Salwa, Kumar L (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
Dose: Liu et al. injected 1.5 μg of mu p75-SAP into the medial septum. See cover article. https://atsbio.com/tt13q3-article1/
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: To determine whether the supportive effect of NGF on learning and memory is specifically dependent upon intact hippocampal cholinergic innervation.
Dose: To determine whether the supportive effect of NGF on learning and memory is specifically dependent upon intact hippocampal cholinergic innervation.
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.
Dose: 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.
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.
Dose: mu p75-SAP (0.596 μg/μl) was injected into the left and right lateral ventricles.
Romero-Miguel D, Lamanna-Rama N, Casquero-Veiga M, Gómez-Rangel V, Desco M, Soto-Montenegro ML. Minocycline in neurodegenerative and psychiatric diseases: An update. (2021) Eur J Neurol 28(3):1056-1081. doi: 10.1111/ene.14642
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.
Dose: 45 mg/Kg, i.p. Hunter et al., 2004
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.
Dose: 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).
Giannoni P, Fossati S, Claeysen S, Marcello E, eds. Identification of Multiple Targets in the Fight against Alzheimer’s Disease (2020) Lausanne: Frontiers Media SA. doi: 10.3389/978-2-88963-909-0
IT-01 192-IgG-SAP and IT-16 mu p75-SAP
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.
Nizari S, Carare RO, Romero IA, Hawkes CA. 3D Reconstruction of the Neurovascular Unit Reveals Differential Loss of Cholinergic Innervation in the Cortex and Hippocampus of the Adult Mouse Brain. (2019) 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.
Dose: 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.
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.
Dose: 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.
Xu H, Chen L, Zhang X, Jiang X, Tian W, Yu W, Wang X, Tian J, Su D. Central cholinergic neuronal degeneration promotes the development of postoperative cognitive dysfunction. (2019) Lab Invest 99(7):1078-1088. doi: 10.1038/s41374-018-0174-9
Dose: 1 microliter of mu-p75-SAP at a concentration of 0.8 μg/μl was injected into the lateral ventricles.
Doyle S, Baker KL, Cunningham C, & Lowry JP. (2018). Real‐Time Electrochemical Monitoring of Choline During Systemic Inflammation in the Freely‐ Moving Mouse. Paper presented at the 17th International Conference on Monitoring Molecules in Neuroscience, Univ Oxford, UK, March 25-28, 2018.
The loss of cholinergic innervation (mu p75‐SAP lesion in the basal forebrain) abolished the scopolamine‐induced choline increase in the hippocampus.
Turnbull MT, Boskovic Z, & Coulson EJ. Acute Down-Regulation of BDNF Signaling Does Not Replicate Exacerbated Amyloid-Β Levels and Cognitive Impairment Induced by Cholinergic Basal Forebrain Lesion. (2018). Frontiers in Molecular Neuroscience, 11 51.
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.
Dose: 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.
Zhang Q, De Corte B, Jung D, Kim Y, Geerling J, & Narayanan N. Cholinergic Modulation Targeting Medial Prefrontal Cortex Leads to Behavior Deficit in Interval Timing Task (P5.195). (2018). Neurology, 90 (15 Supplement)
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.
Dose: 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.
Turnbull MT, Coulson EJ. (2017) Cholinergic Basal Forebrain Lesion Decreases Neurotrophin Signaling Without Affecting Tau Hyperphosphorylation in Genetically Susceptible Mice. J Alzheimers Dis 55(3):1141-54. PMID: 27767994 (Targeting Trends 17q1)
Kim T, Thankachan S, McKenna JT, McNally JM, Yang C, Choi JH, Chen L, Kocsis B, Deisseroth K, Strecker RE, Basheer R, Brown RE, McCarley RW. (2015) Cortically projecting basal forebrain parvalbumin neurons regulate cortical gamma band oscillations. Proc Natl Acad Sci U S A 112(11):3535-3540. (Targeting Trends 15q2)
Li T, Yu Y, & Cai H. Effects of Brain-Derived Neurotrophic Factor-Pretreated Neuron Stem Cell Transplantation on Alzheimer’s Disease Model Mice. (2015). International journal of clinical and experimental medicine, 8 (11):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.)
Nguyen HN, Huppe-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. (Targeting Trends 15q2)
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. (Targeting Trends 13q3)
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. (Targeting Trends 14q1)
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. (Targeting Trends 13q2)
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. (Targeting Trends 13q2)
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. (Targeting Trends 13q1)
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 in an NGFr-lesioned mouse model. Targeting Trends 14(3).
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. (Targeting Trends 13q3)
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. (Targeting Trends 13q3)
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. (Targeting Trends 13q2)
Cunningham C. (2012) Partial basal forebrain cholinergic depletion leaves working memory susceptible to the effects of systemic inflammation. Targeting Trends 13(4).
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. (Targeting Trends 12q3)
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. (Targeting Trends 12q4)
Kerbler GM, Hamlin AS, Pannek K, Kurniawan ND, Keller MD, Rose SE, Coulson EJ. (2012) Diffusion-weighted magnetic resonance imaging detection of basal forebrain cholinergic degeneration in a mouse model. Neuroimage 66C:133-141. (Targeting Trends 13q1)
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. (Targeting Trends 12q4)
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. (Targeting Trends 12q2)
Klinkenberg I, Sambeth A, Blokland A (2011) Acetylcholine and attention. Behav Brain Res 221(2):430-442. (Targeting Trends 11q1)
See also: Society for Neuroscience 2011 Abstracts
See also: Society for Neuroscience 2010 Abstracts
Ho NF, Han SP, Dawe GS (2009) Effect of voluntary running on adult hippocampal neurogenesis in cholinergic lesioned mice. BMC Neurosci 10:57. (Targeting Trends 09q4)
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. (Targeting Trends 09q2)
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(3):1334-1346. (Targeting Trends 10q1)
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. (Targeting Trends 09q2)
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. (Targeting Trends 08q2)
Moreau P-H, Cosquer B, Jeltsch H, Cassel J-C, Mathis C. (2008) Selective lesion of basal forebrain cholinergic neurons in mice with the mu p75-saporin immunotoxin: Neuroanatomy and behavior. Targeting Trends 9(2).
Chauhan N. (2007) Cholinergic Immunolesioning Produced Tangle-like Inclusions in TgCRND8 Brain. Targeting Trends 8(1).
Ihunwo AO,Schliebs R (2007) BBeta-site amyloid precursor protein cleaving enzyme (BACE1) expression by astrocytes following p75-saporin immunolesion in transgenic TG2576 mice. J Environ Neurosci Biomed 1(1):41-77.
See also: Society for Neuroscience 2007 Abstracts
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 Abstr 3:A1610.10.
See also: Society for Neuroscience 2006 Abstracts
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. (Targeting Trends 04q4)(Targeting Trends 04q4)
See also: Society for Neuroscience 2003 Abstracts
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. (Targeting Trends 02q1)
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.