Reducing acetylated tau is neuroprotective in brain injury

Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Si...

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Vydáno v:	Cell Ročník 184; číslo 10; s. 2715
Hlavní autoři:	Shin, Min-Kyoo, Vázquez-Rosa, Edwin, Koh, Yeojung, Dhar, Matasha, Chaubey, Kalyani, Cintrón-Pérez, Coral J, Barker, Sarah, Miller, Emiko, Franke, Kathryn, Noterman, Maria F, Seth, Divya, Allen, Rachael S, Motz, Cara T, Rao, Sriganesh Ramachandra, Skelton, Lara A, Pardue, Machelle T, Fliesler, Steven J, Wang, Chao, Tracy, Tara E, Gan, Li, Liebl, Daniel J, Savarraj, Jude P J, Torres, Glenda L, Ahnstedt, Hilda, McCullough, Louise D, Kitagawa, Ryan S, Choi, H Alex, Zhang, Pengyue, Hou, Yuan, Chiang, Chien-Wei, Li, Lang, Ortiz, Francisco, Kilgore, Jessica A, Williams, Noelle S, Whitehair, Victoria C, Gefen, Tamar, Flanagan, Margaret E, Stamler, Jonathan S, Jain, Mukesh K, Kraus, Allison, Cheng, Feixiong, Reynolds, James D, Pieper, Andrew A
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 13.05.2021
Témata:	Acetylation Alzheimer Disease - etiology Alzheimer Disease - metabolism Alzheimer Disease - prevention & control Animals Anti-Inflammatory Agents, Non-Steroidal - therapeutic use Biomarkers - blood Biomarkers - metabolism Brain Injuries, Traumatic - complications Brain Injuries, Traumatic - metabolism Cell Line Diflunisal - therapeutic use Female Glyceraldehyde-3-Phosphate Dehydrogenase (Phosphorylating) Humans Male Mice Mice, Inbred C57BL Neurons - metabolism Neuroprotection p300-CBP Transcription Factors - antagonists & inhibitors p300-CBP Transcription Factors - metabolism Salicylates - therapeutic use Sirtuin 1 - metabolism tau Proteins - blood tau Proteins - metabolism acetylation congenital muscular dystrophy omigapil P7C3 Alzheimer’s disease salsalate neuroprotection diflunisal neurodegeneration traumatic brain injury tau
ISSN:	1097-4172, 1097-4172
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Shrnutí:	Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimer's disease (AD). We report here that TBI induces tau acetylation (ac-tau) at sites acetylated also in human AD brain. This is mediated by S-nitrosylated-GAPDH, which simultaneously inactivates Sirtuin1 deacetylase and activates p300/CBP acetyltransferase, increasing neuronal ac-tau. Subsequent tau mislocalization causes neurodegeneration and neurobehavioral impairment, and ac-tau accumulates in the blood. Blocking GAPDH S-nitrosylation, inhibiting p300/CBP, or stimulating Sirtuin1 all protect mice from neurodegeneration, neurobehavioral impairment, and blood and brain accumulation of ac-tau after TBI. Ac-tau is thus a therapeutic target and potential blood biomarker of TBI that may represent pathologic convergence between TBI and AD. Increased ac-tau in human AD brain is further augmented in AD patients with history of TBI, and patients receiving the p300/CBP inhibitors salsalate or diflunisal exhibit decreased incidence of AD and clinically diagnosed TBI.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1097-4172 1097-4172
DOI:	10.1016/j.cell.2021.03.032