For a long time, the brain was considered an organ with “immune privilege”, where microglial cells played a phagocytic role, maintaining immune self-sufficiency. However, recent studies have revealed the presence of immune-related structures and immune cell infiltration in the brain, which participates in adaptive immunity.
Aim of Review
This review aims to synthesize recent findings on the activation and long-term maintenance of adaptive immunity in the central nervous system (CNS), exploring how adaptive immune responses function in pathogen clearance, tumor defense, and CNS inflammation. It highlights both the protective and detrimental roles of adaptive immunity in these contexts.
Key Scientific Concepts
Antigen-presenting cells (APCs) present antigen information to naive T cells, initiating adaptive immunity in the CNS. Activated T cells can differentiate into effector T cells to perform immediate immune functions or into tissue-resident memory T cells (TRMs) that persist in the CNS, providing long-term immune surveillance. Over the past 15 years, studies have shown that adaptive immunity is activated and maintained during intracranial pathogen infections, brain tumors, and CNS inflammation. While adaptive immunity can clear pathogens, eliminate tumor cells, and protect the brain, it can also lead to CNS inflammation under certain conditions, resulting in undesirable outcomes.
{"title":"Activation and Long-Term Maintenance of Adaptive Immunity in the Central Nervous System: A Double-Edged Sword?","authors":"Luojinyun Wang, Feng Zhang, Jiehong Wu, Sibo Yang, Daqiang Zhou, Xiaodi Sun, Bohao Chang, Bo Hu, Yifan Zhou","doi":"10.1002/cns.70697","DOIUrl":"10.1002/cns.70697","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>For a long time, the brain was considered an organ with “immune privilege”, where microglial cells played a phagocytic role, maintaining immune self-sufficiency. However, recent studies have revealed the presence of immune-related structures and immune cell infiltration in the brain, which participates in adaptive immunity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aim of Review</h3>\u0000 \u0000 <p>This review aims to synthesize recent findings on the activation and long-term maintenance of adaptive immunity in the central nervous system (CNS), exploring how adaptive immune responses function in pathogen clearance, tumor defense, and CNS inflammation. It highlights both the protective and detrimental roles of adaptive immunity in these contexts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Key Scientific Concepts</h3>\u0000 \u0000 <p>Antigen-presenting cells (APCs) present antigen information to naive T cells, initiating adaptive immunity in the CNS. Activated T cells can differentiate into effector T cells to perform immediate immune functions or into tissue-resident memory T cells (TRMs) that persist in the CNS, providing long-term immune surveillance. Over the past 15 years, studies have shown that adaptive immunity is activated and maintained during intracranial pathogen infections, brain tumors, and CNS inflammation. While adaptive immunity can clear pathogens, eliminate tumor cells, and protect the brain, it can also lead to CNS inflammation under certain conditions, resulting in undesirable outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cns.70697","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145740207","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Myocardial ischemia–reperfusion injury (MIRI) represents an inevitable risk event for acute myocardial infarction. We explored the mechanism of hypoxia-induced high-mobility group box 1 (HMGB1) promoting MIRI by modulating the NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis via the Nrf2/HO-1 pathway.
Methods
In vitro cultured mouse cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to establish an MIRI cell model, then treated with short hairpin-HMGB1, a NLRP3 agonist (Nigericin), and a Nrf2 inhibitor (ML385). Cell viability and injury were assessed via MTT and LDH assays. HMGB1 (nuclear/cytoplasm), Nrf2 (nuclear/cytoplasm), HO-1, NLRP3, ASC, cleaved Caspase-1, and GSDMD-N protein levels, and IL-1β and IL-18 levels in cell supernatants were determined by western blot and ELISA. HMGB1 and Nrf2 distribution were analyzed by immunofluorescence, with their interaction verified by co-immunoprecipitation. An MIRI mouse model was developed and treated with HMGB1 Box A for in vivo verification.
Results
H/R induction declined the nuclear HMGB1 protein level and cell viability, and intensified the cytoplasmic HMGB1 protein level, cell damage, and pyroptosis-related protein and inflammatory cytokine levels, which were averted by HMGB1 knockdown. NLRP3 activation partially reversed HMGB1 knockdown's effect on improving cardiomyocyte pyroptosis. Hypoxia-induced HMGB1 inhibited Nrf2/HO-1 activation by interacting with Nrf2. Nrf2/HO-1 suppression partly counteracted HMGB1 knockdown's suppressive effects on NLRP3 inflammasome activation and pyroptosis. HMGB1 suppressed the Nrf2/HO-1 axis to enhance NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis, thereby exacerbating MIRI in vivo.
