Islet Amyloid Polypeptide: A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease

Abstract

Diabetes affects hundreds of millions of patients worldwide. Despite the advances in understanding the disease and therapeutic options, it remains a leading cause of death and of comorbidities globally. Islet amyloid polypeptide (IAPP), or amylin, is a hormone produced by pancreatic β-cells. It contributes to the maintenance of glucose physiological levels namely by inhibiting insulin and glucagon secretion as well as controlling adiposity and satiation. IAPP is a highly amyloidogenic polypeptide forming intracellular aggregates and amyloid structures that are associated with β-cell death. Data also suggest the relevance of unprocessed IAPP forms as seeding for amyloid buildup. Besides the known consequences of hyperamylinemia in the pancreas, evidence has also pointed out that IAPP has a pathological role in cognitive function. More specifically, IAPP was shown to impair the blood-brain barrier; it was also seen to interact and co-deposit with amyloid beta peptide (Aß), and possibly with Tau, within the brain of Alzheimer's disease (AD) patients, thereby contributing to diabetes-associated dementia. In fact, it has been suggested that AD results from a metabolic dysfunction in the brain, leading to its proposed designation as type 3 diabetes. Here, we have first provided a brief perspective on the IAPP amyloidogenic process and its role in diabetes and AD. We have then discussed the potential interventions for modulating IAPP proteotoxicity that can be explored for therapeutics. Finally, we have proposed the concept of a "diabetes brain phenotype" hypothesis in AD, which may help design future IAPP-centered drug developmentstrategies against AD.

Link between Diabetes and Alzheimer’s Disease Due to the Shared Amyloid Aggregation and Deposition Involving Both Neurodegenerative Changes and Neurovascular Damages

“…It has binding sites in the brain, possibly contributing to the regulation of satiety and inhibition of gastric emptying, and has also been described as having effects on several other organs over time. IAPP has been identified due to its ability to aggregate in the amyloid deposits of pancreatic islets, which are seen primarily in association with type 2 diabetes in humans and diabetes in several other mammalian species, especially monkeys and cats [ 23 ]. At present, it is increasingly accepted that there are close correlations between these two diseases by overlapping their pathology, sharing common complications including impaired carbohydrate metabolism, insulin resistance, oxidative stress, inflammatory response, mitochondrial dysfunction, and amyloidosis ( Figure 2 ) [ 24 ].…”

Circulating miRNAs as a Predictive Biomarker of the Progression from Prediabetes to Diabetes: Outcomes of a 5-Year Prospective Observational Study

“…Deposits of aggregated IAPP are present in the pancreas of a great majority of T2DM patients, thus representing a histopathological hallmark of the disease [ 75 , 76 ]. Although IAPP has emerged as a novel player in T2DM pathology, the mechanisms of the intracellular accumulation of IAPP oligomers and IAPP-mediated toxicity in β-cells still remains unclear [ 77 ]. Another mechanism involved in T2DM progression is suggested to be nNOS signaling in neurons.…”

Pharmacological Treatment of Alzheimer’s Disease: Insights from Drosophila melanogaster

“…The data showed that resveratrol increased lifespan in Drosophila and further ameliorated MPTP-triggered cell death, histological alterations, behavioral deficits and accumulation of nitric oxide and hydrogen peroxide levels in flies. A brain histology test showed that MPTP induced partial loss of neurons in the cerebral hemisphere rescued by resveratrol treatment, which indicated that the neuroprotective effect of resveratrol can improve oxidative stress and inflammation in the brain [103]. As mentioned above, AD and diabetes mellitus (DM) often coexist in patients, but mechanisms associated with DM and AD are bewildering.…”