., 2014). Orexin-SAP. The enhanced gamma oscillations and altered PPI and auditory gating created by psychoactive drugs in rats were mediated by GABAergic neurons in the MS because they were abolished by ablation of these neurons by Orexin-SAP (140 ng total bilateral; Ma et al., 2012). mu p75-SAP. Anxious environment-induced type 2 theta oscillation and associated anxiety were shown to be dependent on the MS cholinergic neurons because lesion of MS cholinergic neurons reduced them (0.65 or 1.3 µg, bilateral; Nag et al., 2009).

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16), Orexin-B-SAP (Cat. #IT-20)

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Tart cherry (fruit of prunus cerasus) concentrated powder (tccp) ameliorates glucocorticoid-induced muscular atrophy in mice.

Ku SK, Lim JM, Cho HR, Bashir KMI, Kim YS, Choi JS (2021) Tart cherry (fruit of prunus cerasus) concentrated powder (tccp) ameliorates glucocorticoid-induced muscular atrophy in mice. Medicina (Kaunas) 57(5):485. doi: 10.3390/medicina57050485

Summary: Tart cherries have shown memory impairment lowering properties.

See: Matchynski JJ et al. Combinatorial Treatment of Tart Cherry Extract and Essential Fatty Acids Reduces Cognitive Impairments and Inflammation in the mu-p75 Saporin-Induced Mouse Model of Alzheimer’s Disease. J Med Food 16(4):288-295, 2013.

Related Products: mu p75-SAP (Cat. #IT-16)

Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions

Madrid LI, Jimenez-Martin J, Coulson EJ, Jhaveri DJ (2021) Cholinergic regulation of adult hippocampal neurogenesis and hippocampus-dependent functions. Int J Biochem Cell Biol 134:105969. doi: 10.1016/j.biocel.2021.105969

Summary: In this review, the authors appraise the evidence linking the contribution of cholinergic signalling to the regulation of adult hippocampal neurogenesis and hippocampus-dependent functions.

Usage: A hallmark feature of all basal forebrain cholinergic neurons is the expression of high levels of the p75 neurotrophin receptor which can be precisely targeted using 192-IgG-SAP. Administration of 192-IgG-SAP (icv, 2.5 µg, Mohapel et al., 2005) resulted in significant impairment in adult hippocampal neurogenesis in rats. In contrast, a study which lesioned MS cholinergic neurons in mice reported no effect on baseline proliferation in the hippocampus. Mice received 3.6 µg of mu p75-SAP into each lateral ventricle (Ho et al., 2009). Although the number of surviving neurons was similar in both lesioned and control animals, most of the progenitor cells in the lesioned animals could not survive without cholinergic input.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

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The effect of nerve growth factor on supporting spatial memory depends upon hippocampal cholinergic innervation

Eu WZ, Chen YJ, Chen WT, Wu KY, Tsai CY, Cheng SJ, Carter RN, Huang GJ (2021) The effect of nerve growth factor on supporting spatial memory depends upon hippocampal cholinergic innervation. Transl Psychiatry 11(1):162. doi: 10.1038/s41398-021-01280-3

Objective: To determine whether the supportive effect of NGF on learning and memory is specifically dependent upon intact hippocampal cholinergic innervation.

Summary: The results demonstrate that the hippocampal cholinergic system is required for maintaining spatial memory function, without having an impact on anxiety.

Usage: Twelve-week-old male C57BL/6Narl mice were used for hippocampal cholinergic denervation. Mice received bilateral injections into the hippocampus; 0.2 μg of mu p75-SAP was administered per site.

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Minocycline in neurodegenerative and psychiatric diseases: An update.

Romero-Miguel D, Lamanna-Rama N, Casquero-Veiga M, Gómez-Rangel V, Desco M, Soto-Montenegro ML (2021) Minocycline in neurodegenerative and psychiatric diseases: An update. Eur J Neurol 28(3):1056-1081. doi: 10.1111/ene.14642

Summary: Review includes the mouse animal model of neurodegenerative disease using mu p75-SAP. Biological Effects: Attenuation of cholinergic neurons loss, glial activation and transcription of pro-inflammatory mediators.

Usage: 45 mg/Kg, i.p.

See: Hunter CL et al. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305-3316, 2004.

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Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice

Nizari S, Wells JA, Carare RO, Romero IA, Hawkes CA (2021) Loss of cholinergic innervation differentially affects eNOS-mediated blood flow, drainage of Aβ and cerebral amyloid angiopathy in the cortex and hippocampus of adult mice. Acta Neuropathol Commun 9(1):12. doi: 10.1186/s40478-020-01108-z

Summary: In this report, icv administration of mu p75-SAP resulted in significant death of cholinergic neurons and fibres in the medial septum, cortex and hippocampus of C57BL/6 mice. This study supports the importance of the interrelationship between cholinergic innervation and vascular function in the etiology and/or progression of cerebral amyloid angiopathy (CAA) and suggests that combined endothelial nitric oxide synthase (eNOS)/cholinergic therapies may improve the efficiency of Aβ removal from the brain and reduce its deposition as CAA.

Usage: mu p75-SAP (0.596 μg/μl) was injected into the left and right lateral ventricles.

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Identification of multiple targets in the fight against Alzheimer’s disease

Giannoni P, Fossati S, Claeysen S, Marcello E, eds (2020) Identification of multiple targets in the fight against Alzheimer’s disease. Front Aging Neurosci 12:169. doi: 10.3389/fnagi.2020.00169

Summary: A collection of 20 articles that depict a broad representation of the most impactful advances in Alzheimer’s disease (AD) comprehension and therapeutic openings.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

In vivo monitoring of cholinergic neurotransmission with a microelectrochemical choline biosensor

Cunningham C, Lowry JP (2019) In vivo monitoring of cholinergic neurotransmission with a microelectrochemical choline biosensor. Neuroscience 2019 Abstracts 614.03. Society for Neuroscience, Chicago, IL.

Summary: Acetylcholine acts as a key neuromodulator within the central nervous system, capable of altering neuronal excitability and coordinating neuronal firing patterns. Conversely, cholinergic neurotransmission plays a crucial role in a variety of cognitive functions, including the encoding of new memories. Cholinergic neuronal loss, and the resulting drop in cholinergic neurotransmission (collectively referred to as hypocholinergia), is closely associated with cognitive dysfunction in a number of chronic neurodegenerative disorders including Alzheimer's disease. However, conventional analytical techniques for monitoring in vivo cholinergic neurotransmission lack the spatiotemporal resolution required to accurately detect endogenous cholinergic dynamics. Here we validate in mice a Pt-based electrochemical biosensor for selective monitoring of choline, a verified marker of cholinergic transmission. Enzymatic choline biosensors (modified with choline oxidase) were sterotaxically implanted in the medial prefrontal cortex (mPFC) and contralateral dorsal hippocampus (dHPC) of female C57Bl6J mice. Real-time choline current recordings over a period of several days revealed circadian fluctuations in both regions, with extracellular choline levels highest during light phases. Administration of pharmacological compounds known to induce central acetylcholine release, scopolamine (1mg/kg) and amphetamine (4mg/kg), evoked a robust increase in choline current. In contrast, peripheral injection of the reversible acetylcholinesterase inhibitor, donepezil (3mg/kg), produced a marked decrease in recorded choline current. The induction of systemic infammation with bacterial lipopolysaccharide (LPS; 500µg/kg) produced characteristic ‘sickness behaviour’ in mice and evoked a tonic rise in central choline levels in both the mPFC and dHPC. Furthermore, the induction of hypocholinergia in selected mice was preformed via intracerebroventricular injections of murine-p75-saporin immunotoxin (1.2µg). Evoked cholinergic neurotransmission was dramatically attenuated in lesioned (hypocholinergic) mice. Collectively, the data suggests that microelectrochemical choline biosensors may serve as a powerful tool for monitoring cholinergic neurotransmission across a number of behavioural and disease states.

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Role of nociceptive afferent input on forelimb reaching and grasping behaviors in the spinal cord injured rat

Walker JR, Ong A, Detloff MR (2019) Role of nociceptive afferent input on forelimb reaching and grasping behaviors in the spinal cord injured rat. Neuroscience 2019 Abstracts 572.09. Society for Neuroscience, Chicago, IL.

Summary: Individuals with spinal cord injury (SCI) suffer a loss of motor and sensory function. The current standard of care to recover fine motor control is rehabilitation focused on a combination of range of motion, aerobic, and strength training (ST). However, limited research has been conducted to determine the role of nociceptive afferent inputs from muscle on spinal plasticity and/or recovery of function. Using a rodent model of SCI strength training rehabilitation, we determined that motor training not only improves forelimb strength and fine motor function but also can modulate the development of neuropathic pain, suggesting that improvements in reaching and grasping may be due, in part, to plasticity of nociceptive afferents. To further explore this, Sprague-Dawley rats received injections of rIB4-conjugated saporin, mu p75-conjugated saporin or unconjugated (vehicle) into the cervical dorsal root ganglia unilaterally to eliminate non-peptidergic and peptidergic nociceptors. There is an uninjured cohort and a group with unilateral C5 SCI. Von Frey and Hargreaves’ tests were performed at baseline and several time points post-injection to assess the effcacy of the nociceptive elimination. Several measures of forelimb strength were recorded over time including the isometric pull task, a single pellet retrieval task and the Montoya staircase test. To confirm the depletion of peptidergic and non-peptidergic nociceptors following saporin injection and/or SCI, cervical DRGs and spinal cords were stained with antibodies against CGRP and isolectin-B4. An understanding of the role of nociceptors in spinal plasticity and functional motor and sensory recovery of SCI patients will guide future research and refine rehabilitation strategies to further improve their quality of life.

