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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Bibliographic Details
Published in:Cell Vol. 184; no. 10; p. 2715
Main Authors: 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
Format: Journal Article
Language:English
Published: United States 13.05.2021
Subjects:
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
Online Access:Get more information
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2021.03.032