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Written | Edited by Chen Wenqiang | xi Traumatic brain injury (TBI) is usually caused by car accidents, falls from high altitudes, sports or assaults.
About 3.
5 million traumatic brain injury events occur in the United States every year, and about 5 million people now live with traumatic brain injury-related disorders.
The current treatment of traumatic brain injury is mainly to stabilize and relieve the condition.
However, studies have shown that traumatic brain injury can significantly increase the probability of suffering from Alzheimer's disease (AD) after injury [1], suggesting that the two have a common pathology mechanism.
Previous studies have shown that S-nitrosylation and acetylation may be the key link between traumatic brain injury and AD [2-3], and autopsy of AD patients and traumatic brain injury patients The results all found acetylation at multiple sites of Tau protein tyrosine [4].
However, these studies have not proved whether Tau acetylation is a key pathophysiological factor of traumatic brain injury.
In order to further reveal the role of Tau protein acetylation in traumatic brain injury and AD pathology, researchers from Case Western Reserve University, Cleveland Medical Center and other units recently published an online publication titled Reducing tau acetylation in Cell.
The research paper on is neuroprotective in brain injury, through a series of biochemical research methods, reveals the pathophysiological mechanism of Tau protein acetylation in the pathogenesis of traumatic brain injury and AD, so as to better help us find brain injury and neurodegeneration Disease treatment strategies.
First, the researchers used a multi-modal mouse traumatic brain injury model recently reported by the research group to simulate the multidimensional trauma of traumatic brain injury, including total concussion, explosive wave exposure, etc.
[5].This model can cause acute nerve fiber degeneration, leading to blood-brain barrier damage and nerve cell death.
By specifically identifying the acetylated K263 and K270 sites, the researchers found that the mouse brain produces a rapid and specific increase in Tau acetylation after injury, and it selectively occurs in neurons, while the total Tau protein level remains unchanged.
The researchers also determined that phosphorylation of Tau protein did not significantly participate in the acute phase of brain injury.
Subsequently, using in vitro and in vivo experiments, the researchers confirmed that the acetylated Tau protein is directly toxic to neurons.
In order to reveal the mechanism of neuronal Tau protein acetylation caused by brain injury, researchers focused on GAPDH protein sulfhydryl nitrosylation, a traditional AD cell biological model, because GAPDH can increase p300/CBP acetyltransferase activity and inhibit Sirtuin1 (Sirt1) deacetylase activity to increase the level of total acetylation.
Researchers found that after traumatic brain injury, both GAPDH and Sirt1 proteins undergo sulfhydryl nitrosylation, and the use of GAPDH sulfhydryl nitrosylation inhibitor CGP3466B can not only prevent the sulfhydryl nitrosylation of GAPDH and Sirt1, but also reduce Tau protein acetylation level.
In addition, mouse cognitive behavior experiments suggest that CGP3466B can also reduce cognitive impairment caused by injury.
These results all suggest that the sulfhydryl nitrosylation of GAPDH mediates multiple pathological features such as Tau protein acetylation, mislocalization of Tau protein, and cognitive impairment after brain injury.
In addition, the researchers also revealed a downstream mechanism that specifically prevents brain injury-induced Tau protein acetylation, neurodegeneration and behavioral disorders by inhibiting the activity of p300/CBP acetyltransferase (see Figure 3 for details).
As another downstream mechanism of GAPDH sulfhydryl nitrosylation, the researchers used WldS mice to also reveal that the increase in Sirt1 activity can prevent brain injury-induced Tau protein acetylation, neurodegeneration, and behavioral disorders.
Since Sirt1 activity depends on NAD+, the spontaneously high NAD+ level of WldS mice suggests that the mice may be less affected by axon degeneration and neurobehavioral damage after brain injury.
This hypothesis is confirmed by experimental evidence.
Because Tau protein can diffuse freely from the brain to the blood, researchers speculate that Tau protein acetylation may be a blood marker of neuropathy after traumatic brain injury.
The researchers found that after brain injury in mice, high levels of acetylated Tau protein were detected in the plasma.
The clinical relevance of this result is confirmed-researchers have found that high levels of acetylated Tau protein can be detected in the plasma of patients who have experienced brain injury, which originates from subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) No increase in the level of acetylated Tau protein will be detected in the patient's plasma.
Finally, in order to confirm the role of Tau protein acetylation in AD and brain injury, the researchers analyzed 9 samples of human brain frontal cortex and found that compared with controls, acetylated Tau protein in AD patients with brain injury has The highest level, but the level of acetylated Tau protein in AD patients without brain injury was still significantly higher than that of the control group.
This article reveals the key interaction mechanism of sulfhydryl nitrosylation and acetylation in neurons after brain injury in causing Tau protein acetylation.
