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Updated: Dec 27, 2025

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Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts

Youssef M Mousa1, Ihab M Abdallah1, Misako Hwang2

  • 1Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, USA.

Scientific Reports
|March 1, 2020
PubMed

Insights

Amylin and pramlintide, peptides linked to type 2 diabetes, worsen Alzheimer's disease (AD) pathology by increasing amyloid-beta (Aβ) burden in the brain. This suggests elevated amylin or pramlintide use may heighten AD risk.

Area of Science:

  • Neuroscience
  • Biochemistry
  • Endocrinology

Background:

  • Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) peptide accumulation.
  • Similarities between Aβ and human amylin have suggested a link between AD and type 2 diabetes.

Purpose of the Study:

  • To investigate the effects of amylin and pramlintide on Aβ pathogenesis in a mouse model of cerebral amyloid angiopathy (CAA) and AD.
  • To elucidate the molecular mechanisms underlying these effects.

Main Methods:

  • TgSwDI mice, an AD and CAA model, received daily intraperitoneal injections of amylin or pramlintide for 30 days.
  • Brain Aβ burden, amyloidogenic pathway modulation (APP, γ-secretase), ganglioside levels (GM1, GM2), and neuropathological markers (synaptic loss, apoptosis, microglia activation) were assessed.

Main Results:

  • Amylin and pramlintide treatments significantly increased Aβ burden in mouse brains.
  • Both peptides altered the amyloidogenic pathway by modulating amyloid precursor protein (APP) and γ-secretase levels within lipid rafts.
  • Increased GM1 and GM2 ganglioside levels were observed, correlating with altered amyloidogenic pathway proteins and contributing to increased Aβ burden, synaptic loss, apoptosis, and microglia activation.

Conclusions:

  • Amylin and pramlintide administration exacerbate Aβ pathology and associated neuropathological changes in TgSwDI mice.
  • These findings suggest that elevated amylin levels or therapeutic use of pramlintide could potentially increase the risk of developing Alzheimer's disease.

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