阿尔茨海默病（AD）是最常见的痴呆，发病机制不清。BACE1作为Aβ产生的限速酶，促进了AD的发生。但其独立于Aβ调节突触功能及在AD病程早期的作用尚属未知。本课题组前期发现BACE1与AMPA受体亚基GluR2存在相互作用，在野生型鼠脑内，BACE1在突触囊泡内的表达量升高，GluR2更多定位于突触体，但在AD转基因鼠脑内突触囊泡内BACE1减少，同时GluR2内化。本项目在前期工作基础上，拟采用电生理、生化、形态学、行为学及遗传学等方法，首先以BACE1敲除小鼠为研究对象揭示BACE1对GluR2介导的AMPA受体功能的调节作用；在神经元细胞突触分隔培养系统中明确BACE1对AMPA受体调节的机制；进而用我们自己设计并已建成的新型BACE1条件性表达小鼠在体控制内源性BACE1表达，最终确定BACE1的重要生理功能及其在早期AD病程中的作用。将为揭示AD早期发病机制提供新的理论基础。

Alzheimer’s disease (AD) is the most common form of dementia among the elderly. BACE1, the rate limiting enzyme for amyloid (Aβ) production, is considered central to the pathogenesis of AD. However, the role of BACE1 in regulation of synaptic functions and in early-stage of AD independent of Aβ production effect is still unclear. Our previous findings demonstrated that BACE1 interacted with AMPA receptor GluR2 subunit, and cytosolic BACE1 protein levels in synapses were decreased in AD transgenic mice compared to wild type mice at 1.5-month of age, accompanied with much lower levels of membrane-associated GluR2 protein in synapses of AD transgenic mice than that of wild type mice. The internalization of GluR2 was enhanced when BACE1 located in synaptic vesicles was decreased in AD transgenic mouse brain. Based on these observations, we propose that BACE1 may be a functional regulator of GluR2-containing AMPA receptors at the post-synaptic membrane and this role would be suppressed due to the requirement of Aβ overproduction during the very early stage of AD-like progression. In our proposed studies, we will first to determine whether BACE1 regulates the functions of GluR2-containing AMPA receptors by using BACE1 knockout mice with electrophysiological, morphological, biochemical methods, and how the function and location of GluR2 at post-synaptic membrane could be changed by BACE1 directly in the primary neuronal culture derived from the hippocampus of BACE1 knockout mice. Furthermore, we will utilize the new conditional BACE1 expression mouse model to elucidate the exact roles of endogenous BACE1 in regulation of synaptic function and early mechanism of AD-like pathology in vivo. The project will advance our understanding of early mechanistic underpinnings of AD pathology.