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Area of Science:

  • Neuroscience
  • Biochemistry
  • Pathology

Background:

  • Alzheimer's disease (AD) is characterized by amyloid precursor protein (APP) processing, producing amyloid-beta (Aβ) peptides.
  • AD disproportionately affects biological females, particularly postmenopausal women, prompting investigation into sex-based differences in AD pathology.
  • Previous animal studies suggest cognitive decline and altered BACE1 activity in female models, but direct human comparisons are lacking.

Purpose of the Study:

  • To examine sex differences in brain markers associated with APP processing in human Alzheimer's disease (AD) and non-diseased brains.
  • To compare APP processing pathways, including enzyme activities and protein levels, between biological males and females with and without AD.

Main Methods:

  • Hippocampal brain samples from non-diseased individuals and AD patients (both sexes) were analyzed.
  • Western blots were used to quantify levels of APP, processing markers (sAPPα, sAPPβ, BACE1, ADAM10), and mediators (proBDNF, matBDNF).
  • Enzyme activity assays were performed for BACE1 and ADAM10.

Main Results:

  • AD samples exhibited lower ADAM10 content and a reduced sAPPα:sAPPβ ratio compared to non-diseased samples.
  • AD samples showed increased BACE1 activity and higher pro-Brain-Derived Neurotrophic Factor (proBDNF) content.
  • No significant differences in APP processing markers or enzyme activities were observed between biological males and females in either group.

Conclusions:

  • Significant differences in APP processing markers exist between AD and non-diseased human brain samples.
  • Contrary to hypothesis, this study found no significant sex differences in key APP processing markers or enzyme activities.
  • These findings highlight the complexity of AD pathology and suggest further research is needed to understand sex-based prevalence disparities.