Mechanical stress increases brain amyloid β, tau, and α‐synuclein concentrations in wild‐type mice

Nogueira, Marcel Levy; Hamraz, Minoo; Abolhassani, Mohammad; Bigan, Erwan; Lafitte, Olivier; Steyaert, Jean-Marc; Dubois, Bruno; Schwartz, Laurent

doi:10.1016/j.jalz.2017.11.003

Cited by 24 publications

(13 citation statements)

References 51 publications

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“…It may be possible to monitor intra-seasonal sport related brain trauma through the evaluation of serum levels of the neurofilament-light chain, but this has not demonstrated good long-term prognostic accuracy to date [76]. Despite the association between tau and mechanical trauma [56], plasma levels of tau are not altered in accord with trauma frequency or severity during the course of an American football season [76]. The current and previous findings [72], suggest different forms of tau pathology provide a diverse set of markers to track CTE development and efficacy of tau-mediated treatments, especially in the pre-symptomatic stages of this disorder [7, 58, 72, 87].…”

Section: Discussionmentioning

confidence: 99%

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Kelley

Perez

Mufson

2019

acta neuropathol commun

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Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition associated with repetitive traumatic brain injury (rTBI) seen in contact-sport athletes and military personnel. The medial temporal lobe (MTL; i.e., hippocampus, subiculum, and entorhinal and perirhinal cortices) memory circuit displays tau lesions during the pathological progression of CTE. We examined MTL tissue obtained from 40 male Caucasian and African American athletes who received a postmortem CTE neuropathological diagnosis defined as stage II, III, or IV. Sections were immunolabeled using an early (AT8) or a late (TauC3) marker for pathological tau and for amyloid beta (Aβ) species (6E10, Aβ1–42 and thioflavin S). Stereological analysis revealed that stage III had significantly less AT8-positive neurons and dystrophic neurites than stage IV in all MTL regions except hippocampal subfield CA3, whereas significantly more AT8-positive neurons, dystrophic neurites, and neurite clusters were found in the perirhinal cortex, entorhinal cortex, hippocampal CA1, and subiculum of CTE stage III compared with stage II. TauC3-positive pathology was significantly higher in the perirhinal and subicular cortex of stage IV compared to stage III and the perirhinal cortex of stage III compared to stage II. AT8-positive neurite clusters were observed in stages III and IV, but virtually absent in stage II. When observed, Aβ pathology appeared as amyloid precursor protein (APP)/Aβ (6E10)-positive diffuse plaques independent of region. Thioflavine S labeling, did not reveal evidence for fibril or neuritic pathology associated with plaques, confirming a diffuse, non-cored plaque phenotype in CTE. Total number of AT8-positive profiles correlated with age at death, age at symptom onset, and time from retirement to death. There was no association between AT8-positive tau pathology and age sport began, years played, or retirement age, and no difference between CTE stage and the highest level of sport played. In summary, our findings demonstrate different tau profiles in the MTL across CTE stages, proffering CA3 tau pathology and MTL dystrophic neurite clusters as possible markers for the transition between early (II) and late (III/IV) stages, while highlighting CTE as a progressive noncommunicative tauopathy.

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Section: Discussionmentioning

confidence: 99%

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Kelley

Perez

Mufson

2019

acta neuropathol commun

View full text Add to dashboard Cite

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“…In a recent study to investigate the link between TBI and neurodegenerative disorders, 5–6-week-old mice were exposed to multiple condition head impacts and the levels of several proteins were examined. The results showed that after repetitive TBI, there was an increase in brain amyloid β, tau, and α-syn in a dose-dependent manner [102]. α-Syn accumulation has also been detected in glial cells [3], predominantly in microglia compared to astrocytes [85].…”

