2024 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)
Inspecting the Heterogeneity Linked to Axonal TDP-43 Pathology in Dementias
Which nerve cells are most vulnerable to abnormal protein accumulation in different neurodegenerative diseases?
Bilal Khalil, Ph.D.
VIB-KU Leuven Center for Brain and Disease Research
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 frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease). Additionally, about half of the individuals with Alzheimer’s have an abnormal build-up of TDP-43 in their brains.
In Alzheimer’s, FTD, and other brain diseases, TDP-43 moves from the nuclei (the control center of the cell) of brain cells and into the cytoplasm (the open area of the cell), where it may accumulate in harmful clumps. Research suggests that increases in TDP-43 build-up may be linked to brain shrinkage and cognitive decline in individuals with Alzheimer’s and other diseases that cause dementia.
There are differences in TDP-43 biology between individuals with Alzheimer’s and individuals with FTD. Dr. Bilal Khalil and colleagues believe that different subtypes of nerve cells are impacted by TDP-43 differently in the two diseases, especially at the level of the axons (the long, thread-like extensions that nerve cells use to communicate with each other).
Research Plan
Dr. Khalil and team will model TDP-43-related brain disease in mice. First, the researchers will use a novel tool called a “microfluidic device” to study how TDP-43 impacts mouse brain cells and their connections grown in a laboratory dish. They will use mouse cells from the regions of the brain that are first impacted in Alzheimer’s and in FTD, the hippocampus and the cortex respectively. The team will study the behavior and movement of TDP-43 and assess the health of axons and synapses (specialized structures that nerve cells use to send signals to one another). Dr. Khalil and colleagues will also study different ways of modeling TDP-43-associated brain diseases in mouse brain slices.
Impact
This study may provide insights into how abnormal proteins accumulate in the brain in Alzheimer’s and other neurodegenerative diseases. The results may identify which types of nerve cells are more vulnerable or more resilient to the impacts of abnormal protein build-up during neurodegeneration.