Affiliations: [a] Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
| [b] Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA
| [c] Paul F. Glenn Center for Biology of Aging Research, Mayo Clinic, Rochester, MN, USA
| [d] The Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA
| [e] Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA
Correspondence:
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Correspondence to: Darren J. Baker, Mayo Clinic, 200 1st ST SW, Rochester, MN 55905, USA. Tel.: +1 507 538 4097; E-mail: baker.darren@mayo.edu.
Abstract: Background:Cellular senescence has been associated with neurodegenerative disease and clearance of senescent cells using genetic or pharmaceutical strategies (senolytics) has demonstrated beneficial effects in mouse models investigating individual disease etiologies of Alzheimer’s disease (AD). However, it has remained unclear if senescent cell clearance in a mouse model exhibiting both plaque and tau pathologies modifies the disease state (3xTg). Objective:To investigate the effects of senescent cell clearance in the 3xTg mouse model. Methods:3xTg mice were treated with senolytics (ABT263 (navitoclax; NAVI), a combination of dasatinib and quercetin (D+Q)), or subjected to transgene-mediated removal of p16-expressing cells (via INK-ATTAC). Results:Senolytic treatments consistently reduced microgliosis and ameliorated both amyloid and tau pathology in 3xTg mice. Using RNA sequencing, we found evidence that synaptic dysfunction and neuroinflammation were attenuated with treatment. These beneficial effects were not observed with short-term senolytic treatment in mice with more advanced disease. Conclusions:Overall, our results further corroborate the beneficial effects senescent cell clearance could have on AD and highlight the importance of early intervention for the treatment of this debilitating disease.
