Reduction of Autophagosome Overload Attenuates Neuronal Cell Death After Traumatic Brain Injury

Quan, Xingyun; Li, Song; Zheng, Xiaoliang; Liu, Shenjie; Ding, Huaqiang; Li, Sijing; Guang-hui, XU; Li, Xin; Liu, Liang

doi:10.1016/j.neuroscience.2021.02.007

Cited by 8 publications

(7 citation statements)

References 39 publications

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“…Conversely, CTSD levels showed a negative correlation with brain water content and a positive correlation with Nissl body content. These findings suggest that impaired autophagic flux worsens brain edema and neural injury, consistent with previous observations in in vivo models [15,16,18,32].…”

Section: Discussionsupporting

confidence: 92%

Impaired autophagic flux in the human brain after traumatic brain injury

Lang,

Sun,

Feng

et al. 2024

NeuroReport

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Emerging evidence indicates that dysfunctional autophagic flux significantly contributes to the pathology of experimental traumatic brain injury (TBI). The current study aims to clarify its role post-TBI using brain tissues from TBI patients. Histological examinations, including hematoxylin and eosin, Nissl staining, and brain water content analysis, were employed to monitor brain damage progression. Electron microscopy was used to visualize autophagic vesicles. Western blotting and immunohistochemistry were performed to analyze the levels of important autophagic flux-related proteins such as Beclin1, autophagy-related protein 5, lipidated microtubule-associated protein light-chain 3 (LC3-II), autophagic substrate sequestosome 1 (SQSTM1/p62), and cathepsin D (CTSD), a lysosomal enzyme. Immunofluorescence assays evaluated LC3 colocalization with NeuN, P62, or CTSD, and correlation analysis linked autophagy-related protein levels with brain water content and Nissl bodies. Early-stage TBI results showed increased autophagic vesicles and LC3-positive neurons, suggesting autophagosome accumulation due to enhanced initiation and reduced clearance. As TBI progressed, LC3-II and P62 levels increased, while CTSD levels decreased. This indicates autophagosome overload from impaired degradation rather than increased initiation. The study reveals a potential association between worsening brain damage and impaired autophagic flux post-TBI, positioning improved autophagic flux as a viable therapeutic target for TBI.

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Section: Discussionsupporting

confidence: 92%

Impaired autophagic flux in the human brain after traumatic brain injury

Lang,

Sun,

Feng

et al. 2024

NeuroReport

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“…Our knowledge of TBI pathophysiology in aged animals is limited, and our understanding of the secondary injury mechanisms that affect long-term outcome remains poor. Whereas direct targeting of inflammatory pathways in old mice appears beneficial in experimental settings [ 31 , 45 ], therapeutic intervention of other proposed injury mechanisms, such as autophagy [ 54 ], has not been addressed in older animals. Both normal aging and the chronic phase of TBI are associated with a basal elevation in microglial activation and neuroinflammation.…”

Section: Introductionmentioning

confidence: 99%

Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice

Ritzel

Lei

et al. 2022

GeroScience

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Elderly patients with traumatic brain injury (TBI) have greater mortality and poorer outcomes than younger individuals. The extent to which old age alters long-term recovery and chronic microglial activation after TBI is unknown, and evidence for therapeutic efficacy in aged mice is sorely lacking. The present study sought to identify potential inflammatory mechanisms underlying age-related outcomes late after TBI. Controlled cortical impact was used to induce moderate TBI in young and old male C57BL/6 mice. At 12 weeks post-injury, aged mice exhibited higher mortality, poorer functional outcomes, larger lesion volumes, and increased microglial activation. Transcriptomic analysis identified age- and TBI-specific gene changes consistent with a disease-associated microglial signature in the chronically injured brain, including those involved with complement, phagocytosis, and autophagy pathways. Dysregulation of phagocytic and autophagic function in microglia was accompanied by increased neuroinflammation in old mice. As proof-of-principle that these pathways have functional importance, we administered an autophagic enhancer, trehalose, in drinking water continuously for 8 weeks after TBI. Old mice treated with trehalose showed enhanced functional recovery and reduced microglial activation late after TBI compared to the sucrose control group. Our data indicate that microglia undergo chronic changes in autophagic regulation with both normal aging and TBI that are associated with poorer functional outcome. Enhancing autophagy may therefore be a promising clinical therapeutic strategy for TBI, especially in older patients.

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“… Sarkar et al (2014) found that P62 was increased in both the cortex and hippocampus of brain-injured rats, suggesting that inactive lysosomal inhibits autophagy and negatively regulates neurological function. Other data revealed a high neuronal survival rate and fewer nervous system defects in VPS34 gene-deficient rats compared to normal rats, indicating that nociceptors are also protected by a reduction in excess autophagosomes ( Quan et al, 2021 ).…”

Section: The Role Of Autophagy In Cns Traumamentioning

confidence: 99%

Targeting autophagy process in center nervous trauma

Wei

Yan

2023

Front. Neurosci.

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The central nervous system (CNS) is the primary regulator of physiological activity, and when CNS is compromised, its physical functions are affected. Spinal cord injury (SCI) and traumatic brain injury (TBI) are common trauma in CNS that are difficult to recover from, with a higher global disability and mortality rate. Autophagy is familiar to almost all researchers due to its role in regulating the degradation and recycling of cellular defective or incorrect proteins and toxic components, maintaining body balance and regulating cell health and function. Emerging evidence suggests it has a broad and long-lasting impact on pathophysiological process such as oxidative stress, inflammation, apoptosis, and angiogenesis, involving the alteration of autophagy marker expression and function recovery. Changes in autophagy level are considered a potential therapeutic strategy and have shown promising results in preclinical studies for neuroprotection following traumatic brain injury. However, the relationship between upward or downward autophagy and functional recovery following SCI or TBI is debatable. This article reviews the regulation and role of autophagy in repairing CNS trauma and the intervention effects of autophagy-targeted therapeutic agents to find more and better treatment options for SCI and TBI patients.

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Reduction of Autophagosome Overload Attenuates Neuronal Cell Death After Traumatic Brain Injury

Cited by 8 publications

References 39 publications

Impaired autophagic flux in the human brain after traumatic brain injury

Impaired autophagic flux in the human brain after traumatic brain injury

Functional and transcriptional profiling of microglial activation during the chronic phase of TBI identifies an age-related driver of poor outcome in old mice

Targeting autophagy process in center nervous trauma

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