Cellular and Molecular Medial Temporal Lobe Pathology in Elderly PreMCI subjects

描述（由申请人提供）：到2050年，预计有认知能力下降风险的老年人将达到1300万，医疗费用将由个人、家庭和整个社会承担。该项目的总体目标是确定内侧颞叶（MTL）内神经元记忆回路断开的最早细胞和分子变化，内侧颞叶（MTL）在老年人认知能力下降之前就开始以高度可预测的区域到区域的模式退化。越来越多的文献表明，即使在典型的AD病理性病变形成之前，由微管相关蛋白tau聚合物组成的神经原纤维缠结（NFT）也会发生内膜/溶酶体（E-L）功能障碍。nft首先发生在鼻内嗅皮层（TEC），然后扩散到鼻内嗅皮层（EC）第二层，然后扩散到MTL的海马形成（HF） CA1神经元。我们的研究表明，MCI患者的HPC CA1神经元中E-L rab GTPase基因表达异常。基于这些发现，我们建议将单细胞表达谱与位点特异性tau抗体神经元标记相结合，以测试在TEC III层nft进化的早期，在EC或HF之前的认知能力下降之前，选择的兔gtpase是否受到差异调节。我们将研究选择的tau细胞骨架亚型和/或rab表达是否与临床前AD的临床诊断、MTL连接组特异性记忆测试、淀粉样蛋白和载脂蛋白E基因型相关。该项目将描述病理如何在mRNA表达水平上改变神经元环境，并提供在痴呆症临床发病前驱动MTL变性分子发病机制的复杂机制的新信息。这种及时、新颖、有力的方法将改变我们对E-L表达对临床前AD MTL神经元易感性的贡献的理解。该项目将为一系列潜在的干预措施奠定基础，这些干预措施与目前正在研究的方法截然不同。此外，关于神经元内位点特异性tau表位、E-L活化和淀粉样蛋白病理在MTL神经元易感性中所起作用的新信息可能提供一组靶点，以更好地为基于CSF tau的痴呆发病筛查提供信息。

DESCRIPTION (provided by applicant): By 2050 older people at risk for cognitive decline are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. The overall goal of the proposed project is determine the earliest cellular and molecular changes underlying the disconnection of the neuronal memory circuit within the medial temporal lobe (MTL), which degenerates in a highly predictable region-to-region pattern beginning prior to the onset of cognitive decline in the elderly. A growing literature implicated endosmal/lysosomal (E-L) dysfunction occur even before the formation of the classic pathologic AD lesion, the neurofibrillary tangle (NFT), composed of polymers of the microtubule-associated protein, tau. NFTs occur first in the transentorhinal cortex (TEC) then spread to the entorhinal cortex (EC) layer II and then to the hippocampal formation (HF) CA1 neurons of the MTL. Our group has shown that E-L rab GTPase genes are dysregulated in HPC CA1 neurons in MCI. Building on these findings, we propose to perform single cell expression profiling combined with site specific tau antibody neuronal labeling to test whether select rab GTPases are differentially regulated early during the evolution of TEC layer III NFTs prior to ether EC or HF prior to cognitive decline. We will examine whether select tau cytoskeletal isoforms and/or rab expression correlate with clinical diagnosis, memory tests specific to the MTL connectome, amyloid and apolipoprotein E genotype in preclinical AD. The project will characterize how pathology alters the neuronal environment at the mRNA expression level and provide new information on the complex mechanism(s) driving the molecular pathogenesis underlying MTL degeneration before clinical onset of dementia. This timely, novel and powerful approach will transform our understanding of the contributions of E-L expression to the vulnerability of MTL neurons in preclinical AD. The project is well positioned to lay the groundwork for a wide range of potential interventions that are truly distinct from approaches currently under investigation. I addition, the novel information gained about role that intraneuronal site-specific tau epitopes, E-L activation and amyloid pathology play in the vulnerability of MTL neurons may provide a panel of targets to better inform CSF tau based screening for dementia onset.