Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

Abstract

G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer’s disease (AD) pathogenesis. However, because GPCRs include a large family of membrane receptors, it is unclear which specific GPCR or pathway with rational ligands can become effective therapeutic targets for AD. Amylin receptor (AmR) is a GPCR that mediates several activities, such as improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reactions and potentially enhancing neural regeneration. Recent studies show that peripheral treatments with amylin or its clinical analog, pramlintide, reduced several components of AD pathology, including amyloid plaques, tauopathy, neuroinflammation and other components in the brain, corresponding with improved learning and memory in AD mouse models. Because amylin shares a similar secondary structure with amyloid-β peptide (Aβ), I propose that the AmR/GPCR pathway is disturbed by a large amount of Aβ in the AD brain, leading to tau phosphorylation, neuroinflammation and neuronal death in the pathological cascade. Amylin-type peptides, readily crossing the blood brain barrier (BBB), are the rational ligands to enhance this GPCR pathway and may exhibit utility as novel therapeutic agents for treating AD.

Activation of amylin receptors attenuates alcohol‐mediated behaviours in rodents

“…In support for a role of amylin receptor activation in memory processes are the data showing that peripherally administered amylin enhances memory in mice under training conditions in a T-maze paradigm (Flood & Morley 1992;Flood et al 1995). More recent studies show that long-term peripheral amylin treatment enriched learning and memory in mouse models of Alzheimer's disease (Zhu et al 2015;Qiu 2017;Zhu et al 2017), suggesting amylin receptors as a drug target for potential treatment of the disease (Qiu 2017). Moreover, a human study showed a positive correlation of plasma amylin and improved cognitive function in elderly population, suggesting a defensive role of amylin receptors against cognitive inclination (Qiu et al 2014).…”

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

“…1A). Moreover, neither amylin nor pramlintide treatment showed significant changes in the level of insoluble Aβ 40 , but both showed significant increase in insoluble Aβ 42 compared to control (p < 0.01; Fig. 1B).…”

“…1B). Furthermore, amylin significantly increased oligomeric Aβ 40 compared to control and pramlintide (p < 0.01 and p < 0.05, respectively); however, neither treatment altered oligomeric Aβ 42 (Fig. 1C).…”

“…1C). Total Aβ 40 and Aβ 42 from total protein fraction were also measured following direct extraction with 70% formic acid; as shown in Fig. 1D, amylin significantly increased total levels of Aβ 42 only (p < 0.001), while pramlintide increased both Aβ 40 (p < 0.05) and Aβ 42 (p < 0.001) when compared to control group.…”

“…Effect of amylin and pramlintide treatments on Aβ burden in TgSwDI mice brains. (A) Using ELISA to quantify the different forms of Aβ, amylin increased the level of soluble Aβ 40 and Aβ 42 compared to control and pramlintide, whereas pramlintide increased the level of soluble Aβ 42 compared to control group. (B) Both peptides showed significant increase of insoluble Aβ 42 compared to control when measured by ELISA; however, none of the treatments changed the level of insoluble Aβ 40 (C) Amylin significantly increased oligomeric Aβ 40 compared to control and pramlintide, but neither treatment altered the oligomeric Aβ 42 .…”