Cellular and Molecular Medial Temporal Lobe Pathology in Elderly PreMCI subjects

到2050年，预计有认知能力下降风险的老年人将达到1300万，医疗保健费用将由个人、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，该神经元记忆回路在老年人认知衰退开始之前以高度可预测的区域到区域模式退化。越来越多的文献表明，内分泌/溶酶体（E-L）功能障碍甚至在经典病理性AD病变（由微管相关蛋白tau的聚合物组成的神经元缠结（NFT））形成之前就已发生。NFT首先发生在经内嗅皮层（TEC）中，然后扩散到内嗅皮层（EC）第II层，然后扩散到MTL的海马结构（HF）CA 1神经元。我们的小组已经表明，E-L rab GTd 3基因在MCI的HPC CA 1神经元中失调。在这些发现的基础上，我们建议进行单细胞表达谱结合位点特异性tau抗体神经元标记，以测试是否选择rab GTP酶差异调节早期TEC层III NFT的演变过程中，醚EC或HF之前的认知能力下降。我们将研究是否选择tau细胞骨架亚型和/或rab表达与临床诊断，记忆测试特定的MTL连接体，淀粉样蛋白和载脂蛋白E基因型在临床前AD。该项目将表征病理学如何在mRNA表达水平上改变神经元环境，并提供有关在痴呆临床发作前驱动MTL变性的分子发病机制的新信息。这种及时、新颖和强大的方法将改变我们对E-L表达对临床前AD中MTL神经元脆弱性的贡献的理解。该项目处于有利地位，可以为真正不同于目前正在调查的方法的广泛的潜在干预措施奠定基础。此外，获得的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学在MTL神经元的脆弱性中发挥的作用的新信息可以提供一组靶标以更好地告知基于CSF tau的痴呆发作筛查。

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.