Lessons from two prevalent amyloidoses-what amylin and Aβ have in common

Abstract

The amyloidogenic peptide Aβ plays a key role in Alzheimer's disease (AD) forming insoluble aggregates in the brain. The peptide shares its amyloidogenic properties with amylin that forms aggregates in the pancreas of patients with Type 2 Diabetes mellitus (T2DM). While epidemiological studies establish a link between these two diseases, it is becoming increasingly clear that they also share biochemical features suggesting common pathogenic mechanisms. We discuss commonalities as to how Aβ and amylin deregulate the cellular proteome, how they impair mitochondrial functions, to which receptors they bind, aspects of their clearance and how therapeutic strategies exploit the commonalities between Aβ and amylin. We conclude that research into these two molecules is mutually beneficial for the treatment of AD and T2DM.

Keywords: ABAD; Alzheimer's disease; amylin; amyloid; diabetes; mitochondria; proteomics; vaccination.

Figure 1

Shared mode of toxicity of human amylin and Aβ42. (A) Alignment of the sequences of human (HA) and rat amylin (RA) and comparison to Aβ 42. Shading shows similarities in the rat and human amylin sequences while important similarities between HA and Aβ 42 are shown in red. (B) HA and Aβ 42 both bind to the amylin receptor that is composed of two molecules of CTR and one molecule of RAMP3. The small HA-derived peptide AC253 abrogates toxicity of both HA and Aβ 42 mediated via the amylin receptor.