targeted-toxins

Bondarenko N, Dilmukhametova L, Kurina A, Murtazina A, Sapronova A, Sysoeva A, Ugrumov M (2017) Plasticity of central and peripheral sources of noradrenaline in rats during ontogenesis. Biochemistry (Mosc) 82:373-379.. doi: 10.1134/S0006297917030166

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Martínez-Gardeazabal J, González de San Román E, Moreno-Rodríguez M, Llorente-Ovejero A, Manuel I, Rodríguez-Puertas R (2017) Lipid mapping of the rat brain for models of disease. Biochim Biophys Acta Biomembr 1859:1548-1557.. doi: 10.1016/j.bbamem.2017.02.011

Objective: To map the spatial distribution of different lipid species in the rat central nervous system (CNS) using IMS to find a possible relationship between anatomical localization and physiology. The data obtained were subsequently applied to a model of neurological disease, the 192IgG-saporin lesion model of memory impairment.

Summary: The specific distribution of different lipids supports their involvement not only in structural and metabolic functions but also as intracellular effectors or specific receptor ligands and/or precursors. Moreover, the specific localization in the CNS described here will enable us to analyze lipid distribution to identify their physiological conditions in rat models of neurodegenerative pathologies, such as Alzheimer’s disease.

Usage: 192 IgG-SAP in aCSF (135 ng/1 μl/hemisphere; 0.25 μl/min) was administered.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gelfo F, Cutuli D, Nobili A, De Bartolo P, D’Amelio M, Petrosini L, Caltagirone C (2017) Chronic lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration. J Alzheimers Dis 56:1505-1518. doi: 10.3233/JAD-160892 PMID: 28222508

Objective: To evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes.

Summary: The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Usage: Neurodegeneration was induced by injecting the immunotoxin 192 IgG-SAP in the medial septum (0.5 ug/side) and nucleus basalis magnocellularis (0.4 ug/side).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Lecrux C, Sandoe C, Neupane S, Kropf P, Toussay X, Tong X, Lacalle-Aurioles M, Shmuel A, Hamel E (2017) Impact of altered cholinergic tones on the neurovascular coupling response to whisker stimulation. J Neurosci 37:1518-1531. doi: 10.1523/JNEUROSCI.1784-16.2016

Summary: The authors assessed the effects of varying ACh tone on whisker-evoked NVC responses in rat barrel cortex. ACh depletion was achieved via unilateral icv injection (4 mcg/2 mcl) with 192 IgG-SAP (Cat. #IT-01) or saline. They conclude that ACh is not only a facilitator, but also a prerequisite for the full expression of sensory-evoked NVC responses.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Kelly SC, Nelson PT, Counts SE (2017) Featured Article: The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Targeting Trends 18

Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)

Read the featured article in Targeting Trends.

See Also:

• Kelly SC et al. The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Neuroscience 2016 Abstracts 786.11 / H7, 2016. Society for Neuroscience, San Diego, CA

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)

Rajakumar R (2016) Developmental disturbances in thalamocortical connection are sufficient to produce almost all features of schizophrenia. Neuroscience 2016 Abstracts 845.01 / LLL41. Society for Neuroscience, San Diego, CA.

