Traumatic brain injury and the pathways to cerebral tau accumulation

Flavin, William P.; Hosseini, Helia; Ruberti, Jeffrey W.; Kavehpour, H. Pirouz; Giza, Christopher C.; Prins, Mayumi L.

doi:10.3389/fneur.2023.1239653

Cited by 3 publications

(3 citation statements)

References 197 publications

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“…Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with no clinically successful treatment available to date [ 15 , 16 ]. TBI is commonly known as the sequela of head injuries, causing a sudden and rapid movement of the brain inside the skull [ 17 , 18 ]. These events could occur in sports or various types of professions, as well as in violence, accidents, or falls [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

Mavroudis,

Balmus,

Ciobica

et al. 2023

Life

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(1) Background: In this study, we aimed to explore the regulatory mechanism of miR-124-3p microglial exosomes, as they were previously reported to modulate neuroinflammation and promote neuronal repair following traumatic brain injury (TBI). (2) Methods: Studies investigating the impact of microglial exosomal miRNAs, specifically miR-124-3p, on injured neurons and brain microvascular endothelial cells (BMVECs) in the context of TBI were reviewed. (3) Results: Animal models of TBI, in vitro cell culture experiments, RNA sequencing analysis, and functional assays were employed to elucidate the mechanisms underlying the effects of miR-124-3p-loaded exosomes on neuroinflammation and neuronal repair. Anti-inflammatory M2 polarization of microglia, mTOR signaling suppression, and BMVECs-mediated autophagy were reported as the main processes contributing to neuroprotection, reduced blood-brain barrier leakage, and improved neurologic outcomes in animal models of TBI. (4) Conclusions: Microglial exosomes, particularly those carrying miR-124-3p, have emerged as promising candidates for therapeutic interventions in TBI. These exosomes exhibit neuroprotective effects, attenuate neuroinflammation, and promote neuronal repair and plasticity. However, further research is required to fully elucidate the underlying mechanisms and optimize their delivery strategies for effective treatment in human TBI cases.

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Section: Introductionmentioning

confidence: 99%

The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

Mavroudis,

Balmus,

Ciobica

et al. 2023

Life

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“…These “invisible injuries” have been regarded as the underlying causes leading to neurologic (e.g., dizziness, spatial disorientation, vision issues), somatic (e.g., headache, sleep disturbance, chronic pain) and mental health (e.g., depression, anxiety, post-traumatic stress disorder [PTSD]) symptoms. More importantly, mTBI due to blast has been regarded as a contributing factor for cognitive (e.g., poor memory, decreased concentration), and neurodegenerative disorders [e.g., Alzheimer’s disease-related dementias (ADRD), tauopathies, frontotemporal dementia (FTD), chronic traumatic encephalopathy (CTE)] ( Elder et al, 2019 ; Robinson-Freeman et al, 2020 ; Siedhoff et al, 2021 ; Flavin et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Individualized high-resolution analysis to categorize diverse learning and memory deficits in tau rTg4510 mice exposed to low-intensity blast

Zuckerman,

Siedhoff,

Balderrama

et al. 2024

Front. Cell. Neurosci.

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Mild traumatic brain injury (mTBI) resulting from low-intensity blast (LIB) exposure in military and civilian individuals is linked to enduring behavioral and cognitive abnormalities. These injuries can serve as confounding risk factors for the development of neurodegenerative disorders, including Alzheimer’s disease-related dementias (ADRD). Recent animal studies have demonstrated LIB-induced brain damage at the molecular and nanoscale levels. Nevertheless, the mechanisms linking these damages to cognitive abnormalities are unresolved. Challenges preventing the translation of preclinical studies into meaningful findings in “real-world clinics” encompass the heterogeneity observed between different species and strains, variable time durations of the tests, quantification of dosing effects and differing approaches to data analysis. Moreover, while behavioral tests in most pre-clinical studies are conducted at the group level, clinical tests are predominantly assessed on an individual basis. In this investigation, we advanced a high-resolution and sensitive method utilizing the CognitionWall test system and applying reversal learning data to the Boltzmann fitting curves. A flow chart was developed that enable categorizing individual mouse to different levels of learning deficits and patterns. In this study, rTg4510 mice, which represent a neuropathology model due to elevated levels of tau P301L, together with the non-carrier genotype were exposed to LIB. Results revealed distinct and intricate patterns of learning deficits and patterns within each group and in relation to blast exposure. With the current findings, it is possible to establish connections between mice with specific cognitive deficits to molecular changes. This approach can enhance the translational value of preclinical findings and also allow for future development of a precision clinical treatment plan for ameliorating neurologic damage of individuals with mTBI.

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“…Traumatic brain injury (TBI) is a major cause of death and disability worldwide, with no clinically successful treatment available to date [15,16]. TBI is commonly known as the sequela of head injuries, causing a sudden and rapid movement of the brain inside the skull [17,18]. These events could occur in sports or various types of professions, as well as in violence, accidents, or falls [19].…”

Section: Introductionmentioning

confidence: 99%

The Role of Microglial Exosomes and Mir-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

Mavroudis¹,

Ciobîcă²,

Nicoară³

et al. 2023

Preprint

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Background: This review aims to explore the regulatory mechanism of microglial exosomes, particularly focusing on the role of miR-124-3p, in modulating neuroinflammation and promoting neuronal repair following traumatic brain injury (TBI). Methods: Multiple studies investigating the impact of microglial exosomal miRNAs, specifically miR-124-3p, on injured neurons and brain microvascular endothelial cells (BMVECs) in the context of TBI were reviewed. Results: Animal models of TBI, in vitro cell culture experiments, RNA sequencing analysis, and functional assays were employed to elucidate the mechanisms underlying the effects of miR-124-3p-loaded exosomes on neuroinflammation and neuronal repair. The increased expression of miR-124-3p in microglial exosomes after TBI inhibited neuronal inflammation and promoted neurite outgrowth. This effect was achieved by promoting the anti-inflammatory M2 polarization of microglia, suppressing mTOR signaling through downregulation of PDE4B, and inducing autophagy in BMVECs. These actions collectively contributed to neuroprotection, reduced blood-brain barrier leakage, and improved neurologic outcomes in animal models of TBI. Conclusion: Microglial exosomes, particularly those carrying miR-124-3p, have emerged as promising candidates for therapeutic interventions in TBI. These exosomes exhibit neuroprotective effects, attenuate neuroinflammation, and promote neuronal repair and plasticity. Targeting miR-124-3p and utilizing microglial exosomes as therapeutic agents hold great potential for future clinical translation in TBI management. However, further research is required to fully elucidate the underlying mechanisms and optimize their delivery strategies for effective treatment in human TBI cases.

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Traumatic brain injury and the pathways to cerebral tau accumulation

Cited by 3 publications

References 197 publications

The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

The Role of Microglial Exosomes and miR-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

Individualized high-resolution analysis to categorize diverse learning and memory deficits in tau rTg4510 mice exposed to low-intensity blast

The Role of Microglial Exosomes and Mir-124-3p in Neuroinflammation and Neuronal Repair after Traumatic Brain Injury

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