Related Products: IB4-SAP (Cat. #IT-10), mu p75-SAP (Cat. #IT-16)

3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain.

Nizari S, Carare RO, Romero IA, Hawkes CA (2019) 3D reconstruction of the neurovascular unit reveals differential loss of cholinergic innervation in the cortex and hippocampus of the adult mouse brain. Front Aging Neurosci 11:172. doi: 10.3389/fnagi.2019.00172

Objective: To further characterize the effect of the loss of cholinergic innervation on the NVU (neurovascular unit) in Alzheimer's Disease.

Summary: Significantly less ChAT staining was detected in the medial septum of saporin-treated mice at 45 days post-surgery. This was accompanied by a significant decrease in cholinergic nerve fiber density in the hippocampus and the cortex. As expected, p75 NTR-negative neurons in the striatum were not affected by mu p75-SAP treatment.

Usage: In this study, the mu-p75-SAP was used to induce death of basal forebrain cholinergic neurons and their fiber projections. mu p75-SAP 0.5 µL (0.596 µg/µL) or 0.9% saline (n = 19) was injected into each ventricle.

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Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction.

Xu H, Chen L, Zhang X, Jiang X, Tian W, Yu W, Wang X, Tian J, Su D (2019) Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction. Lab Invest 99(7):1078-1088. doi: 10.1038/s41374-018-0174-9

Usage: 1 microliter of mu-p75-SAP at a concentration of 0.8 μg/μl was injected into the lateral ventricles.

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Removal of p75 neurotrophin receptor expression from cholinergic basal forebrain neurons reduces amyloid-β plaque deposition and cognitive impairment in aged APP/PS1 mice.

Qian L, Milne MR, Shepheard S, Rogers ML, Medeiros R, Coulson EJ (2019) Removal of p75 neurotrophin receptor expression from cholinergic basal forebrain neurons reduces amyloid-β plaque deposition and cognitive impairment in aged APP/PS1 mice. Mol Neurobiol 56(7):4639-4652. doi: 10.1007/s12035-018-1404-2

Objective: To investigate the contribution of CBF neuronal p75NTR to the progression of Alzheimer's Disease

Summary: Data indicate that a direct interaction between CBF-expressed p75NTR and Aβ does not contribute significantly to the regulation of Aβ load.

Usage: To lesion CBF neurons, a single infusion of mu p75-SAP or control Rabbit IgG-SAP (0.4 mg/ml) was stereotaxically-injected into the basal forebrain.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Cholinergic modulation targeting medial prefrontal cortex leads to behavior deficit in interval timing task

Zhang Q, De Corte B, Jung D, Kim Y, Geerling J, Narayanan N (2018) Cholinergic modulation targeting medial prefrontal cortex leads to behavior deficit in interval timing task. Neurology 90 (15 Supplement):P5.195.

Objective: To determine the effect of cholinergic lesion targeting medial prefrontal cortex on interval timing behavior.

Summary: Mice receiving medial prefrontal mu-p75-saporin injection performed poorly compared to control mice in interval timing task. Cholinergic lesion targeting medial prefrontal cortex caused interval timing behavior deficit in wild type mice.

Usage: mu-p75-SAP, a toxin targeting cholinergic neurons, into the bilateral medial prefrontal cortical regions of wild type mice pre-trained in interval timing task. Control mice (also pre-trained in interval timing task, n=8) received stereotactic injection of Rabbit IgG-SAP.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Real‐time electrochemical monitoring of choline during systemic inflammation in the freely‐ moving mouse

Doyle S, Baker KL, Cunningham C, Lowry JP (2018) Real‐time electrochemical monitoring of choline during systemic inflammation in the freely‐ moving mouse. Monitoring Molecules in Neuroscience . 17th International Conference, Oxford, UK

Summary: The loss of cholinergic innervation (mu p75‐SAP lesion in the basal forebrain) abolished the scopolamine‐induced choline increase in the hippocampus.

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Acute down-regulation of BDNF signaling does not replicate exacerbated amyloid-β levels and cognitive impairment induced by cholinergic basal forebrain lesion

Turnbull MT, Boskovic Z, Coulson EJ (2018) Acute down-regulation of BDNF signaling does not replicate exacerbated amyloid-β levels and cognitive impairment induced by cholinergic basal forebrain lesion. Front Mol Neurosci 11:51. doi: 10.3389/fnmol.2018.00051

Objective: To determine if degeneration of BFCNs causes a decrease in neurotrophin levels in innervated brain areas, which in turn promotes the development of Amyloid beta  pathology and cognitive impairment.

Summary: Lesion of septo-hippocampal BFCNs in a pre-symptomatic transgenic amyloid AD mouse model (APP/PS1 mice) increases soluble Ab levels in the hippocampus, and induces cognitive deficits in a spatial memory task that are not seen in either unlesioned APP/PS1 or non-transgenic littermate control mice. Cognitive decline and Amyloid-beta pathology induced by cholinergic basal forebrain neuron loss occur independent of dysfunctional neuronal BDNF signaling, and may therefore be directly underpinned by reduced cholinergic neurotransmission.

Usage: To lesion BFCNs, a single infusion of murine p75-SAP or control rabbit IgG-SAP (0.4 mg/ml) was stereotaxically injected into the basal forebrain.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting tau hyperphosphorylation in genetically susceptible mice.

Turnbull M, Coulson E (2017) Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting tau hyperphosphorylation in genetically susceptible mice. J Alzheimers Dis 55:1141-1154.. doi: 10.3233/JAD-160805

Summary: Alzheimer’s disease(AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and area major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in AD are unknown. The authors investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Two-month-old male and female pR5 mice were infused with murine p75-SAP (Cat. #IT-16) at a concentration of 0.4 mg/ml or 0.4 mg/ml of control Rabbit IgG-SAP (Cat. #IT-35) using a 30G needle attached to a 5 ml Hamilton syringe and pump. The needle was lowered into the medial septum according to coordinates in a mouse brain atlas, and the toxin was infused at a rate of 0.4 ul/min (1.5 u total volume). The results reveal that the loss of BFCNs in pre-symptomatic pR5 tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals’ performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Effects of brain-derived neurotrophic factor-pretreated neuron stem cell transplantation on Alzheimer’s disease model mice

Li T, Yu Y, Cai H (2015) Effects of brain-derived neurotrophic factor-pretreated neuron stem cell transplantation on Alzheimer's disease model mice. Int J Clin Exp Med 8:21947-21955.

Summary: In order to generate the AD mouse model, mu p75-SAP (1-1.2 μg/μL)  was injected to the bilateral icv areas.

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Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations.

Kim T, Thankachan S, McKenna J, McNally J, Yang C, Choi J, Chen L, Kocsis B, Deisseroth K, Strecker R, Basheer R, Brown R, McCarley R (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112:3535-3540. doi: 10.1073/pnas.1413625112

Summary: Measurements of cortical EEG capture gamma band oscillations (GBO). Abnormalities in these GBO have been found in some neuropsychiatric disorders such as Alzheimer's disease and schizophrenia. The authors analyzed GBO neuronal groups by administering 650-ng bilateral icv injections of mu p75-SAP (Cat. #IT-16) to mice to determine the role of basal forebrain cholinergic neurons in the generation of GBO. The results indicate GABAergic basal forebrain neurons containing parvalbumin were important for GBO integrity, but cholinergic neurons in the basal forebrain were not involved.

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Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections.

Nguyen H, Huppé-Gourgues F, Vaucher E (2015) Activation of the mouse primary visual cortex by medial prefrontal subregion stimulation is not mediated by cholinergic basalo-cortical projections. Front Syst Neurosci 9:1. doi: 10.3389/fnsys.2015.00001

Summary: Mice received 1 μg icv injections of mu p75-SAP (Cat. #IT-16) to eliminate NGFr-positive cells. The results indicate a link between the prelimbic and infralimbic cortices and the primary visual cortex.

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The effects of targeted intracerebral saporin injection on recovery from stroke

Becker A, Goldberg M (2014) The effects of targeted intracerebral saporin injection on recovery from stroke. Neuroscience 2014 Abstracts 800.09. Society for Neuroscience, Washington, DC.

Summary: It is well known that the diffuse neuromodulatory systems of the brain play a role in cortical plasticity that may extend to cortical reorganization after brain injury. The basal forebrain cholinergic system in particular is necessary for both cortical plasticity and behavioral recovery from cortical electrolytic lesions. The role of the cholinergic system in recovery from stroke has never been directly investigated. In this experiment, we asked the question: is the basal forebrain cholinergic system in the mouse necessary for behavioral recovery from stroke? To answer this question, we administered intracerebral injections of the selective immunotoxin mu p75-saporin bilaterally to the cholinergic nucleus basalis in young adult mice. Using choline acetyltransferase immunohisochemistry, cresyl violet staining, and fluoro-jade B staining we discovered a dose at which these injections eliminate local cholinergic neurons while leaving other cell types and cholinergic cells outside the nucleus basalis unharmed. We report the effects of these injections on behavioral recovery from a subsequently induced photothrombotic cortical ischemic stroke.