Conclusion
Hypoxia induces HMGB1's nucleus-to-cytoplasm translocation, which binds to Nrf2 to repress Nrf2 nuclear translocation to suppress Nrf2/HO-1 activation to promote NLRP3 inflammasome/Caspase-1-mediated pyroptosis, thereby exacerbating MIRI.
{"title":"Mechanism of Hypoxia-Induced HMGB1 Regulating NLRP3 Inflammasome/Caspase-1 Pathway-Mediated Pyroptosis in Myocardial Ischemia Reperfusion Injury Through the Nrf2/HO-1 Pathway","authors":"Fuzhen Zheng, Licheng Yan, Fei Ren, Wenlong Cai, Yongrong Lan, Hong Chen, Qian Chen, Guoxing Weng","doi":"10.1111/cns.70661","DOIUrl":"10.1111/cns.70661","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Myocardial ischemia–reperfusion injury (MIRI) represents an inevitable risk event for acute myocardial infarction. We explored the mechanism of hypoxia-induced high-mobility group box 1 (HMGB1) promoting MIRI by modulating the NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis via the Nrf2/HO-1 pathway.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In vitro cultured mouse cardiomyocytes were exposed to hypoxia/reoxygenation (H/R) to establish an MIRI cell model, then treated with short hairpin-HMGB1, a NLRP3 agonist (Nigericin), and a Nrf2 inhibitor (ML385). Cell viability and injury were assessed via MTT and LDH assays. HMGB1 (nuclear/cytoplasm), Nrf2 (nuclear/cytoplasm), HO-1, NLRP3, ASC, cleaved Caspase-1, and GSDMD-N protein levels, and IL-1β and IL-18 levels in cell supernatants were determined by western blot and ELISA. HMGB1 and Nrf2 distribution were analyzed by immunofluorescence, with their interaction verified by co-immunoprecipitation. An MIRI mouse model was developed and treated with HMGB1 Box A for in vivo verification.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>H/R induction declined the nuclear HMGB1 protein level and cell viability, and intensified the cytoplasmic HMGB1 protein level, cell damage, and pyroptosis-related protein and inflammatory cytokine levels, which were averted by HMGB1 knockdown. NLRP3 activation partially reversed HMGB1 knockdown's effect on improving cardiomyocyte pyroptosis. Hypoxia-induced HMGB1 inhibited Nrf2/HO-1 activation by interacting with Nrf2. Nrf2/HO-1 suppression partly counteracted HMGB1 knockdown's suppressive effects on NLRP3 inflammasome activation and pyroptosis. HMGB1 suppressed the Nrf2/HO-1 axis to enhance NLRP3 inflammasome/Caspase-1 pathway-mediated pyroptosis, thereby exacerbating MIRI in vivo.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Hypoxia induces HMGB1's nucleus-to-cytoplasm translocation, which binds to Nrf2 to repress Nrf2 nuclear translocation to suppress Nrf2/HO-1 activation to promote NLRP3 inflammasome/Caspase-1-mediated pyroptosis, thereby exacerbating MIRI.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12696884/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720127","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Dl-3-n-butylphthalide (NBP) is a novel agent for acute ischemic stroke. This study aimed to investigate its effects on cortical angiogenesis and vasodilation during stroke recovery.
Methods
Mice underwent distal middle cerebral artery occlusion (dMCAO) and subsequently received NBP treatment. Therapeutic efficacy was measured by neurological deficits and infarct size. Angiogenesis was assessed by immunofluorescent staining. Laser speckle and two-photon microscopy imaging were employed to evaluate dynamic changes in cortical cerebral blood flow and vascular structure in vivo. The modulation of the Akt/GSK-3β signaling pathway was detected by western blotting.
Results
NBP administration promoted neurological recovery and reduced infarct size in the subacute phase. It facilitated cerebral blood flow and vasodilation, enhanced angiogenesis as evidenced by increased BrdU+/CD31+ cells and improved astrocyte/pericyte coverage around microvessels. Moreover, the pro-angiogenesis effect of NBP depends on the activation of the Akt/GSK-3β pathway, and this effect is blocked by LY294002.
