阿尔茨海默症（AD）占所有痴呆患者总数的80%。AD的病理和行为特征是脑内Aβ沉积、神经纤维缠结、神经元丢失以及学习记忆能力丧失。迄今以Aβ为靶点治疗AD的药物都未成功，因此对AD的发病机理及治疗靶点需要更深入的研究。与Aβ相比，其前体蛋白APP的生理功能及其变化对AD发病的作用知之甚少，更不清楚APP功能缺失是否是导致AD发生的重要原因。虽然有研究发现APP突变影响成年新生神经元的发生与存活，但机制有待深入研究。立项结合多种电生理、分子生物学、免疫荧光化学、光遗传及行为测试，揭示APP功能缺失时海马齿回成年新生神经元的电生理属性、神经元形态、突触传递、内嗅皮层-齿回环路及其介导的认知行为异常，探索导致异常的机制并寻求以成年新生神经元为靶点改善电生理及行为异常的途径。项目的实施不仅揭示APP在AD发生中的作用，也将拓展AD病理发生的知识体系，为探索AD药物新靶点提供线索和参考。

Alzheimer’s disease (AD) is most common in dementia. Among patients with dementia there are about 80% incidence of AD. The hallmark of AD is the accumulation of extracellular amyloid plaques and neurofibrillary tangles in the brain, loss of neuron and/or synaptic connectivity accompanying with progressive learning and memory impairment. All clinical trials targeting Aβ as anti-AD therapy failed thus far suggests a requirement of research strategy shift toward understanding of AD pathogenesis and treatment of AD. Aβ is a cleavage product of amyloid precursor protein (APP) which has been given much focus in trying to understand the pathogenesis of AD. In comparison, APP is far less studied despite the fact that whether or not APP deficiency leads to the pathogenesis of AD remained largely unknown. The prospect of using adult neurogenesis therapy as a regenerative source for neural repair is very exciting. Though APP has been found to be involved in regulation of new neuron survival, the precise mechanism underlying APP regulation of adult neurogenesis, survival and integration into existing circuit remained largely unclear. Utilizing electrophysiology, molecular biology, immunofluorescent staining, optogenetics and behavior measurement, the proposed study aims to uncover the mechanisms underlying APP regulating intrinsic, morphological, synaptic and circuitry activities in the entorhinal cortex → dentate gyrus pathway. To the end of the study we will provide, not only the mechanism underlying APP regulation of new born neuron intrinsic properties and synaptic function, but also the experimental evidence showing a role of enhancing adult-born granular cell survival and function in the improvement of cognitive behavior.