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Immunolesion-induced loss of cholinergic projection neurones promotes beta-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice.

Hartig W, Saul A, Kacza J, Grosche J, Goldhammer S, Michalski D, Wirths O (2014) Immunolesion-induced loss of cholinergic projection neurones promotes beta-amyloidosis and tau hyperphosphorylation in the hippocampus of triple-transgenic mice. Neuropathol Appl Neurobiol 40(2):106-120. doi: 10.1111/nan.12050

Summary: 3xTg transgenic mice were treated with 2 μg of mu p75-SAP (Cat. #IT-16) into the right lateral ventricle to eliminate cholinergic neurons in the basal forebrain. These mice already have age-dependent β-amyloidosis and tau hyperphosphorylation. This new model supplies a potential framework in which to study the entire pathology of Alzheimer's disease.

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Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration.

Laursen B, Mork A, Plath N, Kristiansen U, Frank Bastlund J (2014) Impaired hippocampal acetylcholine release parallels spatial memory deficits in Tg2576 mice subjected to basal forebrain cholinergic degeneration. Brain Res 1543:253-262. doi: 10.1016/j.brainres.2013.10.055

Summary: The Tg2576 mouse strain provides a limited model for Alzheimer's disease because they do not display degeneration of cholinergic neurons in the basal forebrain – the other main hallmark of Alzheimer's disease in humans. Using 0.9 μg icv injections of mu p75-SAP (Cat. #IT-16) the authors evaluated mice that had both Aβ deposition and cholinergic depletion. The data show that these mice display cognitive decline and compromised cholinergic levels, creating a viable model for Alzheimer's disease.

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Effect of medial prefrontal subregions electrical stimulation on the neuronal activity of the primary visual cortex and basal forebrain.

Nguyen HN, Huppé-Gourgues F, Vaucher E (2013) Effect of medial prefrontal subregions electrical stimulation on the neuronal activity of the primary visual cortex and basal forebrain. Neuroscience 2013 Abstracts 639.04. Society for Neuroscience, San Diego, CA.

Summary: The cholinergic system and the medial prefrontal cortex (mPFC) play an important role in visual attention through the modulation of neuronal responses in the primary visual cortex (V1). The mPFC doesn’t project directly to V1, but does project to the horizontal limb of the diagonal band of Broca (HDB), which contains cholinergic neurons and projections to V1. Here, we investigated a possible involvement of the mPFC subregions in the activation of basal forebrain cholinergic neurons to enhance cholinergic transmission in V1. The different subregions of the mPFC, the anterior cingulate (Cg1), the prelimbic (PrL) and the infralimbic (IL) cortices, have anatomical and functional differences. Therefore the objective of this study was to determine if electrical stimulation of the different regions of the PFC activated V1 neurons in mice and if this activation was mediated through the HDB cholinergic pathway. The neuronal activity was evaluated by early gene c-Fos immunoreactivity in V1 and HDB after unilateral electrical stimulation of mPFC subregions (trains of 100 Hz for 0.3s every 2s, 50 μA, 30 mins) provided through a tungsten electrode in urethane anesthetized mice (n=4 mice per subregion). After the mPFC stimulation, mice were kept in darkness for 1h and brains were harvested after 4% paraformaldehyde intracardiac perfusion. The c-Fos expression was quantified on 35 µm coronal brain sections in V1 and HDB: an equivalent threshold was applied to all microphotographs and a c-Fos automated particle analysis tools was used (ImageJ). Moreover, the effect of the selective lesion of cholinergic fibers by the immunotoxin mu p75-saporin (1 μg/μl injections) was evaluated. The results show that electrical stimulation of PrL (Mann-Whitney U, p=0.021) and IL (p=0.021) cortices significantly induced a higher expression of c-Fos neurons in V1 of the stimulated hemisphere, but not in the HDB. Electrical stimulation of Cg1 did not elicit V1 nor HDB c-Fos immunoreactivity (p=0.248). Furthermore, selective lesions of basal forebrain cholinergic neurons did not eliminate the IL-induced c-Fos expression in the ipsilateral V1. Therefore, the mPFC stimulation seems to activate V1 neurons without the contribution of the HDB cholinergic neurons. This suggests there is a functional link between the mPFC and V1 independent from HDB cholinergic projections.

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Featured Article: Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits in an NGFr-lesioned mouse model

Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, Zhou GM, Ayala M, Zhang S (2013) Featured Article: Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits in an NGFr-lesioned mouse model. Targeting Trends 14(3)

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Read the featured article in Targeting Trends.

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Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits.

Liu Y, Weick JP, Liu H, Krencik R, Zhang X, Ma L, Zhou GM, Ayala M, Zhang SC (2013) Medial ganglionic eminence-like cells derived from human embryonic stem cells correct learning and memory deficits. Nat Biotechnol 31(5):440-447. doi: 10.1038/nbt.2565

Summary: Progenitor cells were transplanted into mice that had received 1.5 μg of mu p75-SAP (Cat. #IT-16) into the medial septum.

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Read the featured article in Targeting Trends.

Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in app/ps1 mice.

Ramos-Rodriguez JJ, Pacheco-Herrero M, Thyssen D, Murillo-Carretero MI, Berrocoso E, Spires-Jones TL, Bacskai BJ, Garcia-Alloza M (2013) Rapid beta-amyloid deposition and cognitive impairment after cholinergic denervation in app/ps1 mice. J Neuropathol Exp Neurol 72(4):272-285. doi: 10.1097/NEN.0b013e318288a8dd

Summary: The authors investigated whether specific cholinergic neurodegeneration is responsible for the deposition of plaques. APPswe/PS1dE9 transgenic mice received bilateral icv injections of 1-1.2 μg of mu p75-SAP (Cat. #IT-16) into the basal forebrain. Although the transgenic mice show plaque deposition, they do not exhibit other signs of Alzheimer's disease. Lesioned transgenic animals, however, displayed increased β-amyloid plaque deposition, increased Tau phosphorylation, and early memory impairment that worsened with age.

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Combinatorial treatment of tart cherry extract and essential fatty acids reduces cognitive impairments and inflammation in the mu-p75 saporin-induced mouse model of Alzheimer’s disease.

Matchynski JJ, Lowrance SA, Pappas C, Rossignol J, Puckett N, Sandstrom M, Dunbar GL (2013) Combinatorial treatment of tart cherry extract and essential fatty acids reduces cognitive impairments and inflammation in the mu-p75 saporin-induced mouse model of Alzheimer’s disease. J Med Food 16(4):288-295. doi: 10.1089/jmf.2012.0131

Summary: The authors investigated the efficacy of a combinatorial therapy, Cerise Total-Body Rhythm (TBR) by treating mice with TBR prior to and following icv administration of 0.8 μg of mu p75-SAP (Cat. #IT-16).

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Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice.

Laursen B, Mork A, Plath N, Kristiansen U, Bastlund JF (2013) Cholinergic degeneration is associated with increased plaque deposition and cognitive impairment in APPswe/PS1dE9 mice. Behav Brain Res 240:146-152. doi: 10.1016/j.bbr.2012.11.012

Summary: Extracellular plaques containing amyloid β-peptides (Aβ) and cholinergic dysfunction are two of the main hallmarks of Alzheimer's disease. Using a transgenic mouse line that displays an age-related increase in plaque deposition, the authors examined the relationship between cholinergic degeneration and Aβ overexpresssion. Mice received 0.9-μg bilateral icv injections of mu p75-SAP (Cat. #IT-16). Working memory was significantly impaired in lesioned mice with plaques, and the plaque burden was increased as compared to wild-type mice that also received a lesion.

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Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits.

Brayda-Bruno L, Mons N, Yee BK, Micheau J, Abrous DN, Nogues X, Marighetto A (2013) Partial loss in septo-hippocampal cholinergic neurons alters memory-dependent measures of brain connectivity without overt memory deficits. Neurobiol Dis 54:372-381. doi: 10.1016/j.nbd.2013.01.010

Summary: The authors examined whether partial degeneration of septo-hippocampal neurons alters brain activity patterns even without overt memory loss. Mice received 45 ng of mu p75-SAP (Cat. #IT-16) into the medial septal area. Lesioned animals had significantly altered functional activities in the brain, despite lack of an overt behavioral deficit. Some changes observed are also altered with the initial signs of Alzheimer's disease.

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Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation.

Hamlin AS, Windels F, Boskovic Z, Sah P, Coulson EJ (2013) Lesions of the basal forebrain cholinergic system in mice disrupt idiothetic navigation. PLoS One 8(1):e53472. doi: 10.1371/journal.pone.0053472

Summary: Alzheimer's disease patients perform poorly on spatial navigation tests requiring either distal cues (allothetic) or body-centered cues (idiothetic). The authors used 0.2 μg bilateral infusions of mu p75-SAP (Cat. #IT-16) into the lateral ventricles of mice to examine the hypothesis that the cholinergic medial septo-hippocampal circuit is important for idiothetic navigation. Rabbit IgG-SAP (Cat. #IT-35) was used as a control. Lesioned animals were similar to controls in contextual fear conditioning, spatial working memory, as well as several other parameters. But exploratory behavior requiring idiothetic signals was very disorganized, indicating that cholinergic cells are vital to idiothetic navigation.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Diffusion-weighted magnetic resonance imaging detection of basal forebrain cholinergic degeneration in a mouse model.