Conclusion
In conclusion, NBP enhances recovery after ischemic stroke by promoting cortical angiogenesis and vasodilation through activation of the Akt/GSK-3β pathway. These findings highlight its therapeutic potential for delayed intervention in ischemic stroke.
{"title":"Dl-3-n-Butylphthalide Promotes Cortical Angiogenesis via Akt/GSK-3β Signaling in Ischemic Stroke Mice","authors":"Lan Zhang, Shanshan Wei, Jian Zhang, Rong Chen, Jiangyong Miao, Lina Wang, Peipei Zhang, Wenyan Shang, Renhao Xu, Xiangjian Zhang, Cong Zhang","doi":"10.1002/cns.70698","DOIUrl":"10.1002/cns.70698","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Dl-3-n-butylphthalide (NBP) is a novel agent for acute ischemic stroke. This study aimed to investigate its effects on cortical angiogenesis and vasodilation during stroke recovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice underwent distal middle cerebral artery occlusion (dMCAO) and subsequently received NBP treatment. Therapeutic efficacy was measured by neurological deficits and infarct size. Angiogenesis was assessed by immunofluorescent staining. Laser speckle and two-photon microscopy imaging were employed to evaluate dynamic changes in cortical cerebral blood flow and vascular structure in vivo. The modulation of the Akt/GSK-3β signaling pathway was detected by western blotting.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NBP administration promoted neurological recovery and reduced infarct size in the subacute phase. It facilitated cerebral blood flow and vasodilation, enhanced angiogenesis as evidenced by increased BrdU<sup>+</sup>/CD31<sup>+</sup> cells and improved astrocyte/pericyte coverage around microvessels. Moreover, the pro-angiogenesis effect of NBP depends on the activation of the Akt/GSK-3β pathway, and this effect is blocked by LY294002.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>In conclusion, NBP enhances recovery after ischemic stroke by promoting cortical angiogenesis and vasodilation through activation of the Akt/GSK-3β pathway. These findings highlight its therapeutic potential for delayed intervention in ischemic stroke.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12695697/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720097","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Post-stroke cognitive impairment (PSCI) is a prevalent and disabling condition with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive neuromodulation therapy. This review synthesizes recent advances in rTMS for PSCI, focusing on its mechanisms, therapeutic effects across cognitive domains, and safety profile.
Methods
We summarize evidence indicating that rTMS exerts its effects by modulating cortical excitability, promoting neuroplasticity via BDNF signaling, and regulating dysfunctional brain networks, particularly the central executive and default mode networks.
Results
Clinical studies demonstrate that high-frequency stimulation, primarily targeting the dorsolateral prefrontal cortex (DLPFC), can significantly improve memory, executive function, attention, and activities of daily living (ADLs) in patients with PSCI. A favorable safety profile is reported, with mild and transient adverse effects being most common. However, significant heterogeneity in stimulation parameters (e.g., frequency, intensity, pulses) exists across studies. Current evidence suggests that ensuring a sufficient number of stimulation pulses and duration may be necessary.
Conclusion
rTMS represents a promising therapeutic tool for PSCI, demonstrating benefits in key cognitive and functional domains. Future research must prioritize large-scale, standardized randomized controlled trials to optimize stimulation protocols, confirm long-term efficacy, and explore synergistic combinations with other rehabilitation strategies.
