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Mitochondrial TDP-43 in Alzheimer's Disease

Sponsored by National Institute on Aging

$903.2K Funding
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Project SummaryAlzheimer's disease (AD) is the leading cause of dementia in the elderly characterized by neurofibrillary tanglessenile plaques and a progressive loss of neuronal cells in neocortex and hippocampus. Currently there is noeffective treatment for AD. Genetic mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateralsclerosis (ALS) and frontotemporal dementia (FTD the second most common form of early-onset dementia)and the increased presence of TDP-43 in the cytoplasm is a prominent histopathological feature of degeneratingneurons in more than half of AD patients. Despite an expanding body of evidence suggests that TDP-43 may bethe third protein playing a distinct role in the pathogenesis of AD or related dementia in addition to amyloidbeta (A) and tau the molecular pathomechanisms of TDP-43 remain elusive. Interestingly in our preliminarystudies we found that TDP-43 became highly associated with mitochondria in AD patients neurons treated withA and APP/PS1 (5XFAD) transgenic mice for AD. Based on identified motifs critical for TDP-43 mitochondriallocalization our most recent study revealed that the suppression of TDP-43 mitochondrial localization wassufficient to prevent TDP-43-induced neuronal loss and improve behavioral performances in TDP-43 transgenicmice indicating mitochondria as important mediators for TDP-43 neurotoxicity. Excitingly the inhibition of TDP-43 mitochondrial localization could significantly alleviate neuronal death and behavioral deficits in 5XFAD micewell after symptom onset. These exciting and promising preliminary studies suggest that a detailed investigationinto the potential role of mitochondria-associated TDP-43 in AD and related dementia is warranted. Using bothcultured neuronal and transgenic mouse models for AD and related dementia this study will test the feasibilityof targeting mitochondria-associated TDP-43 as a novel therapeutic approach for AD and related dementia. Theincreased presence of TDP-43 in the cytoplasm is a prominent common histopathological feature ofdegenerating neurons in various major neurodegenerative diseases including AD FTD and ALS. Our proposedstudies of mitochondria-associated TDP-43 and its connection with the generally believed AD culprit A will havevery broad scientific and translational significance.