Mechanisms of TIMP2-mediated hippocampal revitalization in Alzheimer's disease

项目摘要/摘要：鉴于衰老是许多神经系统疾病的主要危险因素，

Project Summary/Abstract: Given that aging is the major risk factor for many neurological disorders, including devastating diseases for which there is no cure like Alzheimer’s disease, novel approaches are needed to confront the growing epidemic. Many studies have shown that factors present within the systemic environment regulate markers of brain aging in a bidirectional (young or old) fashion, which led me to search for specific protein activities that could mediate key phenotypes. One such factor we have focused on in our funded parent grant is tissue inhibitor of metalloproteinases 2 (TIMP2), which we have shown is sufficient to improve learning and memory and is a key component of very young human plasma for mediating improved hippocampal function. Moreover, several studies implicate TIMP2 in relation to risk for Alzheimer’s disease, though the mechanism underlying this relationship (e.g., amyloid-dependent vs. amyloid-independent processes) remains unclear. We demonstrate that expression of TIMP2 is critical for cellular homeostasis and function within the hippocampus, including within glia and for the process of adult neurogenesis. Differential gene expression data in mice lacking TIMP2 indicate that various cellular processes in neural cells are disrupted. We hypothesize that specific aspects of intercellular communication among cells of the hippocampal microenvironment is regulated by TIMP2 and in a manner that regulates Alzheimer’s disease pathology, a finding that may be dependent on the source of TIMP2. We will address this hypothesis in 2 aims: (1) To address the cell type-specific regulation of TIMP2 within the hippocampus via snRNAseq and the impact of the source of its expression on cellular interactions. (2) To address the cell type-specific regulation of TIMP2 within the hippocampus in the context of amyloid and associated AD pathology in APP-knockin mice via snRNAseq and the impact of the source of its expression on cellular interactions. These aims will examine regulation of the CNS cellular microenvironment by TIMP2, which may have implications for development of novel AD therapies.