阿尔茨海默病（Alzheimer’s disease, AD）的发病机制目前尚不清楚，也缺乏能改变疾病结局的治疗药物。β-淀粉样蛋白(Aβ)假说是主流学说，小胶质细胞及其介导的固有免疫反应在Aβ清除和AD病理生理中具有重要作用。CD33是AD风险基因，但具体致病机理不明。我们前期发现CD33能与Aβ结合并募集SHP-1，且AD脑组织样品中存在CD33/Aβ相互作用。因此我们推测CD33/Aβ相互作用介导的小胶质细胞功能障碍是其参与AD发病的主要机制，靶向干预CD33/Aβ相互作用将改善小胶质细胞功能，阻止AD病理进展。我们将利用人源小胶质细胞系、过表达人源CD33的AD小鼠模型等工具，从细胞和动物水平运用分子生物学、神经生化和电生理、行为学等多种手段探索运用单克隆抗体靶向干预CD33/Aβ相互作用对AD的治疗作用及其机制。本研究有助于明确CD33参与AD发病的机理及指导临床干预。

Alzheimer’s disease (AD) is a chronic neurodegenerative disease characterized by progressive impairments in memory, executive function and gradual changes in personality and disturbance in daily life. Currently there is no disease-modifying medications available. The pathogenesis of AD is largely unknown, the β-amyloid (or Aβ) cascade hypothesis is dominant in the field. Microglia and their innate immune responses are key players in Aβ clearance and AD pathogenesis. Mutations in CD33 have been linked to increased Alzheimer’s disease (AD) risk, but neurobiological functions of CD33 and its pathophysiological ligands remain elusive. We found that CD33 could directly bind to Aβ and recruit SHP-1, CD33 also interact with Aβ in human AD brain samples. So we proposed that CD33/Aβ interaction induced microglia dysfunction is the key in AD pathogenesis, targeting CD33/Aβ interaction would restore microglia function and rescue AD phenotype. To address this hypothesis, we will screening monoclonal antibodies to CD33 in human microglia cell line and further test them in AD mice models expressing human CD33 using multiple approaches such as molecular biology, neurochemistry, e-physiology, and behavior tests. Collectively, this project will provide critical insights into the role of CD33 in AD pathogenesis and might result in novel therapeutic approach for AD.