2024 Alzheimer's Association Research Grant (AARG)
Elucidating the role of vascular dysfunction in LATE, LATE-AD, and FTLD-TDP
What is the role of blood vessel dysfunction in certain neurodegenerative diseases?
Shih-Hsiu Wang, M.D., Ph.D.
Duke University
Durham, NC - United States
Background
A hallmark brain change associated with Alzheimer’s is the accumulation of the proteins tau and beta-amyloid into clumps called tangles and plaques, respectively. About half of the individuals with Alzheimer’s also have clumps of another protein, called TAR DNA-binding protein 43 (TDP-43), in their brains. Abnormal build-up of TDP-43 in the brain is a hallmark of other brain diseases, including frontotemporal lobar degeneration (FTLD) and limbic-predominant age-related TDP-43 encephalopathy (LATE). LATE often coexists with Alzheimer’s, and the combination of LATE and Alzheimer’s disease (LATE-AD) leads to more severe disease progression than either disease alone. However, what leads to LATE is not well understood.
Blood vessels in the head and neck provide the brain with vital, oxygen-rich blood that is critical for brain cells’ ability to function properly. Inadequate blood flow can damage and eventually damage cells anywhere in the body, but the brain is especially vulnerable. In the brain, impaired blood flow can negatively impact a person’s memory and function. Previous studies suggest that LATE might be linked to problems with blood flow in the brain, leading Dr. Shih-Hsiu Wang and colleagues to believe that changes in blood vessel function in the brain could play a role in causing LATE.
Research Plan
Dr. Wang and colleagues will explore whether changes in blood flow, caused by lack of oxygen and inflammation, may lead to or contribute to LATE. The team will isolate brain blood vessels from individuals with LATE, LATE-AD, or FTLD and analyze the genetic makeup of the blood vessels to gain insights into vessel development, function, and disease.
Additionally, the researchers will use these samples to identify areas in the brain with inflammation and reduced blood flow to study how these changes relate to TDP-43 buildup and the development of LATE.
Impact
The results of this project may improve our understanding of how blood vessel dysfunction impacts brain health and promotes certain kinds of neurodegenerative diseases characterized by the abnormal accumulation of the TDP-43 protein in the brain.