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Basic Science and Pathogenesis.

Josh Krivinko1, Susan Erickson1, Akayla Lewin1

  • 1University of Pittsburgh, Pittsburgh, PA, USA.

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Age-dependent dendritic spine loss in HET3 mice mirrors human aging, suggesting this model can test therapies to enhance cognitive resilience against Alzheimer's disease (ADRD) pathologies.

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Area of Science:

  • Neuroscience
  • Aging Research
  • Alzheimer's Disease and Related Dementias (ADRD) Research

Background:

  • Age-dependent dendritic spine loss is linked to cognitive decline in Alzheimer's disease and related dementias (ADRD).
  • Slowing spine loss during aging may enhance resilience to cognitive decline.
  • Repurposed drugs identified in human studies may reverse age-dependent spine loss proteomes.

Purpose of the Study:

  • Evaluate the HET3 mouse as a preclinical model for age-dependent spine loss.
  • Assess HET3 mice for associated proteome alterations and cognitive deficits.
  • Validate HET3 mice for testing anti-aging therapies against cognitive decline.

Main Methods:

  • Male HET3 mice (6 and 21 months) were used.
  • Cerebral cortices were analyzed for proteomic changes using liquid chromatography/mass spectrometry.
  • Dendritic spine densities in retrosplenial cortex (RSC) were quantified via immunohistochemistry/confocal microscopy.

Main Results:

  • HET3 mice showed a significant reduction in RSC spine density with age (7.8% decrease).
  • This age-related spine loss magnitude is comparable to human postmortem studies.
  • Proteome signatures of aging and cognitive deficits in HET3 mice will be presented.

Conclusions:

  • The HET3 mouse demonstrates face validity as a model for age-dependent spine loss.
  • This model may be suitable for preclinical testing of interventions.
  • Further studies with larger sample sizes are needed to confirm findings in both sexes.