2024 Alzheimer's Association Research Fellowship (AARF)

Effect of Passive Amylin Immunotherapy on Amylin and Beta-Amyloid Plaque Burden in AD

Can targeting a hormone in the blood reduce brain changes associated with Alzheimer’s? 

Deepak Kotiya, Ph.D.
University of Kentucky Research Foundation
Lexington, KY - United States

Background

Beta-amyloid is a sticky protein fragment that forms abnormal clumps called plaques in the brain, a key hallmark of Alzheimer’s. Researchers have worked to develop antibody therapies that use the body’s immune system to target and remove amyloid plaques. Some of these therapies have shown amyloid-clearing abilities in clinical trials and have been approved by the FDA. However, they have only modest effects on slowing cognitive decline. 

Amylin is a protein-like hormone secreted by the pancreas. It works along with insulin to help the body control blood sugar levels. In people with obesity, insulin resistance, or diabetes, amylin levels in the blood can be unusually high. Recently, it has been shown that amylin can accumulate into abnormal clumps in brain blood vessels, possibly contributing to brain damage and cognitive problems. In addition, amylin can clump together with beta-amyloid in the brain. Dr. Deepak Kotiya and colleagues believe that an immunotherapy targeting amylin may be able to reduce beta-amyloid accumulation and slow cognitive decline.

Research Plan

Dr. Kotiya and the team have developed genetically modified Alzheimer’s-like mice in which they can increase or decrease pancreatic secretion of human amylin. The researchers will treat these mice with immunotherapy against amylin in the blood to determine the efficacy and safety of the therapy. The researchers will first measure the amount of amylin in brain blood vessels and the levels of beta-amyloid accumulation, as well as the clearance rate of beta-amyloid, in response to increasing or decreasing amylin activity. Next, Dr. Kotiya and colleagues will study the effects of two types of anti-amylin antibody treatment on the mice. They will determine the specific pathways by which the therapy may enhance beta-amyloid clearance from the brain.

Impact

This work could also shed new light on the relationship between amylin and beta-amyloid in the brain. Most importantly, these findings may lead to the development of therapeutic strategies aimed at reducing or reversing amylin/beta-amyloid accumulation in Alzheimer’s.