阿尔兹海默病（AD）是目前神经退行性疾病中最具破坏性的一种，基底前脑胆碱能神经元在AD中最早退化，而钙稳态失衡会使其选择性易损。申请人前期研究发现基底前脑内侧隔核胆碱能神经元共表达Calbindin-D28k（CB）（MS-CB/ChAT），且CB随AD病程而减少。MS-CB/ChAT投射至腹侧海马锥体细胞（vCA1PN）且MS-CB/ChAT失活损伤工作记忆，AD小鼠早期即出现工作记忆丢失与突触传递障碍，且MS-CB/ChAT中DAPK1激活。研究表明CB丧失会导致钙超载，引起DAPK1激活与Tau病变，造成神经元损伤。因此，我们提出假设：MS-CB/ChAT中CB降低会引起钙稳态失衡，激活DAPK1与Tau病变，导致细胞损伤与MS-CB/ChAT-vCA1PN突触传递障碍，最终诱导AD早期工作记忆丢失。本项目将从细胞、环路、分子和整体行为水平验证假设，为AD的早期诊断和治疗提供新靶点。

Alzheimer's disease (AD) is currently one of the most destructive neurodegenerative diseases. It is suggested that cholinergic neurons in the basal forebrain are the first to degenerate in AD, and the calcium homeostasis imbalance makes them vulnerable selectively. Previous studies showed that Calbindin-D28k(CB) was co-expressed by cholinergic neurons in the medial septum of basal forebrain (MS-CB/ChAT), and CB decreased gradually during the pathological process of AD. MS-CB/ChAT projected to the excitatory pyramidal neurons in the ventral CA1(vCA1PN), and MS-CB/ChAT inactivation could result in working memory impairment. In the early phase of AD, working memory loss and synaptic transmission disorder were observed, and DAPK1 was activated in MS-CB/ChAT. It is suggested that CB loss can lead to calcium overload, leading to DAPK1 activation and Tau pathology, which resulted in neuronal damage. Therefore, we hypothesized that the reduction of CB in MS-CB/ChAT would cause calcium homeostasis imbalance, DAPK1 activation and Tau pathology, leading to cell damage and synaptic transmission disorder of MS-CB/ChAT-vCA1PN circuit, which eventually induces working memory loss in the early phase of AD. This project will verify the hypothesis from the cellular, circuit, molecular and overall behavior level, so as to provide new targets for the early diagnosis and treatment of AD.