Cellular and Molecular Medial Temporal Lobe Pathology in Elderly PreMCI subjects

描述（由申请人提供）：到2050年，有认知能力下降和阿尔茨海默氏症（AD）风险的老年人预计将达到1300万，医疗保健费用将由个人、家庭和整个社会承担。本项目的动机来自我们对老年人轻度认知障碍（MCI）的神经生物学研究，部分来自当前的PPG。一个新兴的文献表明，改变内分泌/溶酶体（EL）蛋白甚至发生在形成的经典病理性AD病变，神经元缠结（NFT），微管相关蛋白，tau的聚合物组成。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，内皮细胞/溶酶体rab GTd 3基因与MCI中HPC CA 1神经元中的TrkB神经营养细胞存活受体基因一起失调。在这些发现的基础上，我们建议进行单细胞表达谱分析结合位点特异性tau抗体神经元标记，以测试在临床前AD中的乙醚EC或HF之前，在TEC层III NFT的进化过程中，选择rab GTPases基因表达是否在早期受到差异调节。我们将研究是否选择tau细胞骨架亚型和/或rabs与临床诊断，记忆测试的TEC/EC/HF连接体，神经病理学，神经元内的Ass沉积，载脂蛋白E基因型在临床前AD。此外，我们将确定认知功能下降之前EL改变的潜在机制。这种及时、新颖和强大的方法将改变我们对EL对临床前AD中MTL神经元脆弱性的贡献的理解。该项目为广泛的潜在干预措施奠定了基础，这些干预措施与目前正在研究的方法完全不同，并可能为痴呆症的早期诊断提供新的tau/EL生物标志物。

DESCRIPTION (provided by applicant): By 2050 older people at risk for cognitive decline and Alzheimer's (AD) are predicted to reach 13 million and health care costs are borne by individuals, their families, and society at large. This project is motivated from our studies of th neurobiology of mild cognitive impairment (MCI) in the elderly derived, in part, from the current PPG. A burgeoning literature suggests that alteration in endosmal/lysosomal (EL) proteins 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 endosmal/lysosomal rab GTPase genes are dysregulated in concert with the TrkB neurotrophic cell survival receptor gene 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 gene expression are differentially regulated early during the evolution of TEC layer III NFTs prior to ether EC or HF in preclinical AD, prior to cognitive decline. We will examine whether select tau cytoskeletal isoforms and/or rabs are related to clinical diagnosis, memory tests specific to the TEC/EC/HF connectome, neuropathology, intraneuronal Ass deposition, apolipoprotein E genotype in preclinical AD. In addition, we will determine the mechanism(s) underlying EL alterations prior to cognitive decline. This timely, novel and powerful approach will transform our understanding of the contributions of ELs 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 distinc from approaches currently under investigation and may suggest novel tau/EL biomarkers for the early diagnosis of dementia.