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

ABSTRACT: A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-? (A?) peptide. Several studies linked AD with type 2 diabetes due to similarities between A? and human amylin. This study investigates the effect of amylin and pramlintide on A? pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased A? burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased A? production by modulating amyloid precursor protein (APP) and ?-secretase levels in lipid rafts. In addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. Increased brain A? burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase A? levels and related pathology in TgSwDI mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.

SUBMITTER: Mousa YM 

PROVIDER: S-EPMC7048857 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature