Editors' ChoiceAlzheimer’s Disease

A tale of two amyloids

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Science Translational Medicine  06 Sep 2017:
Vol. 9, Issue 406, eaao6119
DOI: 10.1126/scitranslmed.aao6119

Abstract

Plasma β-amyloid drives peripheral insulin resistance, which precedes an increase in cerebral neuropathology in a novel mouse model that combines Alzheimer’s and diabetes pathologies.

Growing evidences support a link between type 2 diabetes (T2D) and Alzheimer’s disease (AD). Islet amyloid polypeptide (IAPP, or amylin) aggregates are found in pancreas of T2D individuals, where they are thought to promote cell death. Amylin aggregates are also found in brains of AD subjects, and amylin can form mixed oligomers with the primary neuropathological protein in AD, β-amyloid (Aβ). However, diabetic mouse models have failed to elicit peripheral amylin aggregation, therefore limiting our understanding of the relationship between diabetes and AD. Because protein aggregation may play a key role in mediating the downstream pathological effects, modeling aggregation and deposition of these two amyloidogenic peptides is necessary to understand their combined impact on peripheral and central phenotypes when AD and T2D overlap.

Here, Wijesekara et al. created a double transgenic (DTG) mouse model showing aggregation and deposition of both Aβ and amylin in islets, resulting in accelerated beta cell loss. Peripheral glucose intolerance and hyperglycemia occurred without a compensatory increase in fasting insulin. Age-related increases in hippocampal Aβ plaques and tau phosphorylation, as well as decreases in insulin signaling and insulin levels, were more pronounced in DTG mice compared with single transgenic animals that exhibited high cerebral Aβ but lacked pancreatic amylin aggregates. In addition, DTG mice exhibited high plasma Aβ prior to peripheral insulin resistance, which then preceded increased cerebral Aβ pathology. Based on this temporal relationship, investigators postulated that immunization with synthetic Aβ would mitigate peripheral insulin resistance. In fact, DTG mice did remain glucose tolerant and normoglycemic during immunization, suggesting that circulating Aβ may contribute to the observed impaired glucose tolerance and hyperglycemia.

These findings indicate that peripheral metabolic dysfunction occurs prior to cerebral neuropathology in a double transgenic mouse model that incorporates important features of T2D and AD pathologies. In presence of amylin aggregates, increased circulating Aβ exacerbates insulin resistance and accelerates pancreatic cell death, ultimately reducing plasma and brain insulin levels. This decline in insulin combined with increased Aβ deposition may be key to synaptic dysfunction. The degree to which the findings in this novel mouse model translate to human studies remains to be determined but nonetheless suggests potential mechanisms that may be involved the overlapping pathologies of T2D and AD.

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