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首页> 美国卫生研究院文献>IOS Press Open Library >Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice
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Immunization Against Specific Fragments of Neurotrophin p75 Receptor Protects Forebrain Cholinergic Neurons in the Olfactory Bulbectomized Mice

机译：针对Neurotrophin p75受体特定片段的免疫保护嗅觉切除小鼠的前脑胆碱能神经元。

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摘要

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.
机译：阿尔茨海默氏病（AD）的特征是进行性认知障碍，与明显的胆碱能神经元丢失和淀粉样β（Aβ）肽在大脑中积累有关。 AD中的细胞毒性至少部分地由Aβ与p75神经营养蛋白受体（p75NTR）的胞外域结合而介导，p75神经营养蛋白受体主要位于基底前脑中产生乙酰胆碱的神经元的膜中。假设p75NTR的开放非结构环可能是Aβ结合的有效位点，我们已经用合成肽免疫嗅球切除（OBX）和假手术（SO）小鼠（分别为n = 82和49）进行了免疫环的不同部分，旨在通过特异性抗体阻断它们。 OBX-小鼠已在先前的研究中得到证实，并在本研究中得到证实，其特征在于典型的行为，形态和生化AD标志，包括前脑神经元的胆碱能缺陷。用p75NTR的KLH缀合片段免疫OBX或SO-小鼠，可针对9个所选片段中的每一个诱导高滴度的特异性血清抗体。但是，仅对氨基酸残基序列为155-164和167- 176。我们得出的结论是，基于特定p75NTR位点的免疫阻断作用以及细胞毒性的方法，对于研究与AD相关的机制以及开发对AD患者胆碱能功能障碍的高度选择性疗法是一种有用和有效的工具。

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