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2017 Grants - Wang
Pathomechanisms of TDP-43 in Alzheimer’s Disease
Xinglong Wang, Ph.D.
Case Western Reserve University School of Medicine
2017 Alzheimer’s Association Research Grant (AARG)
Does abnormal accumulation of the protein TDP-43 contribute to nerve cell loss in Alzheimer’s disease?
Abnormal accumulation of the protein TAR DNA-binding protein 43 (TDP-43) in the brain is a hallmark of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and frontotemporal dementia (FTD). About half of individuals with Alzheimer’s disease also have clumps of TDP-43 in the brain in addition to amyloid plaques and tau tangles. The mechanisms by which the TDP-43 protein promotes brain changes associated with Alzheimer’s disease are not yet understood, but initial studies suggest that TDP-43 may build-up in small cellular structures called mitochondria that are needed to produce energy for cells. Abnormal build-up of TDP-43 in mitochondria could impair energy production and contribute to nerve cell loss in the brain.
Xinglong Wang, Ph.D., and colleagues have planned a series of experiments to better understand the role of TDP-43 in Alzheimer’s disease. The researchers will use nerve cells growing in laboratory dishes to examine what factors (e.g. beta-amyloid, tau, inflammation) may trigger the accumulation of TDP-43 in nerve cell mitochondria. The research team will also determine if treating Alzheimer’s-like mice with a novel molecule that inhibits TDP-43 accumulation in mitochondria can prevent nerve cell loss. In addition, they will test the TDP-43 inhibitor in “induced pluripotent stem cells” (iPSCs) from people with Alzheimer’s disease. iPSCs are a special type of stem cell made from skin or blood cells and then “reprogrammed” to become nerve cells. iPSCs allow scientists to rapidly test drug candidates in nerve cells made directly from people with Alzheimer’s disease.
The results of this study could shed new light on the molecular mechanisms underlying abnormal accumulation of the TDP-43 protein in the Alzheimer’s brain. These findings could also provide the first steps in testing a novel molecule that specifically inhibits TDP-43 build-up in mitochondria as a potential therapy to prevent nerve cell loss in Alzheimer’s and other neurodegenerative diseases.