Although there are also reports that phosphorylation of Tau protein can also occur after brain injury, but it occurs 24 hours after injury.
The acetylation of Tau protein in the acute phase of brain injury observed in this article appeared earlier than phosphorylation, suggesting that it has important pathological significance.
In addition, this article reveals the role of GAPDH sulfhydryl nitrosylation in Tau protein acetylation after brain injury, and observed that multiple neuroprotective agents can reduce Tau protein acetylation, all suggesting new intervention targets and treatment strategies.
In general, the acetylation of Tau protein after brain injury reported in this paper has important clinical significance as a biomarker of neuropathy.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
03.
032 Platemaker: Eleven References [1] Johnson, VE, Stewart, W.
, and Smith, DH (2010).
Traumatic brain injury and amyloid-b pathology: a link to Alzheimer's disease? Nat.
Rev.
Neurosci.
11, 361–370.
[2] Uehara, T.
, Nakamura, T.
, Yao, D.
, Shi, Z.
-Q.
, Gu, Z.
, Ma, Y.
, Masliah, E.
, Nomura, Y.
, and Lipton, SA (2006).
S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.
Nature 441, 513–517.
[3 ] Sen, T.
, Saha, P.
, and Sen, N.
(2018).
Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-b.
Sci.
Signal.
11, eaao6765.
[4] Lucke-Wold, B .
, Seidel, K.
, Udo, R.
, Omalu, B.
, Ornstein, M.
, Nolan, R.
, Rosen, C.
, and Ross, J.
(2017).
Role of tau acetylation in Alzheimer's disease and chronic traumatic encephalopathy: the way forward for successful treatment.
J.
Neurol.
Neurosurg.
4, 140.
[5] Shin, M.
-K.
, Va´ zquez-Rosa, E.
, Cintro´ n-Pe´ rez, C.
, Riegel, A.
, Harper, MM, Ritzel, D.
, and Pieper, AA (2021).
Characterization of the jet-flow overpressure model of traumatic brain injury in mice.
Neurotrauma Rep.
2, 1–13.
Reprint instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome.
Reprinting is permitted, and the copyrights of all published works are owned by BioArt. BioArt reserves all statutory rights and offenders must be investigated.
About 3.
5 million traumatic brain injury events occur in the United States every year, and about 5 million people now live with traumatic brain injury-related disorders.
The current treatment of traumatic brain injury is mainly to stabilize and relieve the condition.
However, studies have shown that traumatic brain injury can significantly increase the probability of suffering from Alzheimer's disease (AD) after injury [1], suggesting that the two have a common pathology mechanism.
Previous studies have shown that S-nitrosylation and acetylation may be the key link between traumatic brain injury and AD [2-3], and autopsy of AD patients and traumatic brain injury patients The results all found acetylation at multiple sites of Tau protein tyrosine [4].
However, these studies have not proved whether Tau acetylation is a key pathophysiological factor of traumatic brain injury.
In order to further reveal the role of Tau protein acetylation in traumatic brain injury and AD pathology, researchers from Case Western Reserve University, Cleveland Medical Center and other units recently published an online publication titled Reducing tau acetylation in Cell.
The research paper on is neuroprotective in brain injury, through a series of biochemical research methods, reveals the pathophysiological mechanism of Tau protein acetylation in the pathogenesis of traumatic brain injury and AD, so as to better help us find brain injury and neurodegeneration Disease treatment strategies.
First, the researchers used a multi-modal mouse traumatic brain injury model recently reported by the research group to simulate the multidimensional trauma of traumatic brain injury, including total concussion, explosive wave exposure, etc.
[5].This model can cause acute nerve fiber degeneration, leading to blood-brain barrier damage and nerve cell death.
By specifically identifying the acetylated K263 and K270 sites, the researchers found that the mouse brain produces a rapid and specific increase in Tau acetylation after injury, and it selectively occurs in neurons, while the total Tau protein level remains unchanged.
The researchers also determined that phosphorylation of Tau protein did not significantly participate in the acute phase of brain injury.
Subsequently, using in vitro and in vivo experiments, the researchers confirmed that the acetylated Tau protein is directly toxic to neurons.
In order to reveal the mechanism of neuronal Tau protein acetylation caused by brain injury, researchers focused on GAPDH protein sulfhydryl nitrosylation, a traditional AD cell biological model, because GAPDH can increase p300/CBP acetyltransferase activity and inhibit Sirtuin1 (Sirt1) deacetylase activity to increase the level of total acetylation.
