Li, Jiangtao2024-12-202024-12-202024-12-19vt_gsexam:42042https://hdl.handle.net/10919/123847Alzheimer's disease (AD), the most prevalent age-related neurodegenerative disorder, is defined by the pathological accumulation of amyloid-β (Aβ) peptides, neurofibrillary tangles (NFTs), neuronal loss, and the activation of astrocytes and microglia. One of the early indicators of AD is a global reduction in cerebral blood flow (CBF), which precedes significant plaque formation and cognitive decline. This persistent decrease in CBF, along with diminished oxygen and glucose delivery to the brain, is thought to contribute to neurodegeneration, although the underlying mechanisms remain unclear. Astrocytes, critical regulators of both Aβ clearance and CBF, have garnered increasing attention in AD research. Astrocytes, one of the most abundant cell types in the central nervous system, play a vital role in maintaining overall brain health and function. In AD, astrocytes express key AD-related genes, including APP, PSEN1, PSEN2, and APOE. While astrocyte gene expression alterations have been observed, the relationship between these transcriptomic changes, protein expression, and cellular function requires further investigation. This dissertation examines astrocyte and vascular changes in AD using a well-described preclinical AD mouse model: hAPPJ20 mice. First, a multi-omics analysis of cortical astrocyte gene and protein expression was conducted at 3, 6, 12, and 18 months in female J20 and wild-type (WT) mice, revealing significant gene and protein expression differences linked to normal aging and AD progression. Several overlapping gene-protein pairs were identified as potential biomarkers for AD treatment and diagnosis. Gene Ontology analysis highlighted enriched pathways related to inflammation, disrupted metabolism, and vascular dysfunction starting at 6 months. Additionally, pathway analysis revealed apoptotic pathways were enriched in astrocytes isolated from diseased tissue. Further analysis revealed for the first time that astrocytes significantly decline by 12 months in the cortex and hippocampus of J20 AD-disease mice. Nest, we explored vascular network remodeling and amyloid-β (Aβ) accumulation in this same model. In male J20 mice, 40% of the total pial arterial Aβ accumulation was found in the meningeal vascular network by 12 months, while females showed around 20%. Aβ deposition was associated with increased vessel diameter and tortuosity of pial collateral vessels. AD mice also exhibited reduced blood flow in the cortical meningeal arteries and significant enlargement of pial collateral vessels compared to wild-type mice.ETDenIn CopyrightAstrocytevascularAlzheimer's diseasetranscriptomeproteomeDissertation