Tau progression in single severe frontal traumatic brain injury in human brains

Okamura, Yasushi; Kawakami, Ito; Watanabe, Katsushige; Oshima, Koichiro; Niizato, Kazuhiro; Ikeda, Kenji; Akiyama, Haruhiko; Hasegawa, Masato

doi:10.1016/j.jns.2019.116495

Cited by 15 publications

(16 citation statements)

References 43 publications

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“…Taken together, our findings reveal critical cross-talk between S-nitrosylation and acetylation in neurons after brain injury, which converges on neuronal ac-tau. Although previous studies have reported phosphorylated tau in human TBI (Yang et al, 2017;Okamura et al, 2019;Gorgoraptis et al, 2019), these observations were beyond the first 24 h after injury, which was examined here. Importantly, independent analysis of the 24-h samples showed no increase in tau phosphorylation.…”

Section: Discussionmentioning

confidence: 91%

Reducing acetylated tau is neuroprotective in brain injury

Shin

Vázquez‐Rosa

Koh

et al. 2021

Cell

114

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Traumatic brain injury (TBI) is the largest non-genetic, non-aging related risk factor for Alzheimers 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 Sirtuinl 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 Sirtuinl 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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Section: Discussionmentioning

confidence: 91%

Reducing acetylated tau is neuroprotective in brain injury

Shin

Vázquez‐Rosa

Koh

et al. 2021

Cell

114

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“…Despite the severity of the subcortical white matter injury in the leucotomy cases, the gray matter was relatively intact; and cortical astrogliosis was absent. We note that Okamura et al [58] also reported neuronal and glia p-tau pathology in 2 Japanese cases following leucotomy and provided a summary of previous neuropathological evaluations of leucotomy cases [58].…”

Section: Inter-relationships Between Cte and Artag: Evolving Conceptsmentioning

confidence: 71%

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

Bachstetter

Garrett

Jicha

et al. 2021

acta neuropathol commun

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Astrocytes with intracellular accumulations of misfolded phosphorylated tau protein have been observed in advanced-stage chronic traumatic encephalopathy (CTE) and in other neurodegenerative conditions. There is a growing awareness that astrocytic tau inclusions are also relatively common in the brains of persons over 70 years of age—affecting approximately one-third of autopsied individuals. The pathologic hallmarks of aging-related tau astrogliopathy (ARTAG) include phosphorylated tau protein within thorn-shaped astrocytes (TSA) in subpial, subependymal, perivascular, and white matter regions, whereas granular-fuzzy astrocytes are often seen in gray matter. CTE and ARTAG share molecular and histopathologic characteristics, suggesting that trauma-related mechanism(s) may predispose to the development of tau astrogliopathy. There are presently few experimental systems to study the pathobiology of astrocytic-tau aggregation, but human studies have made recent progress. For example, leucotomy (also referred to as lobotomy) is associated with a localized ARTAG-like neuropathology decades after the surgical brain injury, suggesting that chronic brain injury of any type may predispose to later life ARTAG. To examine this idea in a different context, we report clinical and pathologic features of two middle-aged men who came to autopsy with large (> 6 cm in greatest dimension) arachnoid cysts that had physically displaced and injured the subjects’ left temporal lobes through chronic mechanical stress. Despite the similarity of the size and location of the arachnoid cysts, these individuals had dissimilar neurologic outcomes and neuropathologic findings. We review the evidence for ARTAG in response to brain injury, and discuss how the location and molecular properties of astroglial tau inclusions might alter the physiology of resident astrocytes. These cases and literature review point toward possible mechanism(s) of tau aggregation in astrocytes in response to chronic brain trauma.

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“…Okamura et al determined changes in pTau levels in the brains of 2 schizophrenic patients who had undergone prefrontal leucotomy, a model of severe TBI [ 68 ]. Case 1 was leucotomized during adolescence, while Case 2 was leucotomized through the orbito-ventromedial cortex in her 20s [ 54 ]. Both survived over 53 years post-surgery.…”

Section: Resultsmentioning

confidence: 99%

“…Both survived over 53 years post-surgery. Neuropathological examination revealed considerable pTau immunostaining in neurons and glia in the frontal cortex as well as lesser staining in the cingulate gyrus, medial nucleus of the thalamus, and nucleus accumbens [ 54 ]. Neurofibrillary tangles and astrocytic tangles, unlike pTau, were less frequent in the cortex [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature

Walker

Chapin

Abisambra

et al. 2022

acta neuropathol commun

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Background The initiation, anatomic pattern, and extent of tau spread in traumatic brain injury (TBI), and the mechanism by which TBI leads to long-term tau pathology, remain controversial. Some studies suggest that moderate to severe TBI is sufficient to promote tau pathology; however, others suggest that it is simply a consequence of aging. We therefore conducted a systematic narrative review of the literature addressing whether a single moderate to severe head injury leads to long-term development of tauopathy in both humans and animal models. Methods Studies considered for inclusion in this review assessed a single moderate to severe TBI, assessed tau pathology at long-term timepoints post-injury, comprised experimental or observational studies, and were peer-reviewed and published in English. Databases searched included: PUBMED, NCBI-PMC, EMBASE, Web of Science, Academic Search Premiere, and APA Psychnet. Search results were uploaded to Covidence®, duplicates were removed, and articles underwent an abstract and full-text screening process. Data were then extracted and articles assessed for risk of bias. Findings Of 4,150 studies screened, 26 were eligible for inclusion, of which 17 were human studies, 8 were preclinical animal studies, and 1 included both human and preclinical animal studies. Most studies had low to moderate risk of bias. Most human and animal studies (n = 12 and 9, respectively) suggested that a single moderate to severe TBI resulted in greater development of long-term tauopathy compared to no history of head injury. This conclusion should be interpreted with caution, however, due to several limitations: small sample sizes; inconsistencies in controlling for confounding factors that may have affected tau pathology (e.g., family history of dementia or neurological illnesses, apolipoprotein E genotype, etc.), inclusion of mostly males, and variation in reporting injury parameters. Interpretation Results indicate that a single moderate to severe TBI leads to greater chronic development of tauopathy compared to no history of head injury. This implies that tau pathology induced may not be transient, but can progressively develop over time in both humans and animal models. Targeting these tau changes for therapeutic intervention should be further explored to elucidate if disease progression can be reversed or mitigated.

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Tau progression in single severe frontal traumatic brain injury in human brains

Cited by 15 publications

References 43 publications

Reducing acetylated tau is neuroprotective in brain injury

Reducing acetylated tau is neuroprotective in brain injury

Space-occupying brain lesions, trauma-related tau astrogliopathy, and ARTAG: a report of two cases and a literature review

Association between single moderate to severe traumatic brain injury and long-term tauopathy in humans and preclinical animal models: a systematic narrative review of the literature

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