Harrington Discovery Institute, University Hospitals Cleveland Medical Center, Cleveland, OH, USA; Department of Psychiatry, Case Western Reserve University, Cleveland, OH, USA; Geriatric Psychiatry, GRECC, Louis Stokes Cleveland VA Medical Center; Cleveland, OH, USA; Institute for Transformative Molecular Medicine, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Cell. 2021 May 13;184(10):2715-2732.e23. doi: 10.1016/j.cell.2021.03.032. Epub 2021 Apr 13.
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.
创伤性脑损伤（TBI）是阿尔茨海默病（AD）最大的非遗传、非衰老相关风险因素。我们在这里报告，TBI 诱导 tau 乙酰化（ac-tau），这些位点在人类 AD 大脑中也被乙酰化。这是由 S-亚硝基化-GAPDH 介导的，它同时使 Sirtuin1 去乙酰化酶失活，并激活 p300/CBP 乙酰转移酶，增加神经元 ac-tau。随后的 tau 定位错误导致神经退行性变和神经行为损伤，ac-tau 在血液中积累。阻断 GAPDH 的 S-亚硝基化、抑制 p300/CBP 或刺激 Sirtuin1 都能保护小鼠免受 TBI 引起的神经退行性变、神经行为损伤以及血液和大脑中 ac-tau 的积累。因此，ac-tau 是 TBI 的治疗靶点和潜在的血液生物标志物，可能代表 TBI 和 AD 之间的病理趋同。在有 TBI 病史的 AD 患者的大脑中，ac-tau 进一步增加，而接受 p300/CBP 抑制剂水杨酸盐或二氟尼柳治疗的患者，AD 的发病率和临床诊断的 TBI 都有所降低。
