2024 Alzheimer's Association Research Fellowship (AARF)
Deciphering TDP-43 molecular signatures in LATE, AD and related dementias
Do the mechanisms by which a specific protein contributes to Alzheimer’s different from other forms of dementia?
Sandra O. Tomé, Ph.D.
Catholic University of Leuven (Katholieke Universiteit Leuven, KU Leuven)
Leuven, Belgium
Background
Abnormal build-up of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of many brain diseases, including Alzheimer’s and other dementias such as frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Studies have shown that about half of individuals with Alzheimer’s have elevated levels of TDP-43 in their brains and increases in TDP-43 may be linked to brain shrinkage and cognitive decline. However, the mechanisms by which TDP-43 contributes to cognitive decline in Alzheimer’s compared with other dementias are unknown.
For this study, Dr. Sandra Tomé and colleagues aim to identify how TDP-43 contributes to cognitive decline in Alzheimer’s and other dementias, including FTD, ALS, and limbic-predominant, age-related TDP-43 encephalopathy, or LATE, a recently characterized form of dementia.
Research Plan
Dr. Tomé and the team will first examine whether there are differences in the structure of and levels of TDP-43 accumulated proteins between Alzheimer’s and other forms of dementia. They will do this by analyzing brain tissue from the hippocampus (the region of the brain responsible for memory and learning) from individuals with Alzheimer’s, FTD, ALS, or LATE, as well as cognitively unimpaired individuals. Next, they will identify the other proteins in the brain that interact with TDP-43 across each type of dementia. Lastly, the researchers will assess whether the brain regions where TDP-43 accumulates are the same regions where nerve cell death and other hallmark brain changes seen in Alzheimer’s occur, including the accumulation of tau tangles and amyloid plaques, for each type of dementia.
Impact
Results of this study may contribute to our understanding of the role of TDP-43 in Alzheimer’s and other brain diseases. The findings may also better inform treatment strategies to target TDP-43 build-up across different forms of dementia.