Researchers found that after traumatic brain injury, both GAPDH and Sirt1 proteins undergo sulfhydryl nitrosylation, and the use of GAPDH sulfhydryl nitrosylation inhibitor CGP3466B can not only prevent the sulfhydryl nitrosylation of GAPDH and Sirt1, but also reduce Tau protein acetylation level.
In addition, mouse cognitive behavior experiments suggest that CGP3466B can also reduce cognitive impairment caused by injury.
These results all suggest that the sulfhydryl nitrosylation of GAPDH mediates multiple pathological features such as Tau protein acetylation, mislocalization of Tau protein, and cognitive impairment after brain injury.
In addition, the researchers also revealed a downstream mechanism that specifically prevents brain injury-induced Tau protein acetylation, neurodegeneration and behavioral disorders by inhibiting the activity of p300/CBP acetyltransferase (see Figure 3 for details).
As another downstream mechanism of GAPDH sulfhydryl nitrosylation, the researchers used WldS mice to also reveal that the increase in Sirt1 activity can prevent brain injury-induced Tau protein acetylation, neurodegeneration, and behavioral disorders.
Since Sirt1 activity depends on NAD+, the spontaneously high NAD+ level of WldS mice suggests that the mice may be less affected by axon degeneration and neurobehavioral damage after brain injury.
This hypothesis is confirmed by experimental evidence.
Because Tau protein can diffuse freely from the brain to the blood, researchers speculate that Tau protein acetylation may be a blood marker of neuropathy after traumatic brain injury.
The researchers found that after brain injury in mice, high levels of acetylated Tau protein were detected in the plasma.
The clinical relevance of this result is confirmed-researchers have found that high levels of acetylated Tau protein can be detected in the plasma of patients who have experienced brain injury, which originates from subarachnoid hemorrhage (SAH) and intracerebral hemorrhage (ICH) No increase in the level of acetylated Tau protein will be detected in the patient's plasma.
Finally, in order to confirm the role of Tau protein acetylation in AD and brain injury, the researchers analyzed 9 samples of human brain frontal cortex and found that compared with controls, acetylated Tau protein in AD patients with brain injury has The highest level, but the level of acetylated Tau protein in AD patients without brain injury was still significantly higher than that of the control group.
This article reveals the key interaction mechanism of sulfhydryl nitrosylation and acetylation in neurons after brain injury in causing Tau protein acetylation.
Although there are also reports that phosphorylation of Tau protein can also occur after brain injury, but it occurs 24 hours after injury.
The acetylation of Tau protein in the acute phase of brain injury observed in this article appeared earlier than phosphorylation, suggesting that it has important pathological significance.
In addition, this article reveals the role of GAPDH sulfhydryl nitrosylation in Tau protein acetylation after brain injury, and observed that multiple neuroprotective agents can reduce Tau protein acetylation, all suggesting new intervention targets and treatment strategies.
In general, the acetylation of Tau protein after brain injury reported in this paper has important clinical significance as a biomarker of neuropathy.
Original link: https://doi.
org/10.
1016/j.
cell.
2021.
03.
032 Platemaker: Eleven References [1] Johnson, VE, Stewart, W.
, and Smith, DH (2010).
Traumatic brain injury and amyloid-b pathology: a link to Alzheimer's disease? Nat.
Rev.
Neurosci.
11, 361–370.
[2] Uehara, T.
, Nakamura, T.
, Yao, D.
, Shi, Z.
-Q.
, Gu, Z.
, Ma, Y.
, Masliah, E.
, Nomura, Y.
, and Lipton, SA (2006).
S-nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration.
Nature 441, 513–517.
[3 ] Sen, T.
, Saha, P.
, and Sen, N.
(2018).
Nitrosylation of GAPDH augments pathological tau acetylation upon exposure to amyloid-b.
Sci.
Signal.
11, eaao6765.
[4] Lucke-Wold, B .
, Seidel, K.
, Udo, R.
, Omalu, B.
, Ornstein, M.
, Nolan, R.
, Rosen, C.
, and Ross, J.
(2017).
Role of tau acetylation in Alzheimer's disease and chronic traumatic encephalopathy: the way forward for successful treatment.
J.
Neurol.
Neurosurg.
4, 140.
[5] Shin, M.
-K.
, Va´ zquez-Rosa, E.
, Cintro´ n-Pe´ rez, C.
, Riegel, A.
, Harper, MM, Ritzel, D.
, and Pieper, AA (2021).
Characterization of the jet-flow overpressure model of traumatic brain injury in mice.
Neurotrauma Rep.
2, 1–13.
Reprint instructions [Original Articles] BioArt original articles, personal reposting and sharing are welcome.
Reprinting is permitted, and the copyrights of all published works are owned by BioArt. BioArt reserves all statutory rights and offenders must be investigated.
