Alzheimer's disease (AD) is the most common form of dementia and currently has no cure. Aging is the major risk factor for AD, however little research has been done to understand the mechanisms that link aging with this pathology. Our long-term goal is to promote the preservation of cognitive function during AD by understanding mechanisms underlying the transition from healthy brain aging to pathological AD brain. Cellular senescence is a hallmark of aging that may influence age-related dysfunctions including the neurocognitive impairment observed in AD patients. Our studies indicate that human astrocytes activate the senescence program in response to oxidative stress, exhaustive replication and beta amyloid (A?). We have also reported induction of astrocyte senescence during AD. We have evidence that senescent astrocytes exhibit profound changes in gene expression including the loss of brain-expressed transcripts and a gain in pro-inflammatory genes, suggesting loss of differentiated function. Loss of function and/or the gain of inflammatory function may have profound implications for the brain microenvironment and the potential to impact virtually every CNS cell type. We propose that such dysfunction may be involved in aspects of AD such as A? deposition and inflammation. In addition to astrocytes, emergent evidence demonstrates a senescence- like phenotype in other CNS cells. Our studies show that HIV-1 infection triggers microglia senescence. This agrees with our analysis of aged human brain tissues revealing the presence of dystrophic microglia in AD, and our in vitro studies showing that microglia undergo telomere shortening, with reduced phagocytic and migratory capacities. Moreover, although senescence has historically been associated with proliferating cells, we have also evidence that neurons express senescence-like markers in the temporal lobe and frontal cortex of AD brain; in concordance with reports demonstrating increase in markers of senescence in neurons during normal aging of rodents. The objective of this proposal is to define the role of CNS senescence in AD. Our central hypothesis is that either a cell-intrinsic loss of function or the acquisition of detrimental neuroinflammatory function(s) in senescent cells could have profound consequences for the aging CNS and for onset of AD pathogenesis. We plan to evaluate the following specific aims: 1) Perform a comprehensive analysis of the senescence program in the AD brain. 2) Determine the relationship between cellular senescence and hallmarks of AD. 3) Evaluate the effects of modulation of senescence in an AD mouse model. The rationale for the proposed research is partly based on the recent demonstration that senescence can propagate between cells via paracrine mechanisms. Thus, the inflammatory environment created by senescent astrocytes in the aged brain may lead to senescence of neighboring cells in a feed-forward mechanism involving neurons, astrocytes, and microglia, contributing to cellular dysfunction and neurocognitive decline in AD. Factors such as A? deposition and neuronal tangle formation may exacerbate this process by accelerating the appearance of senescent cells. This suggests that interventions that inhibit senescence, such as rapamycin, or those that eliminate senescent cells, such as senolytic drugs may be relevant. Our studies are novel because cellular senescence in the brain is a recent observation, and is thus currently understudied. They are relevant because they may point to new ways to prevent and treat AD by intervening with cellular senescence in the brain.
Aging is the major risk factor and driving force for sporadic Alzheimer's disease (AD). The demonstration that senescent cells accumulate with age and Alzheimer's disease and that these cells lose functionality create a new paradigm to explain AD events such amyloid plaque, neurofibrillary tangles and inflammation. These studies will ultimately enhance our understanding of the role of aging and cellular senescence in AD and will lead the way toward functional interventions directed to delay cellular senescence in the AD brain.
