The greatest risk factor for Alzheimer's disease (AD) is aging, with an estimated 5.3 million people aged 65 and older with the disease. The pathology of AD consists primarily of amyloid-beta plaques and neurofibrillary tangles (NFT) composed of microtubule-associated protein tau. The major pathological protein in frontotemporal dementia and motor neuron disease is Transactive response DNA-binding Protein of 43 kDa (TDP-43). Similar to tau, pathological TDP-43 becomes hyper-phosphorylated and is present in neuronal inclusions. Recently, TDP-43 aggregation has also been described in up to 50% of sporadic and 14% of familial Alzheimer's disease cases. We describe that overexpression of TDP-43 increases b-secretase (Bace1) protein levels and knockdown of TDP-43 alters b and g C-terminal fragment processing in cortical neuron cultures. Also, in APP/PS1 mice selectively over-expressing TDP-43 in cortical and hippocampal neurons there is a distinct change in amyloid deposition similar to what is observed in APP mice over-expressing Bace1. Based on these observations, we hypothesize that changes in TDP-43 expression alters APP processing and Bace1 activity in APP/PS1 mice. This overexpression of neuronal and/or glial specific human TDP-43 will lead to changes in APP processing, behavioral deficits, and subsequent neurodegeneration. Mechanisms associated with TDP-43 expression affecting Bace1 activity in an Alzheimer's disease mouse model have not been explored. In this in vivo mouse model we want to explore what effect cell-specific expression of TDP-43 has on the neuropathogenesis of Alzheimer's disease. For those suffering from Alzheimer's disease there is an age-dependent increase BACE activity increasing APP processing leading to accelerated neurodegeneration. Understanding mechanisms associated with these changes and how age contributes could enrich our understanding of the progression of Alzheimer's disease. This in vivo model potentially could lead to the development of new therapeutics targeted at slowing the progression.

Public Health Relevance

The greatest risk factor for Alzheimer's disease is aging, with an estimated 5.3 million people aged 65 and older with the disease. Increases in TDP-43 expression cause changes in amyloid processing. Understanding the role TDP-43 plays in Alzheimer's disease and aging could help us develop new therapeutics targeted at slowing the progression of Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01AG042500-01A1
Application #
8581908
Study Section
National Institute on Aging Initial Review Group (NIA)
Program Officer
Petanceska, Suzana
Project Start
2013-07-15
Project End
2018-06-30
Budget Start
2013-07-15
Budget End
2014-06-30
Support Year
1
Fiscal Year
2013
Total Cost
$135,810
Indirect Cost
$10,060
Name
University of Wisconsin Madison
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715