TY - JOUR
T1 - Islet Amyloid Polypeptide
T2 - A Partner in Crime With Aβ in the Pathology of Alzheimer's Disease
AU - Raimundo, Ana F.
AU - Ferreira, Sofia
AU - Martins, Ivo C.
AU - Menezes, Regina
N1 - We acknowledge iNOVA4Health—UID/Multi/04462/2019, a program financially supported by Fundação para a Ciência e Tecnologia/Ministério da Educação e Ciência, through national funds and co-funded by FEDER under the PT2020 Partnership Agreement. Funding from the INTERFACE Programme, through the Innovation, Technology and Circular Economy Fund (FITEC) is gratefully acknowledged. This study was also supported by FCT via PTDC/BIA-MOL31104/2017 and UID/Multi/04462/2019-SubProj iNOVA4Health 44 to RM and PD/BD/135504/2018 to AR. Sociedade Portuguesa de Diabetologia for the Nuno Castelo-Branco Prize−2016, attributed to RM, was also acknowledged. IM acknowledges FCT-MCTES Program Concurso de Estímulo ao Emprego Científico (CEECIND/01670/2017).
PY - 2020/3/20
Y1 - 2020/3/20
N2 - 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.
AB - 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.
KW - Alzheimer's disease
KW - amylin
KW - Aß-42
KW - diabetes
KW - IAPP
KW - protein aggregation
UR - http://www.scopus.com/inward/record.url?scp=85083102087&partnerID=8YFLogxK
U2 - 10.3389/fnmol.2020.00035
DO - 10.3389/fnmol.2020.00035
M3 - Review article
C2 - 32265649
AN - SCOPUS:85083102087
SN - 1662-5099
VL - 13
JO - Frontiers in Molecular Neuroscience
JF - Frontiers in Molecular Neuroscience
M1 - 35
ER -