Kerbler GM, Hamlin AS, Pannek K, Kurniawan ND, Keller MD, Rose SE, Coulson EJ (2013) Diffusion-weighted magnetic resonance imaging detection of basal forebrain cholinergic degeneration in a mouse model. Neuroimage 66C:133-141. doi: 10.1016/j.neuroimage.2012.10.075

Summary: The authors examined the effectiveness of diffusion MRI using diffusion tensor imaging (DTI) and probabilistic tractography in detecting cholinergic loss in a mouse model. Mice received bilateral 0.2-μg icv injections of mu p75-SAP (Cat. #IT-16). Rabbit IgG-SAP (Cat. #IT-35) was used as control. The animals were then examined using DTI. The data indicate that DTI is a valid technique for assessment of cholinergic loss in septo-hippocampal tracts as a result of Alzheimer's disease.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Limited effect of serotonergic denervation on beta-amyloid and cognitive impairment in APPswe/PS1dE9 mice.

Ortiz-Barajas O, Ramos-Rodriguez J, Berrocoso E, Garcia Alloza M (2012) Limited effect of serotonergic denervation on beta-amyloid and cognitive impairment in APPswe/PS1dE9 mice. Neuroscience 2012 Abstracts 751.12. Society for Neuroscience, New Orleans, LA.

Summary: Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by progressive cognitive and memory impairment. Amyloid-beta (Aβ) deposition, as senile plaques (SP), seems to play a key role in the development and progression of the illness. Moreover SP tend to accumulate in cortex and hippocampus, relevant areas in learning and memory. On the other hand neuronal loss is the pathological feature that best correlates with duration and severity of the illness and at present animal available animal models hardly reproduce the complexity of the disease. We have previously seen that selective cortical and hipocampal cholinergic denervation, using murine p-75 saporin, may worsen cognitive abilities in APPswe/PS1dE9 mice as well as increase SP deposition in denervated areas. In the present work we lesioned 7 months old APPswe/PS1dE9 mice with 1 µl of 5,7-dyhidroxytiptamine (0.16 µg/µl) injected in the raphe nucleus (RN). In order to guarantee selective removal of cortical and hipocampal serotonergic inervation, and protect noardernergic and dopaminergic neurons, animals were i.p. injected with desipramine and nomifensine before surgery. We observed a clear reduction of tryptophan hydroxilase staining in the RN. In the Morris water maze test we observed learning and memory impairment in APPswe/Ps1dE9 mice, without a synergistic effect of the serotonergic lesion. When we assessed SP deposition we did not observe a significant increase of SP in cortex or hipocampus 14 days after the lesion, as we observed after selective cholinergic denervation. Altogether our data suggest that cognitive impairment and induced SP depositioin observed after cholinergic denervation is not achieved when serotonergic system is affected, supporting a selective effect mediated by different neurotransmitter systems. Acknowledgements: MG-A: RYC-2008-02333, ISCIII-Subdirección General de Evaluación y Fomento de la Investigación (PS09/00969), Fundación Dr. Eugenio Rodriguez Pascual, Junta Andalucia Excelencia (CTS-7847).

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Paying attention with a compromised cholinergic system: Attenuated activation of cholinergic neurotransmission in attentional task-performing CHT+/- mice.

Mallory CS, Paolone G, Koshy Cherian A, Blakely RD, Sarter M (2012) Paying attention with a compromised cholinergic system: Attenuated activation of cholinergic neurotransmission in attentional task-performing CHT+/- mice. Neuroscience 2012 Abstracts 536.08. Society for Neuroscience, New Orleans, LA.

Summary: Prefrontal cholinergic neurotransmission is necessary for sustained attentional performance. In rats, prefrontal acetylcholine (ACh) release reaches 140% over baseline during the performance of a sustained attention task (SAT; St. Peters et al., 2011a). SAT performance also increases the density of choline transporters (CHT) in synaptic plasma membranes (Apparsundaram et al., 2005), which we hypothesize is needed to sustain elevations of cholinergic activity and behavioral responses. Here we employed the SAT recently adapted for use in mice (St. Peters et al., 2011b) and developed new techniques that permit monitoring of ACh release via microdialysis of mice performing the SAT in order to determine the impact of genetically manipulated levels of choline transporter capacity. First, reverse dialysis of atropine (50 µM) increased ACh release levels in naive WT mice. In contrast, CHT+/- mice could not sustain these increases, consistent with changes observed in levels of muscarinic receptors in the CHT +/- mice (Bazalakova et al., 2007). However, SAT performance did not differ significantly between WT controls and CHT+/- mice. Furthermore, basal (absolute) levels of ACh release were comparable between strains. However, performance-associated increases in ACh release were strikingly attenuated in CHT+/- mice, reaching 40% over basal levels versus 130% in WT. Performance-associated increases in ACh release in CHT+/- mice were TTX-sensitive, similar to release monitored in WT mice (1 µM via reversed dialysis). To determine whether cholinergic activity was necessary for SAT performance in CHT+/- mice we then removed basal forebrain cholinergic neurons by infusing murine-p75NTR-saporin obtaining similar impairment on SAT performance in both strains. Finally, and because cholinergic activity modulates cortical circuitry primarily via nAChR, mecamylamine (MEC; 50 µM) was reverse dialyzed during SAT performance. WT mice were only moderately impaired in the SAT task, whereas the performance of CHT+/- mice rapidly declined and the performance-associated ACh levels rapidly returned to the pre-task levels. In summary CHT+/- mice are able to perform the basic SAT, despite attenuated levels of cholinergic neurotransmission, likely as a result of compensatory postsynaptic mechanisms. However, their attentional performance and underlying cholinergic signaling exhibit heightened sensitivity to behavioral and pharmacological challenges. Together, these findings suggest that CHT+/- mice are an important model for the impaired cognitive control of attentional performance that is a common symptom of ADHD, schizophrenia and other cognitive disorders.

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Emerging roles of pathogens in alzheimer’s and moderate magnetic field therapy: dc emf 0.5 tesla

Nichols TW (2012) Emerging roles of pathogens in alzheimer’s and moderate magnetic field therapy: dc emf 0.5 tesla. Neuroscience 2012 Abstracts 438.10. Society for Neuroscience, New Orleans, LA.

Summary: Chronic spirochetal infection can cause slowly progressive dementia, cortical atrophy and amyloid deposition in the atrophic form of general paresis. There is a significant association between Alzheimer disease (AD) and various types of spirochete (including the periodontal pathogen Treponemas and Borrelia burgdorferi), and other pathogens such as Chlamydophyla pneumoniae and herpes simplex virus type-1 (HSV-1). (Miklossy 2011 Exp Rev Mol Med) Miklossy’s lab exposed mammalian glia & neuronal cells in vitro to Borrelia burgdorferi spirochetes and bacterial lipopolysaccharides (LPS). Morphological changes analogous to amyloid deposits were observed at 2-8 wks exposure. Increased levels of ß-amyloid precursor protein and hyperphosphorylated tau were detected by WB.The frequency of spirochetes is significantly higher in the brains of Alzheimer patients compared to controls.The statistical analysis is based on the cumulative data of the literature. (P=1.5x10-17,OR=20, 95%CI=8-60! Seven out of ten brains from the Harvard McLean Brain bank were positive for Borrelia DNA. Alan Mac Donald MD. “Borrelia Infection is the root cause of at least 70% of Alzheimer's disease, based on the detection of positive In situ DNA hybridization results in the cytoplasic GVB sites of hippocampal neurons ( with no positive signals detected in the nucleus) for flagellin B DNA sequences of Borrelia burgdorferi.” Antibiotics in Alzheimer’s disease: A randomized controlled trial of doxycycline and rifampin for patients with Alzheimer’s disease 2004. Cognitive decline was statically improved in treatment over placebo. Minocycline protects basal forebrain cholinergic neurons from mu p 75-saporin immunotoxic lesioning 2004 in animal model. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models 2007. Minocycline does not affect amyloid ß phagocytosis by human microglia cells. (Minocycline attenuates the release of TNF-α by human microglia upon exposure to Abeta, SAP and C1q) 2007. Moderate Magnetic Field Therapy (0.5 Tesla) in 15 Alzheimer’s patients. Results; Cognition Improved: group average hours = 184.Mechanism hypothesis: Overview of crosstalk between SMF & IL-6.Wang, Z, Sarje A, Che PL, Yarema K. Moderate strength (0.23-0.28T) static magnetic fields (SMF) modulate signaling and differentiation in human embryonic cells. BMC Genomic 2009;10:356

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Combined loss of entorhinal and basal forebrain cholinergic hippocampal inputs deeply impairs spatial navigation memory in C57BL/6J and hAPPxapoE mice.

Mathis C, Moreau P-H, Zerbinatti C, Goutagny R, Cosquer B, Geiger K, Kelche C, Cassel J-C (2012) Combined loss of entorhinal and basal forebrain cholinergic hippocampal inputs deeply impairs spatial navigation memory in C57BL/6J and hAPPxapoE mice. Neuroscience 2012 Abstracts 203.28. Society for Neuroscience, New Orleans, LA.

