BRAIN RESEARCH BULLETIN
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2019
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IF 3.103
Bin Chen,Zhenghong Chen,Mingjian Liu,Xiaorong Gao,Yijun Cheng,Yongxu Wei,Zhebao Wu,Derong Cui,Hanbing Shang
Intracerebral hemorrhage (ICH) is a devastating subtype of stroke because it has few viable therapeutic options to intervene against primary or second brain injury. Recently, evidence has suggested that ferroptosis, a nonapoptotic form of cell death, is involved in ICH. In this study, we examined whether ICH-induced neuron death is partly ferroptotic in humans and assessed its temporal and spatial characteristics in mice. Furthermore, the ferroptosis inhibitor ferrostatin-1 (Fer-1) was used to examine the role of ferroptosis after ICH. Fold changes in ferroptosis-related gene expression, intracellular iron levels, malondialdehyde (MDA) levels, and both protein levels and cellular localization of cyclooxygenase-2 (COX-2) were measured to monitor ferroptosis. Transmission electron microscopy (TEM) was also performed to examine the ultrastructure of cells after ICH. We found that the expression level of prostaglandin-endoperoxide synthase (PTGS2) was increased in both in vitro and in vivo ICH models; by comparison, expression level of RPL8 was increased in human brain tissue. In mice, iron and MDA levels were significantly increased 3 h after ICH; COX-2 levels were increased at 12 h after ICH and peaked at 3 days after ICH; COX-2 colocalized with NeuN (a neuronal biomarker); and TEM showed that shrunken mitochondria were found at 3 h, 3 days, and 7 days after ICH. Moreover, ICH-induced neurological deficits, memory impairment and brain atrophy were reduced by Fer-1 treatment. Our results demonstrated that neuronal ferroptosis occurs during the acute phase of ICH in brain areas distant from the hematoma and that inhibition of ferroptosis by Fer-1 exerted a long-term cerebroprotective effect.
研究领域:
神经科学
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药理学
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分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Reports Medicine
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2025
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IF 10.6
Kaiyu Xu,Ying Zhang,Yongxuan Chen,Xiaojia Zhu,Yu Li,Longbao Lv,Xiechao He,Zhengfei Hu,Yifan Li,Maosen Ye,Dewei Jiang,Zhanlong He,Weihua Jin,Yanyan Li,Xiaomei Yu,Deng-Feng Zhang,Karl Herrup,Ping Zheng,Yong-Gang Yao,Dong-Dong Wu,Jiali Li
Ataxia-telangiectasia (A-T) is a hereditary neurodegenerative disorder caused by mutations in the ATM (ataxia-telangiectasia mutated) gene. Although existing rodent models reproduce some of the multi-systemic features of A-T, they notably fail to recapitulate the severe neurological manifestations, particularly the profound cerebellar atrophy and associated ataxia. To address this limitation, we have generated ATM-deficient rhesus macaques using CRISPR-Cas9. These macaques exhibit hallmark features of A-T, including growth retardation, lymphopenia, elevated a-fetoprotein levels, oculocutaneous telangiectasias, heightened sensitivity to ionizing radiation, and most critically, cerebellar atrophy, Purkinje cell loss, and early-stage cerebellar neurodegeneration leading to significant motor impairments. Single-nucleus transcriptomic profiling of the cerebellum revealed pronounced gene expression changes associated with ATM deficiency, particularly in molecular layer interneurons (MLIs), which are implicated in Purkinje cell loss. This non-human primate model provides deeper insights into the pathogenesis of A-T and represents a promising and valuable platform for developing therapeutic strategies.
研究领域:
神经生物学
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遗传学
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分子医学
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转化医学
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发育生物学
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基因编辑
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神经退行性疾病
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Autophagy
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2024
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IF 14.6
Kateřina Veverová,Jan Laczó,Alžběta Katonová,Hana Horáková,Veronika Matušková,Francesco Angelucci,Martina Laczó,Zuzana Nedelská,Jakub Hort,He-Ling Wang,Jianying Zhang,Liu Shi,Evandro Fei Fang,Martin Vyhnálek
Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation: Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.
研究领域:
神经病学
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神经退行性疾病
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生物标志物研究
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临床神经科学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）