Primary Author: Wang, Junwei  

Additional Authors: Mousa, Youssef M.; Kaddoumi, Amal

Department/Division: Drug Discovery and Development, Harrison College of Pharmacy 

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that impairs mental ability development, interrupts cognitive functions, and causes dementia. Pre-existing type 2 diabetes (T2D) has been shown to significantly increase the risk of developing AD. One of the well-known characterizations of both AD and T2D is the presence of misfolded protein aggregate, which results in the formation of amyloid-β (Aβ) and human amylin (hAmylin) accumulates in AD and T2D, respectively. Several studies have shown that amylin is involved in AD pathogenesis by inducing neuroinflammation and cell apoptosis. To further study the mechanisms by which amylin exacerbates AD pathology, our lab has successfully shown that hAmylin and its synthetic analog pramlintide increased the Aβ production in AD mouse brains by inducing the amyloid-β precursor protein (APP) processing in lipid rafts. Lipid rafts are rich in gangliosides, and APP, BACE1, and each of the four core subunits of the γ-secretase complex are localized in lipid rafts. Gangliosides, which are synthesized by GalNac-T and several other glycosyltransferases, have been reported for their involvement in the pathogenesis of AD. In vivo findings from our lab support that hAmylin and pramlintide increase Aβ pathology by disrupting ganglioside synthesis. We have discovered that hAmylin and pramlintide significantly enhanced GalNac-T levels in the AD mouse brain by four-fold, which was associated with increased Aβ level and Aβ₄₂: Aβ₄₀ ratio, synaptic loss, and apoptosis.

Keywords: Alzheimer’s Disease, Amylin, Ganglioside