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      Senolytics in a Model of Alzheimer's Disease

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      Innovation in Aging
      Oxford University Press

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          Abstract

          The therapeutic effects of senescent cell killing with senolytics in neurodegeneration mouse models poise this strategy as an intervention candidate for Alzheimer’s Disease (AD). However, it is unclear whether senolytic therapies for AD are translatable to human cells. To determine whether senolytics could be a viable therapeutic for AD, we have treated long-term mixed human neuron/astrocyte primary cultures with amyloid beta oligomers (ABO), which we have shown to induce a phenotype consistent with senescence in neurons. Fifteen days after ABO treatment, we administered Navitoclax (Nav) and the natural killer cell-line NK92, which are known to selectively kill senescent cells in the periphery. Following treatment, we assessed senescence markers in our cultures as well as senescent cell killing selectivity through cleaved Caspase 3 quantification. Our preliminary data show that Nav (8, 4, and 0.5uM) kills both control and ABO treated cells. NK92 cells (10 to 1 effector to target ratio) also kill some control cells, suggesting there is not a clear cut mechanism by which NK92 cells can distinguish senescent from non-senescent neurons or astrocytes. Although analysis of selective killing is ongoing, off-target killing indicates that we need more refined senolytic strategies to implement their safe human use.

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          Author and article information

          Journal
          Innov Aging
          Innov Aging
          innovateage
          Innovation in Aging
          Oxford University Press (US )
          2399-5300
          2021
          17 December 2021
          17 December 2021
          : 5
          : Suppl 1 , Program Abstracts from The GSA 2021 Annual Scientific Meeting, “Disruption to Transformation: Aging in the “New Normal””
          : 640
          Affiliations
          Buck Institute for Research on Aging , Novato, California, United States
          Article
          igab046.2414
          10.1093/geroni/igab046.2414
          8681099
          03bedefc-40ab-439d-a82f-6e9d21c9d6b9
          © The Author(s) 2021. Published by Oxford University Press on behalf of The Gerontological Society of America.

          This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

          History
          Page count
          Pages: 1
          Categories
          Abstracts
          Session 9055 (Poster)
          Alzheimer’s Disease and the Brain
          AcademicSubjects/SOC02600

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