title: Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice.
abstract: Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with marked cholinergic neuron loss and amyloid-β (Aβ) peptide accumulation in the brain. The cytotoxicity in AD is mediated, at least in part, by Aβ binding with the extracellular domain of the p75 neurotrophin receptor (p75NTR), localized predominantly in the membranes of acetylcholine-producing neurons in the basal forebrain. Hypothesizing that an open unstructured loop of p75NTR might be the effective site for Aβ binding, we have immunized both olfactory bulbectomized (OBX) and sham-operated (SO) mice (n = 82 and 49, respectively) with synthetic peptides, structurally similar to different parts of the loops, aiming to block them by specific antibodies. OBX-mice have been shown in previous studies, and confirmed in the present one, to be characterized by typical behavioral, morphological, and biochemical AD hallmarks, including cholinergic deficits in forebrain neurons. Immunization of OBX- or SO-mice with KLH conjugated fragments of p75NTR induced high titers of specific serum antibodies for each of nine chosen fragments. However, maximal protective effects on spatial memory, evaluated in a Morris water maze, and on activity of choline acetyltransferase in forebrain neurons, detected by immunoreactivity to specific antibodies, were revealed only for peptides with amino acid residue sequences of 155-164 and 167-176. We conclude that the approach based on immunological blockade of specific p75NTR sites, linked with the cytotoxicity, is a useful and effective tool for study of AD-associated mechanisms and for development of highly selective therapy of cholinergic malfunctioning in AD patients.
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Bobkova
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Vasily
authors.initials: V
authors.lastname: Vorobyov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Natalia
authors.initials: N
authors.lastname: Medvinskaya
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Inna
authors.initials: I
authors.lastname: Nesterova
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Tatarnikova
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Pavel
authors.initials: P
authors.lastname: Nekrasov
authors.affiliation: Institute of Cell Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Samokhin
authors.affiliation: Institute of Theoretical and Experimental Biophysics, Russian Academy of Sciences, Pushchino, Moscow Region, Russia.
authors.forename: Alexander
authors.initials: A
authors.lastname: Deev
authors.affiliation: School of Biosciences and Neuroscience & Mental Health Research Institute, Cardiff University, Museum Avenue, Cardiff, UK.
authors.forename: Frank
authors.initials: F
authors.lastname: Sengpiel
authors.affiliation: Shemyakin's-Ovchinnikov's Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Koroev
authors.affiliation: Shemyakin's-Ovchinnikov's Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia.
authors.forename: Olga
authors.initials: O
authors.lastname: Volpina
mesh_terms: D016229:Amyloid beta-Peptides / Q000276:immunology; D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D059329:Cholinergic Neurons / Q000378:metabolism*; D008297:Male; D018782:Maze Learning; D051379:Mice; D009830:Olfactory Bulb / Q000293:injuries* / Q000601:surgery; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology*; D016548:Prosencephalon / Q000166:cytology*; D020800:Receptor, Nerve Growth Factor / Q000276:immunology* / Q000378:metabolism; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; D020800:Receptor, Nerve Growth Factor; D010047:Ovalbumin; D002795:Choline O-Acetyltransferase
keywords: Acetyltransferase; Morris water maze; amyloid-beta; cholinergic mediation; olfactory bulbectomy; spatial memory