Summary: The hippocampus plays a key role in spatial learning and memory. Major inputs provided by the cholinergic basal forebrain (CBF) and the entorhinal cortex (EC) neurons are expected to modulate hippocampal functions. Surprisingly, the selective lesion of one or the other produces only moderate performance degradation in spatial navigation tasks, suggesting possible compensation provided by other hippocampal inputs. We therefore assessed the effects of single versus combined lesions of the EC (NMDA excitotoxin) and the CBF (mu-p75 saporin immunotoxin) on several forms of memory in C57BL/6 mice. Single lesions had moderate or no effects, while the combined lesions completely abolished long-term spatial memory retention in the water-maze and the Barnes-maze navigation tasks. Object recognition memory was selectively and profoundly affected by the loss of cholinergic neurons, whereas object location memory was only marginally affected by the lesions. These results suggest that the integrity of both the CBF and the EC is critical to establish an enduring spatial navigation memory. The synergistic interaction between the two lesions is particularly relevant to Alzheimer’s disease (AD) since both structures undergo severe degeneration in parallel to dramatic impairments in spatial navigation tasks. The apolipoprotein E4 (apoE4) allele, a major genetic risk factor for AD, has been proposed as a cholinergic deficit predictor and has been associated with larger EC atrophy in AD patients. Thus, the effects of single and combined EC and CBF lesions were evaluated on Barnes maze navigation performance in hAPPxapoE mice knocked-in for the human apoE3 or apoE4 gene allele on a (normal) human APP YAC transgenic background. Long-term spatial memory performances of hAPPxapoE3 and hAPPxapoE4 mice were dramatically affected by the CBF lesion and the combined lesions, but not by the EC lesion. A similar pattern of deficit was observed on learning performances in apoE4 not in apoE3 mice; the latter were only affected by the combined lesions. In conclusion, the apoE4 genotype had no effect on the consequences of EC and combined lesions, but it worsened the outcome of CBF lesions compared to the apoE3 genotype. Since the mice of the two genotypes showed similar loss of cholinergic neurons, our data may reflect a deleterious impact of apoE4 on the activity of the few surviving neurons (about 20%). Alternatively, our findings would also be consistent with impaired compensatory mechanisms following cholinergic loss which could depend on other hippocampal inputs such as the entorhinal cortex. Further analyses are underway to clarify this issue.

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Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice.

Gil-Bea FJ, Gerenu G, Aisa B, Kirazov LP, Schliebs R, Ramirez MJ (2012) Cholinergic denervation exacerbates amyloid pathology and induces hippocampal atrophy in Tg2576 mice. Neurobiol Dis 48(3):439-446. doi: 10.1016/j.nbd.2012.06.020

Summary: The hallmarks of Alzheimer's disease (AD) include hippocampal cell loss, cholinergic dysfunction, amyloid plaques, and neurofibrillary tangles, among other things. This work sought to examine the interaction between cholinergic denervation, amyloid precursor protein (APP) processing, and hippocampal integrity. Tg2576 transgenic mice received 2 μg of mu p75-SAP (Cat. #IT-16) injected into the third ventricle. These mice overexpress a version of human APP. Lesioned animals displayed various aspects of AD such as hippocampal synaptic pathology and neurodegeneration, indicating that immunolesions in this mouse line produce a viable model for AD.

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Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: Reconciling inflammatory and cholinergic hypotheses of delirium.

Field RH, Gossen A, Cunningham C (2012) Prior pathology in the basal forebrain cholinergic system predisposes to inflammation-induced working memory deficits: Reconciling inflammatory and cholinergic hypotheses of delirium. J Neurosci 32(18):6288-6294. doi: 10.1523/JNEUROSCI.4673-11.2012

Summary: The authors lesioned the basal forebrain of mice with 0.08 μg or 0.4 μg icv injections of mu p75-SAP (Cat. #IT-16) to establish an early dementia-associated cholinergic loss model. The mice were then challenged with systemic inflammation using low-dose lipopolysaccharide (LPS). The mu p75-SAP lesion left hippocampal-dependent reference and working memory relatively intact. LPS-induced inflammation created acute working memory deficits; an aceytlcholinesterase inhibitor protected against this deficit.

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Read the featured article in Targeting Trends.

CXB-909 attenuates cognitive deficits in the mu-p-75 saporin mouse model of Alzheimer’s disease.

Lowrance S, Matchynski J, Rossignol J, Dekorver N, Sandstrom M, Dunbar G (2012) CXB-909 attenuates cognitive deficits in the mu-p-75 saporin mouse model of Alzheimer’s disease. Neuroscience & Medicine 3(1):65-68. doi: 10.4236/nm.2012.31010

Summary: CXB-909 is a small molecule NGF amplifier that has been shown to enhance neurite outgrowth in various neuronal cell lines. This type of molecule has potential therapeutic use in disorders such as Alzheimer's disease. In this work the authors lesioned cholinergic cells in the basal forebrain of mice with bilateral 0.8 μg intracerebroventricular injections of mup75-SAP (Cat. #IT-16). Lesioned animals performed significantly worse than controls in a water maze task. Lesioned animals subsequently treated with CXB-909 displayed improved performance, indicating that CXB-909 can attenuate memory deficits caused by loss of cholinergic input.

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Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex.

Tolner EA, Sheikh A, Yukin AY, Kaila K, Kanold PO (2012) Subplate neurons promote spindle bursts and thalamocortical patterning in the neonatal rat somatosensory cortex. J Neurosci 32(2):692-702. doi: 10.1523/JNEUROSCI.1538-11.2012

Summary: Immature cortices in both human and rat have spontaneous activity associated with the maturation of cortical synapses and neuronal circuits. In order to investigate what cells are controlling these events the authors administered 400 ng of 192-IgG-SAP (Cat. #IT-01) to the S1 cortex hindlimb/forelimb area of rats. mu p75-SAP (Cat. #IT-16) and mouse-IgG-SAP (Cat. #IT-18) were used as controls. This lesion eliminates subplate neurons which results in a significant loss of evoked spindle burst activity.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16), Mouse IgG-SAP (Cat. #IT-18)

Rapid beta-amyloid deposition and behavioural impairment after cholinergic denervation in APPswe/PS1dE9

Pacheco-Herrero M, Thyssen D, Ramos-Rodriguez J, Berrocoso E, Bacskai B, Garcia-Alloza M (2011) Rapid beta-amyloid deposition and behavioural impairment after cholinergic denervation in APPswe/PS1dE9. Neuroscience 2011 Abstracts 47.02. Society for Neuroscience, Washington, DC.

Summary: Alzheimer’s disease (AD) is the most common cause of dementia. Although the ultimate neurotoxic mechanisms are not known, extensive evidence supports the role of amyloid-beta (Aβ) deposition as senile plaques (SP) in the disease. On the other hand, neuronal loss is the pathological feature that best correlates with the duration and severity of the illness and specifically, cholinergic denervation of the basal forebrain seems to be a good predictor of clinical dementia in AD. A close relationship has been documented between Aβ deposition and neurodegeneration, however, whether specific neurodegeneration may lead to senile plaque deposition remains unclear. We addressed this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p-75 saporin, an inmunotoxin that selectively removes cholinergic innervation. We performed intracerebroventricular murine p-75 lesions in animals with an incipient (~3 months) and robust (~7 months of age) Aβ deposition and removed ~50% of basal forebrain cholinergic innervation to cortex and hippocampus. Immediately after injections, cranial windows were implanted and Aβ deposition was monitored in vivo and in real time in the cortex using methoxy-XO4 and multiphoton microscopy. We observed increased SP deposition as soon as 1 week after the lesion. We further corroborated our in vivo data post-mortem, using anti- Aβ and anti-fibrils antibodies as well as thioflavin S staining, both in the cortex and the hippocampus. 7 days after the surgery, when the lesion is established, animals were tested in the new object discrimination and Morris water maze tests. We observed an early memory impairment in young lesioned mice (~3 months) and this effect worsened with age (~7 months of age), when Aβ deposition is more robust. Altogether, our data suggest that cholinergic denervation may contribute to the deposition of Aβ and synergistically contribute to the cognitive impairment observed in AD.

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Acetylcholine and attention.

Klinkenberg I, Sambeth A, Blokland A (2011) Acetylcholine and attention. Behav Brain Res 221(2):430-442. doi: 10.1016/j.bbr.2010.11.033

Summary: This review article summarizes studies investigating the role of acetylcholine in attention and cognition. The roles of 192-IgG-SAP (Cat. #IT-01) and mu p75-SAP (Cat. #IT-16) in these experiments is discussed. Acetylcholine is thought to play a top-down role in the prefrontal, parietal, and somatosensory regions; playing an important role in the control of attentional orienting and stimulus discrimination.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

The effects of a combination of antioxidants and essential fatty acids as treatment for Alzheimer’s disease in the mu-p75 saporin-injected model

Matchynski JJ, Lowrance SA, Rossignol J, Dekorver NW, Puckett ND, Pappas CA, Trainor KJ, Delongchamp JL, Radwan J, Heldt JC, Dey ND, Dunbar GL (2010) The effects of a combination of antioxidants and essential fatty acids as treatment for Alzheimer’s disease in the mu-p75 saporin-injected model. Neuroscience 2010 Abstracts 856.15/I21. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is marked by a progressive loss of memory and affects over five million people nationwide (Alzheimer’s Association, 2010). It is characterized by an increase in oxidative stress, amyloid plaques, neurofibrillary tangles, and the loss of cholinergic neurons. Mice injected with the ribosome deactivating protein, mu-p75 saporin, model the deficits in memory, loss of cholinergic neurons, and increased oxidative stress observed in AD. The current study aimed to decrease the deficits observed in the saporin mouse model using a combination of antioxidants from tart cherries and essential fatty acids, Cerise© total body rhythm (TBR). Mice dosed with TBR or methylcellulose were given bilateral ventricular injections of phosphate buffer saline or saporin. Memory and motor functioning were then measured in a series of behavioural tests. Results indicate that TBR decreased the memory deficits observed in object recognition, place recognition, and Morris-water-maze tasks, as well as the inflammatory response and loss of cholinergic neurons in the medial septum. The findings suggest that TBR could provide an effective, adjunctive treatment that may delay the onset or decrease the severity of AD.

