# Programming amylin secretion to slow brain aging - an animal model

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2020 · $650,332

## Abstract

PROJECT SUMMARY
Proteostasis dysfunction of pancreatic β-cells results in accumulation of oligomerized amylin within pancreatic
islets, which is a hallmark of type-2 diabetes. We recently showed that oligomerized amylin also incorporates
into the brain blood vessel walls, forms neuritic deposits and co-localizes with Alzheimer's disease (AD) 
β-amyloid peptides (Aβ) as mixed Aβ-amylin plaques in brains of individuals with late-onset AD as well as familial
early-onset AD. It is unknown whether cerebral amylin deposits are a consequence of AD or type-2 diabetes,
or a “hidden” trigger of AD. Moreover, we found that overexpressing human amylin within pancreatic islets in
rats induces systemic amylin dyshomeostasis, brain amylin accumulation, microglia activation and behavior
changes. Furthermore, elevated human amylin in the periphery greatly accelerates behavior changes in a rat
model of AD pathogenesis. These findings suggest the hypothesis that amylin dyshomeostasis in pancreatic
islets and subsequent secretion of oligomerized amylin in the blood can affect the progression of AD by
compromising the ability of microglia to efficiently clear Aβ and by inducing mixed Aβ-amylin pathology. Thus,
ameliorating amylin dyshomeostasis in the periphery can limit the progression of AD. The overarching goal of
this proposal is to test our hypothesis and investigate molecular mechanisms underlying the interaction of
amylin with Aβ pathology. We will accomplish this goal by characterizing novel transgenic mice with inducible
and reversible expression of human amylin in the pancreas (HuAmy line). We will carefully dissect proteostasis
dysfunction of pancreatic β-cells in the periphery and the consequent liability it imposes on the central nervous
system. We will also cross HuAmy line and 85Dbo line to generate APP/PS1 transgenic mice with regulated
expression of human amylin in the periphery. We predict that turning off the human amylin transgene
expression at early time points during aging mitigates the disease progression in HuAmy:APP/PS1 mice by
limiting the blood-brain barrier injury and rescuing the ability of microglia to clear Aβ. This investigation using
novel regulated amylin expression represents the most direct in vivo approach to rigorously test the
involvement of peripheral amylin in the biological pathways of AD pathogenesis. The completion of these aims
will elucidate the interplay of amylin dyshomeostasis with the progression of Aβ pathology and whether
ameliorating amylin dyshomeostasis in the periphery can reduce or reverse AD in a preclinical model. We
believe that the proposed investigation fills significant gaps in our understanding of the molecular link between
type-2 diabetes and AD.

## Key facts

- **NIH application ID:** 9928871
- **Project number:** 5R01AG057290-04
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Florin Despa
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $650,332
- **Award type:** 5
- **Project period:** 2017-09-15 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928871

## Citation

> US National Institutes of Health, RePORTER application 9928871, Programming amylin secretion to slow brain aging - an animal model (5R01AG057290-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928871. Licensed CC0.

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