Cellular and Molecular Medial Temporal Lobe Pathology in Elderly PreMCI subjects

描述(申请人提供)：到2050年，有认知衰退和阿尔茨海默氏症(AD)风险的老年人预计将达到1300万，医疗费用由个人、他们的家庭和整个社会承担。这个项目的动机是我们对老年人轻度认知障碍(MCI)的神经生物学研究，部分源于目前的PPG。一篇新兴的文献表明，内膜/溶酶体(EL)蛋白的改变甚至在经典的病理性AD病变-神经纤维缠结(NFT)形成之前就已经发生了，神经纤维缠结(NFT)由微管相关蛋白tau的聚合物组成。NFTs首先出现在经嗅觉皮质(TEC)，然后扩散到内嗅皮层(EC)II层，然后扩散到MTL的海马结构(HF)CA1神经元。我们的研究小组已经发现，在MCI的HPC CA1神经元中，内膜/溶酶体Rab GTPase基因与TrkB神经营养细胞生存受体基因一起调控失调。基于这些发现，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，以测试在认知功能下降之前，在临床前AD的TEC Layer III NFTs的演变过程中，部分Rab GTP酶基因的表达是否在TEC Layer III NFTs的进化早期受到差异调控。我们将研究是否选择tau细胞骨架异构体和/或RAB与临床前AD的临床诊断、TEC/EC/HF连接体的特异性记忆测试、神经病理学、神经元内Ass沉积、载脂蛋白E基因型有关。此外，我们还将确定认知衰退前EL改变的机制(S)。这一及时、新颖和强大的方法将改变我们对ELS在临床前AD中MTL神经元脆弱性中的作用的理解。该项目处于有利地位，为一系列潜在的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真正不同，并可能为痴呆的早期诊断提出新的tau/EL生物标记物。

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.