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Krx-0501 reduces cognitive deficits in a saporin mouse model of Alzheimer’s disease

Lowrance SA, Matchynski JJ, Rossignol J, Dekorver N, Fink K, Salibi P, Dunbar GL (2010) Krx-0501 reduces cognitive deficits in a saporin mouse model of Alzheimer’s disease. Neuroscience 2010 Abstracts 856.8/I14. Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a progressive neurodegenerative disease marked by memory loss and dysfunction of cholinergic neurons. Neurotrophic factors, like nerve growth factor (NGF), have shown to improve cognitive function in AD patients. The inability of NGF to cross the blood brain barrier (BBB) and painful side effects have caused serious concerns over its future use as a treatment. Substituted pyrimidines, such as KRX-0501 (KRX; Keryx Biopharmaceuticals, New York, NY) on the other hand, readily cross the BBB and exert beneficial neurotrophic-like effects in vivo. In this study KRX was administered daily to mice that were given intra-cerebroventricular injections of mu p-75 Saporin (SAP; Advanced Targeting Systems, San Diego, CA) or vehicle (phosphate buffered saline). KRX treatment began at seven weeks of age and continued for 32 days. Doses were set at 10, 15, and 20mg/kg respectively. Animals were tested for cognitive impairment using the Morris water maze (MWM) task, object recognition (OR) and place recognition (PR) tasks while motor deficits were tested using MWM swim speed, rotarod (RR) and the open field (OF) tasks. On day 33 of KRX treatment, mice were sacrificed by transcardial perfusion. In a second experiment, mice received SAP or vehicle surgery and were sacrificed for enzyme-linked immunosorbent assay (ELISA) analysis. MWM results revealed significantly lower escape latencies of control animals relative to SAP animals. In addition mice treated with the low and middle doses of KRX displayed decreased escape latency on the MWM. In the OR task, only mice in the highest treatment group performed significantly above chance levels. No between group differences were seen in the PR task, swim speed, latency to fall from the RR, and distance travelled in the OF. Immunohistochemistry (IHC) using the glial fibrillary acidic protein antibody indicated that astrocyte activation took place primarily around the surgical injection sites. IHC labeling against choline-acetyltransferase revealed a significant decrease in cholinergic neurons of the medial septum. Finally, ELISA protein analysis of midbrain sections revealed that the KRX treatments did not increase levels of endogenous NGF. These results show that SAP injections produced a reproducible destruction of cholinergic neurons, accompanied by memory deficits in the MWM, in the absence of motoric deficits. The KRX treatment attenuated memory deficits, despite unabated cholinergic cell loss in the medial septum, and did so without affecting levels of endogenous NGF.

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Functional cholinergic neurons from human embryonic stem cells

Liu Y, Krencik R, Liu H, Ma L, Zhang X, Zhang S-C (2010) Functional cholinergic neurons from human embryonic stem cells. Neuroscience 2010 Abstracts 331.5/B19. Society for Neuroscience, San Diego, CA.

Summary: Basal forebrain cholinergic neurons play a critical role in regulating memory and cognition. Degeneration or dysfunction of these neurons is associated with neurological conditions including Alzheimer’s disease and dementia. In this study, we aimed at generating cholinergic neurons from human embryonic stem cells (hESCs) for therapeutic development. hESCs were first differentiated to primitive neuroepithelial cells in a chemically defined medium. In the presence of sonic hedgehog, over 97% of the differentiated cells became Nkx2.1-expressing ventral forebrain progenitors. These ventral progenitors further differentiated to cholinergic neurons with basal forebrain characteristics by expressing ChAT, VAChAT, FoxG1, Nkx2.1, Islet1, ßIII-tubulin, MAP2, P75, Synapsin but not GABA, Glutamate, or Mash2. The hESC-generated cholinergic neurons were electrophysiologically active in vitro. Following transplantation into the hippocampus of mice, in which cholinergic neurons in the medial septum were destroyed by IgG-P75-saporin, the grafted human cells produced large cholinergic neurons. The animals transplanted with cholinergic neurons demonstrated an improvement in learning and memory deficit. These results indicate that the human stem cell-generated cholinergic neurons are functional, thus providing a new source for drug discovery and cell therapy for neurological disorders that affect cholinergic neurons.

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ATS Poster of the Year Winner

Efficacy of a murine-p75-saporin immunotoxin for selective lesions of basal forebrain cholinergic neurons in mice.

Nag N, Baxter MG, Berger-Sweeney JE (2009) Efficacy of a murine-p75-saporin immunotoxin for selective lesions of basal forebrain cholinergic neurons in mice. Neurosci Lett 452:247-251. doi: 10.1016/j.neulet.2009.01.006

Summary: The authors tested a new version of mu p75-SAP (Cat. #IT-16) in mice. Mice received bilateral injections of 0.65 or 1.3 µg of immunotoxin into each lateral ventricle. Both amounts produced a complete loss of cholinergic neurons in the medial septum, while a dose-dependent loss of cholinergic neurons was seen in the nucleus basalis magnocellularis.

Related Products: mu p75-SAP (Cat. #IT-16)

Amyloid-beta expression in retrosplenial cortex of triple transgenic mice: relationship to cholinergic axonal afferents from medial septum.

Robertson RT, Baratta J, Yu J, LaFerla FM (2009) Amyloid-beta expression in retrosplenial cortex of triple transgenic mice: relationship to cholinergic axonal afferents from medial septum. Neuroscience 164:1334-1346. doi: 10.1016/j.neuroscience.2009.09.024

Summary: In this work the authors developed a model to examine the relationship between afferent projections and the formation of amyloid-beta (Aβ) deposits. Mice received 1.86 µg unilateral injections of 192-IgG-SAP (Cat. #IT-01) into the lateral ventricle. Lesioned animals had persistent Aβ immunoreactivity in layer III of the granular division of retrosplenial cortex (RSg). This data indicates that septal cholinergic axonal projections transport Aβ or amyloid precursor protein to layer III of the RSg.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

Intracerebroventricular injections of mu-P-75 saporin can produce memory deficits without impairing motor deficits in a mouse model of Alzheimer’s disease.

Matchynski JJ, Lowrance S, Rossignol J, Puckett N, Derkorver N, Radwan J, Trainor K, Sandstrom M, Dunbar G (2009) Intracerebroventricular injections of mu-P-75 saporin can produce memory deficits without impairing motor deficits in a mouse model of Alzheimer’s disease. Neuroscience 2009 Abstracts 528.1/H34. Society for Neuroscience, Chicago, IL.

Summary: Intracerebroventricular injections of mu-P-75 saporin (Advanced Targeting Systems, San Diego, CA) effectively and efficiently destroys cholinergic neurons and creates memory deficits in mice, mimicking some of the key symptoms of Alzheimer’s disease. Early attempts to use mu-P-75 saporin in mice required a relatively high mean effective dose (ED50) of 3.6 µg in order to create behavioral deficits (Berger-Sweeney et al., 2001, The Journal of Neuroscience, 21: 8164-8173; Hunter et al, 2004, European Journal of Neuroscience, 19: 3305-3316). Recent advances in producing the saporin have lowered the ED50 to doses to 0.4 µg, although the resulting memory deficits are transient, and doses above 0.8 µg can cause motor deficits (Moreau et al., 2008, Hippocampus, 18: 610-622). In an effort to elucidate the behavioral effects of a higher (0.8 µg) dose, we gave bilateral intracerbroventricular injections of mu-P-75 saporin (n=6) or sterile phosphate buffered saline (n=3) into C57/BL6 mice and assessed their cognitive abilities on both a Morris water maze (MWM) and an object-recognition task, while monitoring their motor abilities using a rotarod task. Mice receiving the mu-P-75 saporin performed significantly worse than sham animals on an object recognition task and tended to have longer latencies and swim paths during the seven days of MWM testing. Importantly, no between-group differences were observed for latency to fall on the rotarod task. Collectively, these results suggest that the 0.8 µg dose of saporin is both safe and effective for mimicking AD-like memory deficits, without causing significant motor deficits.

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Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice.

Ho NF, Han SP, Dawe GS (2009) Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice. BMC Neurosci 10:57. doi: 10.1186/1471-2202-10-57

Summary: The act of running can induce hippocampal neurogenesis. In this work the authors investigated whether running can offset the loss of septohippocamal cholinergic neurons caused by a lesion using mu p75-SAP (Cat. #IT-16). Mice received 3.6 µg of the toxin into each lateral ventricle. Although the number of surviving neurons was similar in both lesioned and control animals, most of the progenitor cells in the lesioned animals could not survive without cholinergic input.

Related Products: mu p75-SAP (Cat. #IT-16)

Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear.

