MOLECULAR MECHANISMS UNDERLYING CELLULAR SENESCENCE IN ALZHEIMER'S DISEASE MICE

Cellular senescence is a hallmark of aging, which is the main risk factor for Alzheimer’s disease (AD). Previous studies have demonstrated increased levels of senescence markers in the brain during AD, suggesting that cellular senescence may play an important role in the disease. On the other hand, altered neuronal excitability and gene expression mediated by the transcription factor cAMP response element binding protein (CREB) and its co-activator CRTC1, have been identified during early pathological stages of Alzheimer’s disease. Our group recently identified several candidate CREB/CRTC1-target genes related to synaptic dysfunction and neuronal aging, suggesting that gene programs regulated by CREB/CRTC1 may play a major role in the regulation of both synaptic plasticity and aging. Here, we investigated the potential role of CREB-mediated transcription on the age-dependent expression of senescence markers and synaptic genes in the hippocampus APP/Tau mice, a model of AD neuropathology exhibiting age-dependent amyloidosis, tau pathology, and neurodegeneration. We detected increased expression of senescence markers and reduced levels of synaptic proteins in the hippocampus of APP/Tau mice, coinciding with altered expression of CREB-target genes. Histological analyses revealed that expression of senescence markers was highly restricted to microglial cells. Interestingly, modulation of CREB activity affected the expression of synaptic plasticity and senescence markers in vitro. These results suggest a common underlying pathway linking cellular senescence and synaptic dysfunction in AD through altered CREB/CRTC1-regulated transcription.