Summary: Partial ablation of subplate of the developing frontal cortex was achieved by two different approaches in PD1 S-D rat pups: infusions of either P75 receptor antibody-conjugated to saporin or β-nerve growth factor, and both resulted in identical changes: ~20% loss of subplate and aberrant distribution of thalamocortical fibers within the cortex. Control littermates received similar infusions of vehicle. Pups were allowed to grow under standard care. All animals survived, and showed no noticeable differences in milestones or activities. No differences were observed between lesioned and control groups in standard behavioral tests at 6-8 weeks of age. However, lesioned group showed significantly increased stress- or amph-induced locomotor activity, PPI deficit, social interaction deficits, and executive functional deficits after 9 weeks of age. A month-course of haloperidol or risperidon completely ameliorated locomotor abnormalities but did not affect social interaction deficit. Histological examination revealed several interesting changes: (1) 18% loss of gray matter thickness in the mPFC and no change in thickness in other cortical areas at 12 weeks, while at 20 weeks PFC loss remained at 18% but parietal and temporal cortices showed progressive thinning (20-36%); (2) significant loss of neuropil in the mPFC characterized by loss of synaptophysin and spinophilin labeling; (3) no changes in the number of neuronal cell bodies in PFC; (4) significantly increased lateral and third ventricular volume; (5) significant loss of dopaminergic fibers in lower layers of the PFC; (6) significant loss of GAD67-IR terminals in PFC; (6) significant decrease in the intensity of PAR labeling and abnormal distribution of PAR-IR terminals/cell bodies without loss of neurons; (7) significant loss of GAT-1-IR terminals only in upper layers of the PFC; (8) loss of PAR-IR terminals and cell bodies in the hippocampus; (9) abnormal distribution but no loss of CR-IR neurons in the entorhinal cortex; and (10) significantly reduced volume of basolateral amygdala. No changes were seen in ChAT neurons of the septum or N. basalis. All structural changes noted above were seen as early as 12 weeks and were not affected by antipsychotic treatment between 12 and 16 weeks. Results suggest that disturbances in thalamocortical pathfinding (due to genetic or other mechanisms) are sufficient to cause features of schizophrenia in normal animals.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Kelly SC, Nelson PT, Counts SE (2016) The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Neuroscience 2016 Abstracts 786.11 / H7. Society for Neuroscience, San Diego, CA.

Summary: Noradrenergic locus coeruleus (LC) neuron loss is a major feature of Alzheimer’s disease (AD). The LC is the primary source of norepinephrine (NE) in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex and hippocampus. Furthermore, LC-mediated NE signaling is thought to play a role in blood brain barrier maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease (CVD) and AD. However, the extent to which LC projection system degeneration occurs in the earliest stages of AD is not fully characterized to date. To address these issues, we analyzed LC tissue samples from University of Kentucky AD Center subjects who died with a premortem diagnosis of no cognitive impairment (NCI) and Braak stages 0-II at autopsy, NCI subjects with Braak stages III-V thought to be in a preclinical AD (PCAD) stage, and subjects with mild cognitive impairment (MCI) or mild AD (n = 5-6 cases/group). Paraffin-embedded pontine tissue blocks containing the LC were cut at 20µm, immunostained with tyrosine hydroxylase (TH, a marker for NE synthesis), and analyzed by stereology to estimate total LC neuron number (total number of neuromelanin-containing LC neurons) and the percentage of TH+ LC neurons. Preliminary analysis reveal a ~20% loss of both total and TH+ LC neurons in PCAD (p = 0.08), a ~30-35% loss of these neurons in MCI (p < 0.05), and a ~45-50% loss of total and TH+ neurons in AD (p < 0.01) compared to NCI. Studies were also performed to compare additional LC neuronal pathologies (phospho-tau, TDP-43, and 8dOHG) in the diagnostic groups. A substantial increase in 8dOHG and phospho-tau is observed in PCAD compared to NCI. The morphometric data will be correlated with postmortem neuropathologic and CVD variables (e.g., microinfarcts and cerebral amyloid angiopathy) to gauge the relationship between LC neurodegeneration and cerebral AD and vascular pathology. To model these relationships in vivo, we stereotactically lesioned LC projection neurons innervating the PFC, a major LC projection zone, in the TgF344-19 rat model of AD (6 months old) using the noradrenergic immunotoxin, dopamine-β-hydroxylase-saporin, or a control lesion (n = 8/group). Prior to sacrifice at 9 months, immunotoxin- and control-lesioned rats will be tested behaviorally on the Barnes maze task. Postmortem PFC will be analyzed for LC fiber innervation, NE and NE metabolite levels, CVD pathology and AD-like pathology. Taken together, these data will shed light on the multifactorial noradrenergic pathways contributing to neuronal and vascular pathologies during the onset of AD.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

ATS Poster of the Year Winner. Read the featured article in Targeting Trends.

