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Michael A. Gitcho
Assistant Professor
Biological Sciences
Delaware State University
mgitcho@desu.edu
My research is focused on understanding how age, stress, and changes in metabolism contribute to neurodegeneration in Alzheimer’s disease, frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS). We are specifically interested in an RNA binding protein, TDP-43. TDP-43 is the major pathological protein in FTD and ALS. In order to elucidate mechanisms associated with neurodegeneration, we use primary neuronal & astrocyte cultures and animal models to understand these processes. Under pathological conditions, TDP-43 becomes phosphorylated and proteolytically cleaved. Recently, TDP-43 pathology has been shown to be present in up to 50% of sporadic Alzheimer’s disease cases.
One focus of my research is to examine what effect oxidative stress and toxicity has on TDP-43. To examine this we utilized an in vitro Aß-mediated toxicity model to answer the following questions. What effect does oxidative stress have on TDP-43 subcellular localization? Do changes in expression of TDP-43 affect cell viability and survival? Are mechanisms of protein turnover (autophagy and/or the ubiquitin proteasome system) altered by changes in TDP-43 expression and localization? Preliminary data reveal that in primary mixed cultures of cortical neurons/astrocytes treated with Aß1-42 for 24 hours show a change in localization of endogenous TDP-43 when the cells are under stress (Figure 1).
Cortical neuronal/astrocyte cultures treated with . . . Figure 1. Cortical neuronal/astrocyte cultures treated with 5.0µM Aß1-42 for 24 hours show an increase in endogenous TDP-43 localized to the cytoplasm (TDP-43; ProteinTech, 488nm green, GFAP; DAKO, 647nm red, and DAPI; 358nm blue, 630X).

To investigate how age contributes to these changes in TDP-43, we are using a transgenic mouse model (APP/PS1) that develops plaques at ~4 months of age. Interestingly, endogenous phosphorylated TDP-43 accumulates in the cytoplasm of neurons and astrocytes in this model (Figure 2). What role if any does TDP-43 play in Alzheimer’s disease? Are changes in localization and phosphorylation of TDP-43 protective or pathogenic?

Figure 2. Endogenous phosphorylated TDP-43 accumulates in the hippocampus of 10-month-old APP/PS1 mice (phosphorylated TDP-43, 488nm green, GFAP; DAKO, 647nm red, and DAPI; 358nm blue, 630X).

 

Cortical neuronal/astrocyte cultures treated . . .

Funding:
National Institute on Aging
Mentored Research Scientist Development Award (K01)
“Selective over expression of TDP-43 in APP/PS1 mice alters APP processing”

Alzheimer’s Association
New Investigator Research Grant
Age-Dependent increase of phosphorylated TDP-43 in APP mice

http://www.alz.org/research/alzheimers_grants/for_researchers/overview-2012.asp?grants=2012gitcho

“Gene Newly Linked To Inherited ALS May Also Play Role In Common Dementia”
http://www.sciencedaily.com/releases/2008/02/080220123542.htm

Gitcho CV
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