Tronson NC, Schrick C, Guzman YF, Huh KH, Srivastava DP, Penzes P, Guedea AL, Gao C, Radulovic J (2009) Segregated populations of hippocampal principal CA1 neurons mediating conditioning and extinction of contextual fear. J Neurosci 29:3387-3394. doi: 10.1523/JNEUROSCI.5619-08.2009

Summary: This work examines what cell groups are responsible for controlling contextual fear. 180 ng of mu p75-SAP (Cat. #IT-16) was injected into the medial septum of mice. Saporin (Cat. #PR-01) was used as a control. In lesioned animals, fear extinction was lost along with the cholinergic input from the medial septum, while fear conditioning was left intact.

Related Products: mu p75-SAP (Cat. #IT-16), Saporin (Cat. #PR-01)

Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice.

Moreau PH, Cosquer B, Jeltsch H, Cassel JC, Mathis C (2008) Neuroanatomical and behavioral effects of a novel version of the cholinergic immunotoxin mu p75-saporin in mice. Hippocampus 18(6):610-622. doi: 10.1002/hipo.20422

Summary: 192-IgG-SAP (Cat. #IT-01) has been used for over a decade to examine the cholinergic system in the basal forebrain of rats. Establishing the same reagent for mice has been problematic. Here the authors describe the use of a mouse-specific lesioning agent, mu p75-SAP (Cat. #IT-16). After deciding on a dosage of 0.4 µg administered in the form of bilateral intracerebroventricular injections, mice were lesioned and tested. Lesioned animals displayed increased locomotor activity, and spatial learning and memory deficits, with minimal side effects.

Related Products: mu p75-SAP (Cat. #IT-16), 192-IgG-SAP (Cat. #IT-01)

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Effect of running on neurogenesis in cholinergic lesioned mice

Ho N, Han S, Dawe GS (2006) Effect of running on neurogenesis in cholinergic lesioned mice. Neuroscience 2006 Abstracts 318.5. Society for Neuroscience, Atlanta, GA.

Summary: Neurogenesis occurs mainly in two regions of the adult rodent brain, the dentate gyrus of the hippocampus and the subventricular zone. There are many factors which regulate neurogenesis, but voluntary exercise has consistently been shown to enhance neurogenesis. Exercise has been reported to specifically stimulate neural cell proliferation in the hippocampus but not the olfactory bulb. One of the major sources of afferents to the hippocampus are the septohippocampal projections, in which axons from the medial septum and diagonal band of Broca (MSDB) project to the hippocampus. Major components of the septohippocampal pathway that act as ‘pacemakers’ for hippocampal theta rhythm, which increases in conjunction with the voluntary running, are the cholinergic and GABAergic projections rising from cells in the MSDB. This present study investigates the effect of a partial cholinergic lesion in the basal forebrain and MSDB of mice, a partial model of the neurodegeneration that occurs in Alzheimer’s disease, on neural cell proliferation and neurogenesis. Murine p75-SAP, a conjugate of a p75 antibody that targets selectively cholinergic cells and cytotoxic saporin, was injected into the ventricles of female adult Swiss mice. After recovery from surgery mice were then administered bromodeoxyuridine (BrdU). BrdU immunopositive cells were quantified 24 hours and 4 weeks to assess for neural cell proliferation and survival of newly generated cells. Partial cholinergic denervation led to a decrease in the survival of new born cells in the dentate gyrus. We compared the effects of voluntary running for a period of 12 days in non-lesioned and lesioned mice under similar experimental conditions. Running resulted in an increase in neural cell proliferation for both the non-lesioned and lesioned groups. Running led to a marked increase in cell proliferation in lesioned mice compared to the controls, and also enhanced neurogenesis, as determined by the colocalization of BrdU and the neuronal nuclei marker NeuN in cells within the dentate gyrus. The present study suggests that voluntary running may have a positive effect on neurogenesis in neurodegenerative models in rodents. Further work needs to be done to elucidate the underlying mechanisms of exercise-induced neurogenesis.

Related Products: mu p75-SAP (Cat. #IT-16)

Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain

Chauhan NB (2006) Cholinergic immunolesioning produced tangle-like inclusions in TgCRND8 brain. Neuroscience 2006 Abstracts 271.8. Society for Neuroscience, Atlanta, GA.

Summary: Today’s Alzheimer’s disease (AD) research lacks a “complete” model that would represent both plaque and tangle pathology together with correlative memory deficits. Although currently developed transgenic model including APP/PS1/tau mutations do not “truly” represent AD because tangles observed in AD brain are independent of tau mutations. Subtly increased β-amyloid (Aβ) levels either due to familial mutations or sporadic causes, primarily targets pre-tangle cytopathology and degeneration of basal forebrain cholinergic neurons (BFCN) via deranged signaling of glygogen synthase kinase 3-beta (GSK3β)-, protein kinase A (PKA)-, and extracellular signal-regulated kinase (ERK2) of ERK-mitogen-activated protein kinase (MAPK) cascade, leading to reduced phosphorylation of cAMP responsive element binding protein (CREB) that results in synaptic and memory deficits much earlier than the emergence of classic AD-pathology. Thus, subtly elevated Aβ, together with BFCN deficits resulting from Aβ-induced deranged signaling, set up a vicious feedback loop to produce characteristic plaque- and tangle-pathology observed in AD. Based on these facts, we wished to test if selective lesioning of basal fore brain cholinergic neurons during the early stages of amyloid build-up will exacerbate tau phosphorylation and produce tangle-like inclusions in transgenic mice with APP mutations. We produced selective immunotoxic lesions of BFCN by injecting the BFCN-specific cholinergic immunotoxin, which is known to specifically target p75-expressing BFCN and spare p75-expressing cerebellar neurons (Mu-p75-Saporin, Advanced Targeting Systems, #IT-16), intracerebroventricularly (ICV) in TgCRND8 mice harboring Swedish (KM670/671NL) and Indiana (V717F) mutations. This model exhibited tangle-like inclusions, provoked already existing plaque pathology, and worsened already impaired behavioral deficits.

Related Products: mu p75-SAP (Cat. #IT-16)

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Selective cholinergic immunolesioning in alpha7 nAChR KO mice: Anatomical, neurochemical and functional effects

Ledri M, Cusulin C, Novati A, Aztiria E, Leanza G (2006) Selective cholinergic immunolesioning in alpha7 nAChR KO mice: Anatomical, neurochemical and functional effects. FENS 2006 Abstracts 3:A1610.10. Federation of European Neuroscience Societies, Vienna, Austria.

Related Products: mu p75-SAP (Cat. #IT-16)

Immunolesion of p75 NGF receptor in the mouse SCN attenuated light-induced phase shift of the circadian wheel-running rhythm

Vijayakumar S, Masood A, Smith M, Clark JP, Nelson DE, Ding JM (2005) Immunolesion of p75 NGF receptor in the mouse SCN attenuated light-induced phase shift of the circadian wheel-running rhythm. Neuroscience 2005 Abstracts 766.18. Society for Neuroscience, Washington, DC.

Summary: Mammalian circadian rhythms are regulated by the suprachiasmatic nucleus (SCN) of the hypothalamus. Alhough the SCN can orchestrate these rhythms in the absence of external cues, it is entrained to environmental cycles through the retinohypothalamic tract. Light-induced phase shifts in circadian rhythm is a classic example of short-term environmental stimuli inducing lasting changes in intracellular signals and gene expression within the SCN cells that alter the phase of the SCN pacemaker and allow entraiment. Since neurotrophins are known to mediate neural plasticity, we investigated the role of brain-derived neurotrophic factor (BDNF) on resetting the phase of the SCN both in vitro and in vivo. We used the SCN brain slice model to study the direct effect of BDNF on the circadian rhythm. Briefly, coronal hypothalamic slices containing the SCN were prepared using 129B/6 mice. The circadian rhythm of the SCN neurons in the brain slice was monitored for 2-3 days by continuously sampling the spike frequencies with single-unit extracellular electrodes. Brief microdrop applications of BDNF (10 uM) induced robust phase delays at CT 16 and phase advances at CT 22. BDNF binds to neurotrophin receptors, including the low affinity p75NTR, which is localized in the SCN. When the toxin Saporin is conjugated to the antibody against p75NTR, it selectively destroys the cells expressing the p75NTR. Three weeks after the stereotaxic injection of the mu p75-Saporin (Advanced Targeting System) into the third ventricle (1 ul over 20 min), the p75NTR immunoreactivity in the mouse SCN is abolished. Immunolesion of the p75NTR in the SCN attenuated light-induced phase delays of the wheel running rhythm at CT16. Consistent with previous findings, our results support a role for BDNF and its receptor p75NTR, in resetting the circadian rhythm of the SCN in mice.

Related Products: mu p75-SAP (Cat. #IT-16)

Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning.

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC (2004) Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12):3305-3316. doi: 10.1111/j.0953-816X.2004.03439.x

Summary: In Alzheimer’s disease basal cholinergic degeneration is accompanied by glial activation and the release of pro-inflammatory cytokines. To investigate whether neural events other than degeneration can cause effects of Alzheimer’s disease, the authors treated mice with minocycline after lesioning the basal forebrain with 3.6 µg of mu p75-SAP (Cat. #IT-16). Administration of minocycline reduced the loss of cholinergic neurons, reduced glial response to the lesion, and lessened the cognitive impairment due to mu p75-SAP lesions.

