Author ORCID Identifier

https://orcid.org/0000-0001-9245-0161

Year of Publication

2020

Degree Name

Doctor of Philosophy (PhD)

Document Type

Doctoral Dissertation

College

Medicine

Department

Pharmacology and Nutritional Sciences

First Advisor

Dr. Florin Despa

Abstract

Alzheimer disease (AD) and cerebral vascular disease (CVD) are common causes of impaired cognition and behavior in humans. Epidemiological studies have shown that AD and CVD development and progression associated with metabolic risk factors including type 2 diabetes (T2D). However, the underlying molecular mechanisms remain elusive, which hampers the development of treatment and prevention strategies. Research results from our laboratory and others have shown that amylin, a hormone secreted by the pancreas and involved in glucose homeostasis, induces small-vessel-type pathologies and modulates amyloid composition in both familial (genetically predisposed) and sporadic forms of AD. The results indicate amylin as a potential molecular modifier of the course of Alzheimer’s and brain microvascular pathologies.

The present work provides a basis for understanding the role of pancreatic amylin in brain injury and neurologic deficits associated with aging and metabolic dysfunction. First, we used brain tissues from humans with T2D and AD, and a rat model expressing human amylin in the pancreas (the HIP rat), to test the impact of amylin dysregulation on the brain. We found that high blood levels of amylin promoted vascular accumulation of amylin leading to endothelial cell dysfunction and microvascular injury. Amylin-mediated injury of the cerebrovasculature leads to brain white matter disease and neurological dysfunction in HIP rats. Next, we sought to understand the role of amylin in the development of AD pathology and progression of the disease. Using brain tissues from humans with sporadic and familial forms of AD, AD model rats expressing human amylin (ADHIP rats) and AD model rats expressing non-amyloidogenic rat amylin, we found that high blood levels of amylin modulates AD pathology via amylin-Aβ cross-seeding in the grey matter and also contributes to non-AD molecular pathways such as injuries to small blood vessels supplying the white matter. By staining and imaging of brain amylin and Aβ, we showed that amylin accumulated in the brain parenchyma and small blood vessels, and formed mixed plaques with Aβ. Elevated plasma amylin with aging in ADHIP rats was associated with brain microvascular damage and neurological dysfunction. Based on these studies, we inferred that amyloid-forming amylin secreted by the pancreas modulates brain amyloid composition in both sporadic and familial forms of AD, and that pancreatic expression of human amylin in AD model rats accelerates behavioral deficits. Further, we tested effects of lowering peripheral amylin and the suppression of amylin secretion in AD model rats. We found that the amylin-related pathological processes are reduced by pharmacological lowering amylin deposition in brain capillaries and amylin-Aβ cross-seeding. Genetic suppression of amylin in AD model rats reduces amylin-Aβ cross-seeding and neurologic deficits.

Our data show evidence for a role of pancreatic amylin in AD and cerebral microvascular pathology and suggest that drugs reducing amylin accumulation in brain capillaries or preventing amylin from interacting with Aβ-associated pathology could provide benefit in patients with AD. Therefore, targeting amylin dyshomeostasis may be an effective strategy to prevent or slow the advancement of Alzheimer and cerebrovascular disease.

Digital Object Identifier (DOI)

https://doi.org/10.13023/etd.2020.403

Funding Information

American Heart Association Pre-doctoral Fellowship: 3048114028 (2018-2020)

HIPvsWT male.wmv (32126 kB)
Supplementary video 1

WT_HIP_female960x540.avi (5406 kB)
Supplementary video 2

Available for download on Tuesday, March 16, 2021

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