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Basic Science and Pathogenesis.

Dylan Finneran1, Briana G Jackman1, Taylor Desjarlais1

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Area of Science:

  • Neuroscience
  • Cellular Biology
  • Aging Research

Background:

  • Aging is a primary risk factor for Alzheimer's disease (AD).
  • Cellular senescence, the accumulation of senescent cells, is associated with AD pathology.
  • The causal role of senescent cells in AD progression remains unclear.

Purpose of the Study:

  • To investigate the impact of astrocyte-specific cellular senescence on AD-like pathology and behavior.
  • To determine if over-expressing Cdkn2a in astrocytes influences tauopathy progression in mice.

Main Methods:

  • Developed astrocyte-specific adeno-associated virus (AAV) vectors to over-express Cdkn2a transcripts.
  • Injected vectors into the brains of nontransgenic and PS19 tauopathy mice.
  • Assessed behavioral changes and tissue pathology after four months.

Main Results:

  • Tauopathy affected affective behaviors, but Cdkn2a over-expression had no significant impact.
  • Cdkn2a over-expression in PS19 mice significantly improved pre-pulse inhibition.
  • No significant effects of Cdkn2a over-expression on learning, memory, or brain mass were observed.

Conclusions:

  • Astrocyte-specific Cdkn2a over-expression has minimal behavioral effects in normal mice.
  • In tauopathy models, Cdkn2a over-expression selectively improved auditory startle response but not other behaviors or cognition.