阿尔茨海默病（AD）发病机制不清。β淀粉样蛋白（Aβ）聚集被认为是发病关键因素，但以Aβ为靶点的新药研发屡屡失败。我们发现：在AD转基因小鼠症状前期，Aβ在海马CA1锥体神经元内聚集最显著，但Aβ产生的限速酶BACE1却在CA1的突触前CA3区高表达；同时CA1锥体神经元过度放电、海马突触传递效能降低、抑制性突触后电流幅度降低、突触后受体亚基在突触小体的定位减少。提示Aβ产生与突触传递密切相关。本研究基于我们的独特资源BACE1条件敲除／敲进兼报告基因小鼠，拟采用行为学、形态学、电生理、光遗传及在体药理学方法验证我们提出的科学假说：AD病程早期，CA1锥体神经元内Aβ的大量产生和聚集依赖于突触前机制；Aβ在CA1锥体神经元内聚集阻止突触后膜受体膜转运，造成AD病程早期CA1锥体神经元异常放电及海马环路突触传递效能降低。为基于神经网络调控，以BACE1为靶点研发新药精准治疗AD提供理论依据。

The mechanism of Alzheimer’s disease (AD) is unclear and there is no effective treatment. Extracellular Aβ aggregates was considered playing a main causative role in the pathogenesis of AD. However, therapeutic strategies based on the Aβ hypothesis have failed repeatedly in clinical trials. Recently, we found that Aβ accumulated obviously in CA1 pyramidal neurons, while BACE1, the limiting enzyme of Aβ production, was highly expressed in CA3, that is the presynaptic region for CA1 at the presymptomatic stage of an AD transgenic mouse model (5XFAD). Meanwhile, hyperactivity of CA1 pyramidal neuron, hippocampal synaptic transmission decline, decreased amplitude of inhibitory postsynaptic current, reduced location of postsynaptic receptor subunits in synaptosomes have been found in hippocampus of the 5XFAD mice. Here, we set out to test our hypothesis that Aβ production in CA1 pyramidal neurons depends on presynaptic mechanism in the early stage of AD, and the aggregated Aβ may trap postsynaptic membrane receptor subunits and prevent the membrane transport of these receptors, which results in abnormal discharge of CA1 pyramidal neurons and the decline of synaptic transmission in hippocampal circuit in the early AD-like pathological process. We will use our BACE1 conditional knock-out or BACE1 conditional knock-in mouse carrying fluorescent protein reporter gene with behavioral, electrophysiological, morphological, photogenetic and pharmacological in vivo methods to perform the proposed study. The research will provide more accurate theoretical basis for the development of new AD therapeutics.