Related Products: mu p75-SAP (Cat. #IT-16)

The effects of ethanol and cholinergic lesions on anxiety in mice

Hummer TA, Johnson AD, Givens B (2003) The effects of ethanol and cholinergic lesions on anxiety in mice. Neuroscience 2003 Abstracts 859.16. Society for Neuroscience, New Orleans, LA.

Summary: Ethanol’s anxiolytic properties in mice are well-documented as measured with an elevated plus-maze. The effect of IP ethanol injections and cholinergic lesions on anxiety was investigated. Animals were injected with 0.5 µg of the cholinergic immunotoxin anti-murine-p75-saporin or control saline into the right lateral ventricle. After recovery (14-17 d), mice were given an IP 1.6 g/kg ethanol (10% v/v) or vehicle injection. After 60 min, animals were placed on the elevated plus-maze for a 10 min session and then perfused. Mice displayed increased open arm entries and time following ethanol. Saporin did not effect measures of anxiety nor interact with the effects of ethanol. Choline acetyltransferase staining was performed to confirm the extent of the cholinergic lesioning, and ethanol assays confirmed the presence or absence of ethanol in the blood stream. The research demonstrates that, as measured in the plus-maze, the basal forebrain cholinergic system has no significant involvement in anxiety nor in ethanol’s anxiolytic effects.

Related Products: mu p75-SAP (Cat. #IT-16)

Neuroinflammatory response to mu p75-saporin immunotoxin-induced degeneration of basal forebrain cholinergic neurons

Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AE (2003) Neuroinflammatory response to mu p75-saporin immunotoxin-induced degeneration of basal forebrain cholinergic neurons. Neuroscience 2003 Abstracts 527.15. Society for Neuroscience, New Orleans, LA.

Summary: Basal forebrain cholinergic neurons, which provide the major cholinergic innervation to the cortical regions and play a key role in the processing of information involved in cognitive processes, degenerate during both normal aging and Alzheimer’s disease. Neuroinflammation, specifically the activation of microglia, is known to affect the progression of neuronal degeneration. Activated microglia produce inflammatory mediators that have neuropathic as well as neuroprotective actions, and it has been suggested that inflammatory mediators produced by activated microglia may play a role in the decline of specific neuronal sub-types in neurodegenerative diseases. The immunotoxin mu p75-SAP has been shown to selectively destroy cholinergic neurons in the basal forebrain of mice, resulting in reduced choline acetyl-transferase activity and cognitive impairments. To characterize the inflammatory response to mu p75-SAP lesions, 3 month-old mice received icv injections of mu p75-SAP (3.6 mg) followed by treatment with an anti-inflammatory agent, minocycline (45 mg/kg i.p.), or saline. Seven days after lesioning, immunohistochemistry was used to analyze markers for cholinergic and non-cholinergic neurons and inflammation. Cholinergic lesioning resulted in a dramatic increase in CD45, a microglial marker, but no change in GFAP, an astroglial marker, in the basal forebrain region. Lesioned animals had elevated levels of phosphorylated p38, a MAP kinase protein involved in inflammatory pathways. Minocycline treatment reduced this inflammatory response. Furthermore, preliminary results suggest that animals treated with minocycline after mu p75-SAP lesioning are partially protected from cholinergic degeneration.

Related Products: mu p75-SAP (Cat. #IT-16)

The efficacy of intraparenchymal anti-p75 immunotoxin on medial septal cholinergic neurons in mice

Schaevitz LR, Baxter MG, Stearns NA, Huang YY, Lappi DA, Berger-Sweeney J (2002) The efficacy of intraparenchymal anti-p75 immunotoxin on medial septal cholinergic neurons in mice. Neuroscience 2002 Abstracts 778.11. Society for Neuroscience, Orlando, FL.

Summary: We have shown previously that anti-murine-p75-SAP (saporin conjugated to a rat monoclonal antibody against the mouse p75 nerve growth factor receptor) selectively destroys basal forebrain cholinergic neurons in vivo after intracerebroventricular injections (J. Neurosci. 21:8164-73). Cholinergic neuronal loss was more extensive in the medial septum (MS) than the nucleus basalis magnocellularis; it is unclear whether this distinction is due to toxin diffusion from the ventricles or differential sensitivity of the neuronal populations. Intraparenchymal (IPC) injections to specific targets can help resolve the issue. Here, we examine the efficacy of anti-murine-p75-SAP IPC injections on cholinergic neurons. Saline or different doses of toxin (0.1, 0.2, 0.4, 0.9, 4.7, and 9.4 microg/microL) were injected into the MS of adult male C57BL/6J mice. Ten days post lesion, brain sections were stained for choline acetyltransferase and p75 (cholinergic markers) to determine toxin efficacy, and calbindin and parvalbumin (non-cholinergic markers) to determine toxin specificity. Toxin doses below 1.0 microg/microL had no effect on cholinergic or non-cholinergic neurons, while doses above 4.7 microg/microL resulted in the complete destruction of both cholinergic and non-cholinergic neurons. More thorough testing of doses between 1 and 4 microg/microL will be required to determine the optimal toxin dose for IPC injections.

Related Products: mu p75-SAP (Cat. #IT-16)

Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior.

Berger-Sweeney JE, Stearns NA, Murg SL, Floerke-Nashner LR, Lappi DA, Baxter MG (2001) Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 21(20):8164-8173. doi: 10.1523/JNEUROSCI.21-20-08164.2001

Summary: 192-Saporin (Cat. #IT-01) has long been an effective agent for elimination of cholinergic neurons in the basal forebrain of rats. Until the development of mu p75-SAP (Cat. #IT-16) there was no equivalent agent for use in mice. The authors tested mu p75-SAP in vitro and in vivo (1.8-3.6 µg in right lateral ventricle), using cytotoxic, histochemical, and behavioral assays. The data shows that mu p75-SAP is a highly selective and efficacious lesioning agent for cholinergic neurons in the mouse. The authors conclude that mu p75-SAP will be a powerful tool to use in combination with genetic modification to investigate cholinergic damage in mouse models of Alzheimer’s disease.

Related Products: mu p75-SAP (Cat. #IT-16), 192-IgG-SAP (Cat. #IT-01)

A specific cholinergic immunotoxin in mice.

Berger-Sweeney JE, Murg SL, Baxter MG, Stearns NA, Lappi DA (2000) A specific cholinergic immunotoxin in mice. Neuroscience 2000 Abstracts 563.13. Society for Neuroscience, New Orleans, LA.

Summary: We have shown previously that 192 IgG-saporin, a p75 (nerve growth factor [NGF] receptor) antibody linked to the ribosome-inactivating protein saporin, is an effective lesioning agent for cholinergic basal forebrain neurons in rats (Berger-Sweeney et al., J. Neurosci. 14:4507-4519). The 192 IgG antibody, however, does not crossreact with the mouse NGF receptor, making it unsuitable for mouse studies. Here, we tested the efficacy of a new immunotoxin targeting the mouse p75 receptor. A rat monoclonal antibody (Advanced Targeting Systems) to the extracellular domain of the mouse p75 receptor, which can be internalized and transported retrogradely in mouse neurons (Rossner et al., Metab. Brain Dis. 15:17-28), was coupled to saporin. Different doses of the toxin, or saline (0.5 µl) were injected into the lateral ventricle (icv) of adult C57BL/6 mice (n = 3–6/ group). Two weeks later, brains were processed for choline acetyltransferase (ChAT) neurochemistry or ChAT immunocytochemistry (to examine lesion efficacy), and glutamic acid decarboxylase (GAD) neurochemistry or calbindin/parvalbumin immunocytochemistry (to examine lesion specificity). Toxin doses ranging from 0.4 – 3.6 µg reduced hippocampal and neocortical ChAT activity in a dose-dependent fashion. Immunocytochemistry confirmed a significant loss of ChAT-positive neurons in the basal forebrain. These same doses did not alter hippocampal or neocortical GAD activity, or alter calbindin or parvalbumin staining (non-cholinergic neurons) in the basal forebrain. These data suggest that we have created a specific cholinergic immunotoxin for use in mice.

Related Products: mu p75-SAP (Cat. #IT-16)

Intracerebroventricular infusion of CHO5, a rat monoclonal antibody directed against mouse low-affinity nerve growth factor receptor (p75NTR), specifically labels basal forebrain cholinergic neurons in mouse brain.

Rossner S, Schliebs R, Bigl V (2000) Intracerebroventricular infusion of CHO5, a rat monoclonal antibody directed against mouse low-affinity nerve growth factor receptor (p75NTR), specifically labels basal forebrain cholinergic neurons in mouse brain. Metab Brain Dis 15(1):17-27. doi: 10.1007/BF02680011

Summary: 192-Saporin (Cat. #IT-01) has long been a useful tool for neurobiological research in the rat. For various reasons, many researchers want to perform the same studies in the mouse but have been prevented from doing so by the lack of a suitable antibody against the mouse p75NTR. Rossner et al. describe a rat monoclonal antibody against the mouse p75NTR (Cat. #AB-N02) that demonstrates co-localization of p75NTR and ChAT, and also co-localization of p75NTR and TrkA in the mouse basal forebrain. Internalization and retrograde transport of this antibody in cholinergic basal forebrain neurons is also shown. This evidence indicates that the anti-mouse p75NTR will be effective for use as an immunotoxin.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16), Antibody to NGFR (Cat. #AB-N02)