Abstract
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 (Aß). 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 Aß 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 Aß 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.