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. Mechanisms associated with accumulation of phosphorylated TDP-43 pathology and how it relates to AD pathology with respect to amyloid deposition, NFT formation, and neuronal degeneration have not been explored. With an accumulation of endogenous phosphorylated TDP-43 in the hippocampus and cortex of APP/PS1 mice, we hypothesize that TDP-43 overexpression will alter pathological age-dependent changes in TDP-43 and/or Abeta deposition. For those suffering from Alzheimer's disease, progression is inevitable. Increases in Abeta deposition cause an age-dependent change in solubility, localization, and phosphorylation of TDP-43. Understanding mechanisms associated with these changes and how age contributes to increased accumulation of TDP-43 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.
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 Abita deposition cause an age-dependent change in solubility; localization; and phosphorylation of TDP-43. Understanding mechanisms associated with these changes and how age contributes to increased accumulation of TDP-43 could lead to the development of new therapeutics targeted at slowing the progression of Alzheimer's disease.
| Davis, Stephani A; Itaman, Sheed; Khalid-Janney, Christopher M et al. (2018) TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics. Neurosci Lett 678:8-15 |
| Davis, Stephani A; Gan, Kok Ann; Dowell, James A et al. (2017) TDP-43 expression influences amyloid? plaque deposition and tau aggregation. Neurobiol Dis 103:154-162 |
