TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimer's disease

Publication date: Available online 31 October 2019Source: Biochimica et Biophysica Acta (BBA) - Molecular Basis of DiseaseAuthor(s): Ju Gao, Luwen Wang, Chao Gao, Hiroyuki Arakawa, George Perry, Xinglong WangAbstractAlzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and neuropathologically by the presence of senile plaques and neuronal loss in the brain. While current drugs for AD are always employed as symptomatic therapies with variable benefits, there is no treatment to delay its progression or halt neurodegeneration. TAR DNA-binding protein 43 (TDP-43) proteinopathy has increasingly been implicated as a prominent histopathological feature of AD and related dementias. Our recent studies have implicated mitochondria as critical targets of TDP-43 neurotoxicity. Here, we demonstrate that the suppression of mitochondrial-associated TDP-43 protects against neuronal loss and behavioral deficits in 5XFAD transgenic mice recapitulating AD-related phenotypes. In AD patients and 5XFAD mice, the level of TDP-43 is increased in mitochondria, and TDP-43 highly co-localizes with mitochondria in brain neurons exhibiting TDP-43 proteinopathy. Chronic administration of a TDP-43 mitochondrial localization inhibitory peptide, PM1, significantly alleviates TDP-43 proteinopathy, mitochondrial abnormalities, microgliosis and even neuronal loss without effect on amyloid plaque load in 12-month-old 5XFAD ...
Source: Biochimica et Biophysica Acta (BBA) Molecular Basis of Disease - Category: Molecular Biology Source Type: research

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Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
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