脑源性神经营养因子前体对阿尔茨海默病鼠海马神经发生和β淀粉样蛋白代谢的调控作用

Alzheimer's disease (AD) is a neurodegenerative disease and seriously harm to the health of the elderly.The most important pathological features of AD are abnormal brain amyloid-beta (Aβ) aggregation and neuron loss.Our previous studies showed that, the level of brain derived neurotrophic factor precursor ( proBDNF ) in AD brain transferring into the mature brain derived neurotrophic factor ( BDNF ) decreased, proBDNF relatively elevated, and proBDNF can reduce the learning and memory function and hippocampal neuronal proliferation in AD rats.But the role of proBDNF in the pathogenesis of AD and its mechanism is unclear.In this project,we will inject adenovirus proBDNF gene carrier,proBDNF specific affinity of antibodies, or p75NTR extracellular protein into hippocampus of transgenic AD mice.We will also observe the effects of proBDNF on the regulation of hippocampal neurogenesis and Aβ metabolism, and explore its possible mechanisms. The project is expected to make important progress in AD research on how to reduce Aβ deposition and promote AD hippocampal neurogenesis .It may offer a new target point of AD treatment.

阿尔茨海默病（Alzheimer's disease，AD）是一种严重危害老年人健康的神经系统退行性疾病，其重要病理特征是β-淀粉样蛋白（Aβ）在脑内沉积以及海马神经元的缺失，但机制不详。我们前期研究表明，AD脑内脑源性神经营养因子前体（proBDNF）转化为成熟脑源性神经营养因子（BDNF）水平降低，proBDNF水平相对升高，proBDNF可降低AD鼠学习记忆功能以及海马神经元的增殖，但有关proBDNF在AD发病中的作用及其机制尚不清楚。本项目通过转基因AD鼠海马区注射腺病毒proBDNF基因载体、proBDNF特异性亲和抗体或者p75神经营养因子受体（p75NTR）胞外段蛋白，观察proBDNF对AD鼠海马神经发生以及Aβ代谢的调控作用，并探讨其可能机制。本项目有望在如何减少Aβ沉积，促进AD海马的神经发生等方面研究取得重要进展,为AD的防治提供新的靶点。

阿尔茨海默病(Alzheimer's disease，AD)是老年人群痴呆的主要病因，是遗传和环境因素共同作用的结果。脑源性神经营养因子(BDNF)在其中具有重要的作用。作为BDNF前体蛋白的脑源性神经营养因子前体(brain-derived neurotrophic factor precursor, proBDNF)能够影响神经细胞的多项生物功能。我们前期研究表明，脑源性神经营养因子前体（proBDNF）可降低AD鼠学习记忆功能以及海马神经元的增殖，但有关proBDNF在AD发病中机制尚不清楚。本项目通过转基因AD鼠海马区注射腺病毒proBDNF基因载体、p75神经营养因子受体（p75NTR）胞外段蛋白，从离体及在体水平观察proBDNF对AD鼠海马神经发生以及β淀粉样蛋白（Aβ）代谢的调控作用。本项目明确了：1.AD条件下，proBDNF/BDNF蛋白比值相对升高；2.proBDNF可抑制培养神经细胞存活、抑制轴突生长、促进细胞凋亡；3.proBDNF可通过抑制海马神经发生、降低海马突触可塑性，从而降低AD鼠的学习记忆功能；4.proBDNF可促进海马Aβ的沉积和老年斑的形成；5.阻断p75NTR受体可抑制proBDNF的细胞毒性及促Aβ聚集的作用。本项目在如何减少Aβ沉积，促进AD海马的神经发生等方面研究取得重要进展,从理论上为AD的防治提供新的靶点。