Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease

摘要: Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that accumulation of Aβ in brains subjects with Alzheimer's disease (AD) might compete for binding to receptor (AmR). If true, adding exogenous type peptides would reduce AD pathological cascade, improving cognition. Here report a 10-week course peripheral treatment human significantly reduced multiple different markers associated pathology, including reducing levels phospho-tau, insoluble tau, two inflammatory (Iba1 CD68), as well cerebral Aβ. also led improvements learning memory mouse models. Mechanistic studies showed antagonist successfully antagonized some protective effects in vivo, suggesting require interaction its cognate receptor. Comparison signaling cascades emanating from AmR suggest electively suppresses activation CDK5 pathway by Treatment dependent manner, dramatically decreasing p25, active form corresponding reduction tau phosphorylation. This first documenting ability tauopathy inflammation animal models AD. The data clinical analog amylin, pramlintide, exhibit utility therapeutic agent other neurodegenerative diseases.