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Dernière publication 01/01/2020

TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP

Alzheimer's disease (AD) is the leading cause of dementia in the elderly, characterized clinically by progressive decline in cognitive function and...

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    [title] => TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP
    [paragraph] => TDP-43 inhibitory peptide alleviates neurodegeneration and memory loss in an APP transgenic mouse model for Alzheimer's disease
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Authors
J Gao, L Wang, C Gao, H Arakawa, G Perry, X Wang

 Lab
Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
Journal
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease
Abstract
Alzheimer'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 mice well after the onset of symptoms. Additionally, PM1 also improves the cognitive and motor function in 12-month-old 5XFAD mice and completely prevents the onset of mild cognitive impairment in 6-month-old 5XFAD mice. These data indicate that mitochondria-associated TDP-43 is likely involved in AD pathogenesis and that the inhibitor of mitochondria-associated TDP-43 may be a valuable drug to treat underlying AD.
BIOSEB Instruments Used
Grip strength test (BIO-GS3)

Keywords/Topics
Maladie d'Alzheimer; Neurodégénérescence
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Une méthode simple pour quantifier objectivement la force musculaire des rats et souris et l'effet de drogues, toxines, maladies musculaires (ex: myopathie) et neurodégénératives. Cette mesure de force est souvent employée en association avec le test de coordination motrice ROTAROD: un sujet présentant une coordination normale montrera des résultats médiocres en cas de faible force musculaire. Un must pour vos recherches sur l'activité, la coordination et le contrôle musculaire: particulièrement utile pour vos études sur les maladies de Parkinson et Huntington.
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