Ruiz AD, Hays S, Berry A, Vallejo S, Barron L, Carrier X (2016) Enhanced motor recovery by vagus nerve stimulation requires cholinergic innervation in a rat model of ischemic stroke. Neuroscience 2016 Abstracts 807.20 / HH11. Society for Neuroscience, San Diego, CA.

Summary: Stroke is a debilitating neurological insult that affects approximately 795,000 people in the U.S. each year. Following a stroke, many patients are left with impairment in upper extremity function, even after intensive rehabilitation therapy. Recent studies indicate that vagus nerve stimulation (VNS) paired with rehabilitative training significantly enhances recovery of forelimb function in models of ischemic stroke, intracerebral hemorrhage, and traumatic brain injury. Nevertheless, the mechanisms that underlie VNS-dependent enhancement recovery are largely unknown. The cholinergic nucleus basalis (NB) is a critical substrate in cortical plasticity, and several studies suggest that VNS activates cholinergic circuitry. Previous studies demonstrated that cholinergic innervation of the motor cortex is required for VNS-dependent enhancement of cortical plasticity. In this study we examine whether cholinergic innervation is required for VNS-dependent enhanced recovery in a rat model of ischemic stroke. A cohort of rats was trained to proficiency on the isometric force task, an automated and qualitative measure of forelimb function and then received a cortical ischemic lesion to impair the trained forelimb. Rats then received injections of the highly selective immunotoxin IgG-192-saporin into the nucleus basalis to deplete cortical cholinergic innervation (NB-) or control injections (NB+). Two weeks after stroke and immunolesion, rats underwent rehabilitative training for 6 weeks with or without VNS paired with forelimb movement. At the conclusion of behavioral testing, pseudorabies virus labelling was performed to assay anatomical plasticity in motor circuits controlling the forelimb. Preliminary findings indicate that VNS-dependent enhancement of stroke recovery requires cholinergic innervation.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Gulino R, Forte S, Parenti R, Gulisano M (2016) Novel targets for modulation of plasticity in a mouse model of motoneuron degeneration. Neuroscience 2016 Abstracts 812.14 / OO13. Society for Neuroscience, San Diego, CA.

Summary: A successful spinal cord repairing strategy should involve the activation of neural precursor cells. Unfortunately, their ability to generate neurons aſter injury appears limited. Another process promoting functional recovery is synaptic plasticity. We have previously studied some mechanisms of spinal plasticity by using a mouse model of motoneuron depletion induced by cholera toxin-B saporin. TDP-43 is a nuclear RNA/DNA binding protein involved in amyotrophic lateral sclerosis. Although considerable attention has been devoted to the toxic effects of the TDP-43 cytoplasmic aggregates, the functional role of this factor remains poorly investigated. Notably, TDP-43 is present in the dendrites where it behaves as a modulator of local RNA translation. Moreover, it is crucial for synaptic plasticity and locomotion in Drosophila. Here, we would like to deepen the investigation of this model of spinal plasticity. Aſter lesion, we observed a glial reaction and an activity-dependent modification of Synapsin-I, Shh, Noggin, Numb and TDP-43 proteins. Multivariate regression was used to model the possible association between these proteins, as well as with the motor performance. We found that Shh and Noggin could affect motor performance and that these proteins could be associated with both TDP-43 and Numb, thus suggesting that TDP-43 is likely an important regulator of synaptic plasticity. Given the well-known role of morphogens such as Shh, Noggin and Numb in neurogenesis and the above described functions of TDP-43, we believe that an in vivo manipulation of their signaling pathways after lesion could represent a putative method of improving regeneration and recovery by affecting synaptic plasticity and/or neurogenesis.

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