Cellular senescence, inflammation, and cognition in aging and Alzheimer's disease: What's the connection?

Cellular senescence and inflammation may contribute to the pathogenesis of Alzheimer's disease (AD). We sought to define their inter-relationship in cell culture and animal models of AD and determine if senolytic compounds could alleviate these conditions thereby improving cognition.Male and female C57BL/6 mice received monthly oral treatment with fisetin (100 mg/kg BW), dasatinib+quercertin (D+Q; 5 mg/kg BW and 50 mg/kg BW, respectively), or vehicle control from 4 to 12 months of age followed by cognitive assessment with Morris water maze and novel object recognition. Hippocampal tissue from untreated 12 month old male AβPP/PS1 and C57BL/6 mice underwent RNA sequencing (RNAseq) to assess cellular senescence and inflammation. Primary neurons were treated with Aβ42 (10µM) and fisetin (15µM), dasatinib (1µM), quercetin (10µM), D+Q, or vehicle control. Cell viability, senescent cell burden, and cytokine profiles were assessed.Long-term memory in mice treated with senolytic compounds was improved in males, but not in females. RNAseq results revealed elevated senescent and inflammatory markers in the hippocampus of AβPP/PS1 mice compared to C57BL/6 mice. Preliminary cell culture data indicate that primary neurons receiving senolytic treatment tended to have decreased senescence and inflammatory markers compared to controls.Preliminary results support elevated cellular senescence and inflammation in the hippocampus of an AD mouse and treatment with senolytic compounds may improve cognition in a sex-dependent manner. Senolytic treatments in primary neuronal cultures appeared to reduce Aβ42 -related cellular senescence. Together, our results support that elimination of senescent cells and the corresponding inflammatory profile may be effective at treating impaired memory in AD. Supported by the National Institutes of Health (R01 AG057767, R01 AG061937), Center for Alzheimer's Research and trEatment (CARE), and the Kenneth Stark Endowment.