Molecular mechanisms involved in the destabilization of two types of R3-R4 tau fibrils associated with chronic traumatic encephalopathy by Fisetin.

Chronic traumatic encephalopathy is a neurodegenerative tauopathy pathologically characterized by fibrillary tau aggregates in the depth of sulci. Clearing fibrous tau aggregates is considered a promising strategy in the treatment of CTE. Fisetin (FS), a natural polyphenolic small molecule, was confirmed to disassociate the tau filaments in vitro. However, the molecular mechanisms of FS in destabilizing the CTE-related R3-R4 tau fibrils remain largely unknown. In this study, we compared the atomic-level structural differences of the two types of CTE-related R3-R4 tau fibrils and explored the influence and molecular mechanisms of FS on the two types of fibrils by conducting multiple molecular dynamics (MD) simulations. The results reveal that the type 1 fibril displays higher structural stability than the type 2 fibril, with a lower root-mean-square-fluctuation value and higher ß-sheet structure probability. FS can destabilize both types of fibrils by decreasing the ß-sheet structure content, interrupting the mainchain H-bond network, and increasing the solvent accessible surface area and ß7-ß8 angle of the fibrils. H-bonding, π-π stacking and cation-π are the common interactions driving FS molecules binding on the two types of fibrils, while the hydrophobic interaction occurs only in the type 2 fibril. Due to the relatively short simulation time, our study captures the early molecular mechanisms. However, it does provide beneficial information for the design of drugs to prevent or treat CTE.

Understanding the Molecular Progression of Chronic Traumatic Encephalopathy in Traumatic Brain Injury, Aging and Neurodegenerative Disease.

Traumatic brain injury (TBI) is one of the leading causes of death and disability among children and adults in America. In addition, the acute morbidity caused by TBI is implicated in the development of devastating neuropsychiatric and neurodegenerative sequela. TBI is associated with the development of a neurodegenerative condition termed 'Punch Drunk syndrome' or 'dementia pugilistica', and the more recently renamed 'chronic traumatic encephalopathy'. Chronic traumatic encephalopathy (CTE) is a slowly progressive neurodegenerative condition caused by a single or repetitive blow to the head. CTE was first described in boxers and was later found to be associated with other contact sports and military combat. It is defined by a constellation of symptoms consisting of mood disorders, cognitive impairment, and memory loss with or without sensorimotor changes. It is also a Tauopathy characterized by the deposition of hyperphosphorylated Tau protein in the form of neurofibrillary tangles, astrocytoma tangles, and abnormal neurites found in clusters around small vessels, typically at the sulcal depths. Oxidative stress, neuroinflammation, and glutaminergic toxicity caused due to the insult play a role in developing this pathology. Additionally, the changes in the brain due to aging also plays an important role in the development of this condition. In this review, we discuss the molecular mechanisms behind the development of CTE, as well as genetic and environmental influences on its pathophysiology.

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

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.

CCL2 is associated with microglia and macrophage recruitment in chronic traumatic encephalopathy.

BACKGROUND: Neuroinflammation has been implicated in the pathogenesis of chronic traumatic encephalopathy (CTE), a progressive neurodegenerative disease association with exposure to repetitive head impacts (RHI) received though playing contact sports such as American football. Past work has implicated early and sustained activation of microglia as a potential driver of tau pathology within the frontal cortex in CTE. However, the RHI induced signals required to recruit microglia to areas of damage and pathology are unknown. METHODS: Postmortem brain tissue was obtained from 261 individuals across multiple brain banks. Comparisons were made using cases with CTE, cases with Alzheimer's disease (AD), and cases with no neurodegenerative disease and lacked exposure to RHI (controls). Recruitment of Iba1+ cells around the CTE perivascular lesion was compared to non-lesion vessels. TMEM119 staining was used to characterize microglia or macrophage involvement. The potent chemoattractant CCL2 was analyzed using frozen tissue from the dorsolateral frontal cortex (DLFC) and the calcarine cortex. Finally, the amounts of hyperphosphorylated tau (pTau) and Aß42 were compared to CCL2 levels to examine possible mechanistic pathways. RESULTS: An increase in Iba1+ cells was found around blood vessels with perivascular tau pathology compared to non-affected vessels in individuals with RHI. TMEM119 staining revealed the majority of the Iba1+ cells were microglia. CCL2 protein levels in the DLFC were found to correlate with greater years of playing American football, the density of Iba1+ cells, the density of CD68+ cells, and increased CTE severity. When comparing across multiple brain regions, CCL2 increases were more pronounced in the DLFC than the calcarine cortex in cases with RHI but not in AD. When examining the individual contribution of pathogenic proteins to CCL2 changes, pTau correlated with CCL2, independent of age at death and Aß42 in AD and CTE. Although levels of Aß42 were not correlated with CCL2 in cases with CTE, in males in the AD group, Aß42 trended toward an inverse relationship with CCL2 suggesting possible gender associations. CONCLUSION: Overall, CCL2 is implicated in the pathways recruiting microglia and the development of pTau pathology after exposure to RHI, and may represent a future therapeutic target in CTE.

Preventive potential of low intensity pulsed ultrasound for chronic traumatic encephalopathy after repetitive head collisions in contact sports.

Chronic traumatic encephalopathy (CTE), a disease process well-recognized in boxers, American football players and military personnel, is a progressive neurodegenerative disease caused by repetitive blows to the head. Subjects with CTE can have a wide range of emotional, cognitive and physical symptoms. The cognitive group patients had a significantly higher probability of developing dementia in later years. Currently, there are no disease modifying regimen for CTE. Timely intervention of head blow could diminish the development of CTE. Low-intensity pulsed ultrasound (LIPUS) is a common adjunct used to promote bone healing for fresh fracture. Recent reports suggest that LIPUS can noninvasively modulate the cortical function and have neuroprotective effect in various animal models of traumatic brain injury, stroke, Alzheimer's disease and major depressive disorder. The multifunctional mechanisms of LIPUS neuroprotective effect include several trophic factor stimulations, anti-inflammatory properties and reduction of brain edema. From the above evidence, LIPUS intervention could be a strategy for the prevention of the clinical CTE sequelae of repetitive head blows. We hypothesized that due to its neuroprotective effects, the non-invasive and easy-to-use method of LIPUS brain stimulation could have a preventive effect on players who have head blows during the match. The development of a time sensitive protocol, resembling the therapeutic algorithm for traumatic brain injury, would potentially prevent the development of subsequent CTE adverse outcome. Further long-term longitudinal studies of LIPUS stimulation are warranted to verify the prevention efficacy of this intervention for CTE.