阿尔茨海默病（AD）严重危害人类健康，但缺乏有效的治疗手段，亟需寻找新治疗靶点。文献提示阻断p75NTR可缓解AD神经元功能障碍，但其作用机制并不明确。课题组预实验发现，细胞实验中p75NTR的Cys259突变和死亡结构域DD敲除，可减少Aβ对神经元的损伤；AD模型中p75NTR的Cys259突变和DD敲除时，Aβ斑块形成减少。因此我们提出假说：通过Cys259突变和DD敲除以阻断p75NTR信号通路可减少Aβ斑块形成、减轻神经元损伤和退行性变，从而延缓AD病程进展。为了验证假说，课题组拟1）利用分解p75NTR功能结构而构建的转基因小鼠（全敲除、Cys259突变和DD敲除），体外验证p75NTR介导神经元损伤和退行性变；2）研究带有不同p75NTR突变体的AD模型的病理表型；3）解析p75NTR的Cys259突变和DD敲除影响Aβ病理的分子机制。为探索治疗AD的新靶点提供理论依据。

Alzheimer’s disease (AD) is a leading cause of dementia among older adults, however, there is still no effective treatment available. There are increasing evidences that p75 neurotrophin receptor (p75NTR) participates in many critical processes in the nervous system and its function has been linked to pathological changes in neurodegenerative diseases such as AD. However, p75NTR exerts both positive and negative effects, thus dissecting its role in AD pathology remains a significant challenge. Our preliminary data shows that blocking p75NTR could alleviate Aβ-induced neuronal damage in vitro and reduce Aβ plaques in a murine AD model. To decipher the signaling pathway of p75NTR in AD, we will first test in vitro, the mechanistic models of p75NTR-mediated neuronal injury and neurodegeneration using mice carrying defined mutations in the gene encoding p75NTR, including p75 Exon III knock out (p75 KO), a deletion of the death domain (dDD), and an Ala substitution of transmembrane Cys259 (C259A). Secondly, we will investigate the phenotypes of AD transgenic mice, 5XFAD/KO, 5XFAD/dDD and 5XFAD/C259A, by crossing a murine model of AD, with mice carrying p75 mutants, respectively. Aβ accumulation, gliosis and neuronal damage will be examined using immunohistochemistry and electrophysiology techniques. The key determinants for the neuropathological functions of p75NTR in AD will be explored, which can provide evidences to identify new therapeutic targets for AD.