J Lipid Atheroscler.  2019 Sep;8(2):144-151. 10.12997/jla.2019.8.2.144.

Diabetes-related Amylin Dyshomeostasis: a Contributing Factor to Cerebrovascular Pathology and Dementia

• Ly H
• Despa F

• KMID: 2458379
• DOI: http://doi.org/10.12997/jla.2019.8.2.144

Abstract

Type 2 diabetes (T2D) increases the risk for cerebrovascular disease (CVD) and dementia. The underlying molecular mechanisms remain elusive, which hampers the development of treatment or/and effective prevention strategies. Recent studies suggest that dyshomeostasis of amylin, a satiety hormone that forms pancreatic amyloid in patients with T2D, promotes accumulation of amylin in cerebral small blood vessels and interaction with Alzheimer's disease (AD) pathology. Overexpression of human amylin in rodents (rodent amylin does not form amyloid) leads to late-life onset T2D and neurologic deficits. In this Review, we discuss clinical evidence of amylin pathology in CVD and AD and identify critical characteristics of animal models that could help to better understand molecular mechanisms underlying the increased risk of CVD and AD in patients with prediabetes or T2D.

Keyword

Type 2 diabetes mellitus; Diabetes complications; Cerebrovascular disease; Dementia; Alzheimer's disease; Amyloid

MeSH Terms

Alzheimer Disease
Amyloid
Blood Vessels
Cerebrovascular Disorders
Dementia*
Diabetes Complications
Diabetes Mellitus, Type 2
Humans
Islet Amyloid Polypeptide*
Models, Animal
Neurologic Manifestations
Pathology*
Prediabetic State
Rodentia
Amyloid
Islet Amyloid Polypeptide

Figure

• 

  Fig. 1 Diabetes-related amylin dyshomeostasis leads to the formation of pancreatic amyloid and promotes amylin accumulation in the peripheral circulation. Circulating oligomerized amylin deposits in the brain microvasculature and induces small vessels injury by deranging the microvascular endothelium. Oligomerized amylin also forms mixed amylin-Aβ plaques in the brain parenchyma, accentuating neurotoxicity. Diabetes-related amylin dyshomeostasis promotes a feed-forward pathological process by which circulating oligomerized amylin injures brain microvasculature and synergizes with Aβ pathology to induce dementia. Aβ, β amyloid.

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