Functional Genomics of Brain Aging and Alzheimer’s Disease: Focus on Selective Neuronal Vulnerability

摘要

Abstract: Pivotal brain functions, such as neurotransmission, cognition, and memory, decline with advancing age and, nespecially, in neurodegenerative conditions associated with aging, such as Alzheimer’s disease (AD). Yet, deterioration in nstructure and function of the nervous system during aging or in AD is not uniform throughout the brain. Selective neu-nronal vulnerability (SNV) is a general but sometimes overlooked characteristic of brain aging and AD. There is little nknown at the molecular level to account for the phenomenon of SNV. Functional genomic analyses, through unbiased nwhole genome expression studies, could lead to new insights into a complex process such as SNV. Genomic data gener-nated using both human brain tissue and brains from animal models of aging and AD were analyzed in this review. Con-nvergent trends that have emerged from these data sets were considered in identifying possible molecular and cellular npathways involved in SNV. It appears that during normal brain aging and in AD, neurons vulnerable to injury or cell ndeath are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy nproduction. In AD, vulnerable neurons also exhibit down-regulation of genes related to synaptic neurotransmission and nvesicular transport, cytoskeletal structure and function, and neurotrophic factor activity. A prominent category of genes nthat are up-regulated in AD are those related to inflammatory response and some components of calcium signaling. These ngenomic differences between sensitive and resistant neurons can now be used to explore the molecular underpinnings of npreviously suggested mechanisms of cell injury in aging and AD.