Grants and Contracts Details
We propose that an early and possibly treatable contributor to the multifactorial etiology of Alzheimer’s disease (AD) involves amylin dyshomeostasis. Amylin is a pancreatic hormone co-secreted with insulin taht crosses the blood brain barrier and modulates satiety. Similar to the â amyloid (Aâ) peptide, amylin is cleaved by the insulin degrading enzyme (IDE) and forms amyloid. The amylin amyloid is a pathological hallmark of the pancreatic islet in patients with T2D and has also been implicated as a contributor to heart and kidney failure in T2D. Amylin from humans (and few other species) forms toxic oligomers that incorporate in cell membranes and disrupt their integrity and function. The role of amyloidogenicity in amylin-induced toxicity is supported by the observation that rodents overexpressing rodent (non-amyloidogenic) amylin neither accumulate amylin nor develop T2D. Recent studies, including ours, demonstrated that amylin accumulates also in brains of AD patients, particularly in diabetics. Brain amylin was identified as soluble oligomers, plaques and mixed amylin-Aâ deposits. Using diabetic rats that overexpress human amylin in the pancreas (HIP rats), we found that elevated circulating oligomerized amylin promotes the brain amylin deposition causing neuroinflammation and reduced exploratory drive, vestibulomotor function and long-term recognition memory. At the cellular level, HIP rat brains display mitochondrial dysfunction, Ca2+ dysregulation and increased Aâ production (or impaired clearance). We, therefore, hypothesize that amylin dyshomeostasis negatively affects brain function and interacts with Aâ to accelerate AD. Therefore, lower blood levels of amylin could slow the pathological progression of AD. To test these hypotheses, we will investigate human tissues, clinical data and a unique combination of clinically relevant rodent models.
|Effective start/end date||9/15/16 → 11/30/22|
- National Institute on Aging: $1,874,100.00
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