Sex-Dependent Changes in Alzheimer's Disease Pathogenesis: New Insights from a Sporadic Model

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A recent study published in Molecular Neurobiology has shed light on the potential role of sex in the development of Alzheimer's disease (AD). The research, conducted by a team of scientists from Federal University Rio Grande do Sul, explored the effects of the unfolded protein response (UPR) on AD pathogenesis, specifically focusing on sex-dependent changes in gene expression.

Key Takeaways:

  • The study used a sporadic model of AD induced by intracerebroventricularly-administered streptozotocin (STZ) in Wistar rats to evaluate potential modulations in proteins involved in the UPR and the dependence of alterations on the sex of the animals.
  • At 16 weeks post-STZ, cognitive deficit was observed in all rats treated with STZ, as well as an increase in glial fibrillary acid protein (GFAP), and a reduction in synaptophysin in the hippocampus.
  • However, at 4 weeks, cognitive deficit was found only in males, in association with a reduction in synaptophysin.
  • The study identified sex-dependent differences in the gene expression of OASIS (an ATF-6-like UPR sensor in astrocytes), calpastatin (inhibitor protein of calpain 1/2), calpain-10, calcineurin, sorcin, and CHOP.
  • The results contributed to the understanding of AD pathogenesis and indicated that the STZ-triggered UPR observed may be sex-dependent.

Statistics:

  • The study evaluated rats at two time points: 4 and 16 weeks post-STZ.
  • At 16 weeks, cognitive deficit was observed in 100% of rats treated with STZ, with a significant increase in GFAP and a reduction in synaptophysin.
  • At 4 weeks, cognitive deficit was found in 100% of males treated with STZ, with a significant reduction in synaptophysin.
  • The study identified sex-dependent differences in the gene expression of 6 proteins involved in the UPR.

Sources:

  • NewsRx. Studies from Federal University Rio Grande do Sul Further Understanding of Alzheimer Disease (Sex-dependent Changes In the Gene Expression of Upr-associated Calcium-binding Proteins In the Stz-induced Model of Alzheimer's Disease). Health & Medicine Week. June 13, 2025; p 6734.