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2020 Alzheimer's Association Research Grant (AARG)

Targeting Cerebral Smooth Muscle Cell Mitochondria in Alzheimer's Disease

Can improving blood flow in the brain help to clear protein deposits and improve cognitive impairments in Alzheimer’s?

Silvia Fossati, Ph.D.
Temple University
Philadelphia, PA - United States



Background

One of the hallmark brain changes observed in Alzheimer’s is the accumulation of the beta-amyloid protein in the brain. Beta-amyloid can accumulate near brain blood vessels, leading to stiffening the vessels and making it difficult for surrounding muscle cells to properly pump blood. This restricts the blood flow throughout the brain. This process is known as “cerebral amyloid angiopathy” or CAA. Studies show that poor brain blood flow can lead to brain damage and cognitive symptoms.

According to recent research the damage of specialized structures called mitochondria — a powerhouse of energy generation in cells — inside muscle cells may be associated with the accumulation of beta-amyloid. Dr. Silvia Fossati and colleagues believe that Food and Drug Administration (FDA)-approved drugs that target mitochondria might also help restore healthy muscle cell function and improve brain blood flow in Alzheimer’s.
 

Research Plan

Dr. Fossati’s team will study the biological mechanism underlying dysfunction of the mitochondria that occurs in muscle cells in CAA and Alzheimer’s. The researchers will first measure how beta-amyloid is distributed in human brain muscle cells in a laboratory dish. 

In collaboration with a research group from UK, Dr. Fossati and her team will further characterize beta-amyloid and the dysfunction of mitochondria in brain tissue of young adults, cognitively unimpaired older adults and people who had CAA (from the UK Brain Banks in Newcastle and Edinburgh). The researchers will then administer the FDA-approved drugs known to affect the mitochondria in order to determine if these drugs can improve mitochondria function in the muscle cells. 

Furthermore, the researchers will also treat genetically engineered Alzheimer’s-like mice with CAIs and study the impact on mitochondria function and on brain blood flow in the mice, including how mice use blood vessels to clear beta-amyloid from the brain.
 

Impact

This work may lay the groundwork to determine if certain FDA-approved drugs might be repurposed to tackle Alzheimer’s in a new approach. The findings might also provide important information related to the role of mitochondria in Alzheimer’s and could reveal opportunities to improve brain blood flow in other brain diseases.

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