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Basic Science and Pathogenesis.

Clémentine Puech1, Anjana Sadanand2, Neil Coleman2

  • 1University of Missouri, Columbia, MO, USA.

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Alzheimer's disease (AD) affects women more, potentially linked to sleep issues. APP signaling improved sleep and memory in a mouse model, with stronger effects seen in females, highlighting sex-specific brain health differences.

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Area of Science:

  • Neuroscience
  • Genetics
  • Molecular Biology

Background:

  • Alzheimer's disease (AD) disproportionately affects women over 65.
  • Sleep disturbances are an early AD indicator and risk factor, impairing amyloid-beta (Aβ) clearance.
  • The role of amyloid precursor protein (APP) intracellular signaling in sleep and AD remains unclear.

Purpose of the Study:

  • Investigate if the APP intracellular domain (mAICD) and its GαS signaling affect sleep and blood-brain barrier (BBB) integrity in the 5XFAD AD mouse model.
  • Determine sex-specific effects of mAICD signaling on cognitive function and BBB integrity.

Main Methods:

  • Adeno-associated virus (AAV) delivery of mAICD and a non-GαS interacting variant in neonatal 5XFAD mice.
  • Assessment of sleep patterns, cognitive behaviors, and BBB integrity in adult male and female mice.

Main Results:

  • APP-mediated signaling mitigated memory decline linked to sleep disturbances in 5XFAD mice.
  • Sex differences in cognitive performance emerged in 5XFAD mice, with better performance correlating with sleep in females.
  • Sleep measures and BBB integrity were correlated, particularly in female mice, indicating sex-dependent neurovascular impairment.

Conclusions:

  • APP signaling plays a significant role in restoring sleep and memory in an AD mouse model.
  • A strong link exists between cognitive performance and BBB leakage in female mice, suggesting sex-dependent neurovascular dysfunction.
  • Findings underscore the importance of APP signaling in AD pathogenesis and potential sex-specific therapeutic targets.