Section: Exogenous and Environmental Factors Modulating Selective Regmentioning

confidence: 99%

Selective vulnerability in α-synucleinopathies

et al. 2019

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Parkinson’s disease, dementia with Lewy bodies, and multiple system atrophy are neurodegenerative disorders resulting in progressive motor/cognitive deficits among other symptoms. They are characterised by stereotypical brain cell loss accompanied by the formation of proteinaceous aggregations of the protein α-synuclein (α-syn), being, therefore, termed α-synucleinopathies. Although the presence of α-syn inclusions is a common hallmark of these disorders, the exact nature of the deposited protein is specific to each disease. Different neuroanatomical regions and cellular populations manifest a differential vulnerability to the appearance of protein deposits, cell dysfunction, and cell death, leading to phenotypic diversity. The present review describes the multiple factors that contribute to the selective vulnerability in α-synucleinopathies. We explore the intrinsic cellular properties in the affected regions, including the physiological and pathophysiological roles of endogenous α-syn, the metabolic and genetic build-up of the cells and their connectivity. These factors converge with the variability of the α-syn conformational strains and their spreading capacity to dictate the phenotypic diversity and regional vulnerability of each disease. Finally, we describe the exogenous and environmental factors that potentially contribute by igniting and modulating the differential pathology in α-synucleinopathies. In conclusion, we think that it is the confluence of this disruption of the cellular metabolic state and α-syn structural equilibrium through the anatomical connectivity which appears to initiate cascades of pathological processes triggered by genetic, environmental, or stochastic events that result in the “death by a thousand cuts” profile of α-synucleinopathies.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02010-2) contains supplementary material, which is available to authorized users.

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“…Stress can increase APP and tau phosphorylation in AD progression (Caruso and others 2018). Repetitive mild TBI-induced mechanical stress increases brain levels of Aβ1-42 peptide, tau, and α-synuclein-mediated neurodegeneration in mice (Levy Nogueira and others 2018). Restraint stress in AD mouse models (Tg2576) showed increased Aβ (1-42), tau hyperphosphorylation, and cortical neuronal atrophy (Lee and others 2009).…”

Section: Influence Of Personal Traits On Tbi-mediated Ad Pathogenesismentioning

confidence: 99%

Brain Injury–Mediated Neuroinflammatory Response and Alzheimer’s Disease

et al. 2019

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Traumatic brain injury (TBI) is a major health problem in the United States, which affects about 1.7 million people each year. Glial cells, T-cells, and mast cells perform specific protective functions in different regions of the brain for the recovery of cognitive and motor functions after central nervous system (CNS) injuries including TBI. Chronic neuroinflammatory responses resulting in neuronal death and the accompanying stress following brain injury predisposes or accelerates the onset and progression of Alzheimer’s disease (AD) in high-risk individuals. About 5.7 million Americans are currently living with AD. Immediately following brain injury, mast cells respond by releasing prestored and preactivated mediators and recruit immune cells to the CNS. Blood-brain barrier (BBB), tight junction and adherens junction proteins, neurovascular and gliovascular microstructural rearrangements, and dysfunction associated with increased trafficking of inflammatory mediators and inflammatory cells from the periphery across the BBB leads to increase in the chronic neuroinflammatory reactions following brain injury. In this review, we advance the hypothesis that neuroinflammatory responses resulting from mast cell activation along with the accompanying risk factors such as age, gender, food habits, emotional status, stress, allergic tendency, chronic inflammatory diseases, and certain drugs can accelerate brain injury-associated neuroinflammation, neurodegeneration, and AD pathogenesis.

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Mechanical stress increases brain amyloid β, tau, and α‐synuclein concentrations in wild‐type mice

Abstract: Dose-dependent and cumulative influence of repetitive mild traumatic brain injury-induced mechanical stress may trigger and/or accelerate neurodegeneration by pushing protein concentration over the disease threshold.

Cited by 24 publications

References 51 publications

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Tau pathology in the medial temporal lobe of athletes with chronic traumatic encephalopathy: a chronic effects of neurotrauma consortium study

Selective vulnerability in α-synucleinopathies

Brain Injury–Mediated Neuroinflammatory Response and Alzheimer’s Disease

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