Reducing tau acetylation rescues cognitive deficits in a mouse model of traumatic brain injury‐induced acceleration of Alzheimer’s disease
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Le résumé fourni par la source
BACKGROUND: TBI is the 3rd greatest risk factor for developing AD, behind genetics and aging. TBI is associated with a 3-4 year earlier onset of cognitive impairment, and increased cortical thinning and amyloid plaques in people with AD. The underlying mechanisms of this relationship are not understood, and as a result there are no treatments that protect patients from accelerated AD after TBI. We reported that tau is pathologically acetylated after TBI. Acetylated tau is significantly more elevated in the brains of human AD subjects with a history of TBI, compared to AD alone and healthy controls. Therefore, we hypothesized that early tau acetylation after TBI is mechanistically involved in the acceleration of AD. METHOD: We developed a mouse model of TBI-mediated acceleration of AD-like pathology and cognitive impairment in 5xFAD mice. Our unique blast mediated multimodal TBI model is reproducible and clinically relevant. 8-week-old male and female 5xFAD and WT littermates underwent sham/TBI and were assessed after two weeks via Morris water maze, immunohistochemistry, western blot, and single nuclear RNA sequencing. For treatment studies, the FDA-approved non-steroidal inflammatory drug diflunisal, which inhibits the p300-CBP acetyltransferase enzyme that acetylates tau, or vehicle was initiated 24 hours after TBI and continued daily. To investigate potential mechanisms, we developed an in vitro TBI model with Hela cells that stably express amyloid precursor protein or tau. RESULT: TBI causes learning deficits in young 5xFAD mice that do not occur in sham 5xFAD mice or in TBI-injured WT littermates. TBI accelerates amyloid plaques in 5xFAD mice. 5xFAD mice show greater elevation of acetylated tau after TBI, compared to WT mice. Hippocampal snRNA sequencing showed that TBI or 5xFAD mutations alone primarily perturb neurons. By contrast, TBI in 5xFAD mice drastically alters transcription in multiple cell types. Diflunisal treatment reduces acetylated-tau and rescues behavior deficits after TBI in 5xFAD mice. Amyloid precursor protein and tau expressing cells are more susceptible to in vitro TBI, compared to wild type cells. CONCLUSION: TBI accelerates onset of AD-like pathologies in 5xFAD mice. Preliminary evidence shows that pharmacologically reducing acetylated tau rescues TBI-induced cognitive deficits in 5xFAD mice.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Reducing tau acetylation rescues cognitive deficits in a mouse model of traumatic brain injury‐induced acceleration of Alzheimer’s disease
- Date Crossref
- 01/12/2024
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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University Hospitals of Cleveland pays non établi dans la noticeÉtablissement de santé
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Louis Stokes Cleveland VA Medical Center pays non établi dans la noticeÉtablissement de santé
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Case Western Reserve University pays non établi dans la noticeUniversité ou école supérieure
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Cleveland Clinic pays non établi dans la noticeÉtablissement de santé
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Johns Hopkins Medicine pays non établi dans la noticeÉtablissement de santé
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Cornell University pays non établi dans la noticeUniversité ou école supérieure
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MIND Research Institute pays non établi dans la noticeOrganisation à but non lucratif
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University Hospitals Cleveland Medical Center pays non établi dans la noticeUniversité ou école supérieure
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College of Pharmacy and Research Institute of Pharmaceutical Sciences pays non établi dans la noticeUniversité ou école supérieure
University Hospitals of Cleveland, Louis Stokes Cleveland VA Medical Center et Case Western Reserve University, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.