Intraneuronal Amylin Deposition Peroxidative Membrane Injury and Increased IL-1ß
Synthesis in Brains of Alzheimer's Disease Patients with Type-2 Diabetes and in
Diabetic HIP Rats.
Authors Verma N, Ly H, Liu M, Chen J, Zhu H, Chow M, Hersh LB, Despa F
Submitted By Florin Despa on 5/31/2016
Status Published
Journal Journal of Alzheimer's disease : JAD
Year 2016
Date Published 5/1/2016
Volume : Pages Not Specified : Not Specified
PubMed Reference 27163815
Abstract Amylin is a hormone synthesized and co-secreted with insulin by pancreatic
ß-cells that crosses the blood-brain barrier and regulates satiety. Amylin from
humans (but not rodents) has an increased propensity to aggregate into
pancreatic islet amyloid deposits that contribute to ß-cell mass depletion and
development of type-2 diabetes by inducing oxidative stress and inflammation.
Recent studies demonstrated that aggregated amylin also accumulates in brains of
Alzheimer's disease (AD) patients, preponderantly those with type-2 diabetes.
Here, we report that, in addition to amylin plaques and mixed amylin-Aß
deposits, brains of diabetic patients with AD show amylin immunoreactive
deposits inside the neurons. Neuronal amylin formed adducts with
4-hydroxynonenal (4-HNE), a marker of peroxidative membrane injury, and
increased synthesis of the proinflammatory cytokine interleukin (IL)-1ß. These
pathological changes were mirrored in rats expressing human amylin in pancreatic
islets (HIP rats) and mice intravenously injected with aggregated human amylin,
but not in hyperglycemic rats secreting wild-type non-amyloidogenic rat amylin.
In cultured primary hippocampal rat neurons, aggregated amylin increased IL-1ß
synthesis via membrane destabilization and subsequent generation of 4-HNE. These
effects were blocked by membrane stabilizers and lipid peroxidation inhibitors.
Thus, elevated circulating levels of aggregated amylin negatively affect the
neurons causing peroxidative membrane injury and aberrant inflammatory responses
independent of other confounding factors of diabetes. The present results are
consistent with the pathological role of aggregated amylin in the pancreas,
demonstrate a novel contributing mechanism to neurodegeneration, and suggest a
direct, potentially treatable link of type-2 diabetes with AD.

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