{"title":"Recent Advances in Repetitive Transcranial Magnetic Stimulation for the Treatment of Post-Stroke Cognitive Impairment","authors":"Yu Liu, Yansong Li, Ding Ding, Aiguo Xie, Jiaran Yan, Xiaojin Xu, Zihan Zhao, Jing Wu, Jing Wang, Mingfeng Qian","doi":"10.1002/cns.70702","DOIUrl":"10.1002/cns.70702","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Post-stroke cognitive impairment (PSCI) is a prevalent and disabling condition with limited effective treatment options. Repetitive transcranial magnetic stimulation (rTMS) has emerged as a potential non-invasive neuromodulation therapy. This review synthesizes recent advances in rTMS for PSCI, focusing on its mechanisms, therapeutic effects across cognitive domains, and safety profile.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We summarize evidence indicating that rTMS exerts its effects by modulating cortical excitability, promoting neuroplasticity via BDNF signaling, and regulating dysfunctional brain networks, particularly the central executive and default mode networks.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Clinical studies demonstrate that high-frequency stimulation, primarily targeting the dorsolateral prefrontal cortex (DLPFC), can significantly improve memory, executive function, attention, and activities of daily living (ADLs) in patients with PSCI. A favorable safety profile is reported, with mild and transient adverse effects being most common. However, significant heterogeneity in stimulation parameters (e.g., frequency, intensity, pulses) exists across studies. Current evidence suggests that ensuring a sufficient number of stimulation pulses and duration may be necessary.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>rTMS represents a promising therapeutic tool for PSCI, demonstrating benefits in key cognitive and functional domains. Future research must prioritize large-scale, standardized randomized controlled trials to optimize stimulation protocols, confirm long-term efficacy, and explore synergistic combinations with other rehabilitation strategies.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12695691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720132","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anticholinergic drugs (ACDs) and the neurodegeneration biomarker neurofilament light chain (NfL) are associated with dementia; however, the interplay between anticholinergic drug exposure and neurodegeneration in dementia risk remains underexplored.
Methods
This prospective cohort study analyzed 1529 dementia-free adults (median follow-up 5.2 years) from the Shanghai Aging Study. Cumulative anticholinergic burden was quantified using the anticholinergic cognitive burden (ACB) scale and total standardized daily dose (TSDD) over 1 year pre-baseline. Neurofilament light chain (NfL) levels were assayed via single-molecule array (Simoa).
Results
Elevated NfL (adjusted HR 1.77, 95% CI, 1.07–2.92) and TSDD exposure (HR 1.55, 1.08–2.24) were independently associated with incident dementia risk. Participants with both TSDD exposure and high NfL levels showed substantially greater cumulative dementia incidence versus those with no TSDD/low NfL (log-rank p < 0.0001; adjusted HR 2.24, 1.20–4.20). Individuals with both high TSDD and high NfL demonstrated a significantly higher dementia risk (HR 6.34, 95% CI, 1.90–21.20) compared to low-burden counterparts.
Conclusions
These findings identify plasma NfL as a critical modifier of anticholinergic-related cognitive vulnerability, providing mechanistic insights for risk stratification and supporting biomarker-guided deprescribing strategies in older adults exposed to ACDs.
{"title":"Joint Effects of Anticholinergic Burden and Neurofilament Light on Dementia Risk: The Shanghai Aging Study","authors":"Danyi Chi, Xiaoniu Liang, Zhenxu Xiao, Xiaowen Zhou, Qianhua Zhao, Bin Wang, Ding Ding","doi":"10.1002/cns.70691","DOIUrl":"10.1002/cns.70691","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Anticholinergic drugs (ACDs) and the neurodegeneration biomarker neurofilament light chain (NfL) are associated with dementia; however, the interplay between anticholinergic drug exposure and neurodegeneration in dementia risk remains underexplored.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This prospective cohort study analyzed 1529 dementia-free adults (median follow-up 5.2 years) from the Shanghai Aging Study. Cumulative anticholinergic burden was quantified using the anticholinergic cognitive burden (ACB) scale and total standardized daily dose (TSDD) over 1 year pre-baseline. Neurofilament light chain (NfL) levels were assayed via single-molecule array (Simoa).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Elevated NfL (adjusted HR 1.77, 95% CI, 1.07–2.92) and TSDD exposure (HR 1.55, 1.08–2.24) were independently associated with incident dementia risk. Participants with both TSDD exposure and high NfL levels showed substantially greater cumulative dementia incidence versus those with no TSDD/low NfL (log-rank <i>p</i> < 0.0001; adjusted HR 2.24, 1.20–4.20). Individuals with both high TSDD and high NfL demonstrated a significantly higher dementia risk (HR 6.34, 95% CI, 1.90–21.20) compared to low-burden counterparts.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>These findings identify plasma NfL as a critical modifier of anticholinergic-related cognitive vulnerability, providing mechanistic insights for risk stratification and supporting biomarker-guided deprescribing strategies in older adults exposed to ACDs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12695687/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145720118","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Huimin Zhu, Zijian Liu, Jing Feng, Die Hu, Xia Li, Zhenyu Guo, Xueying Zhu, Cong Gai
<div> <section> <h3> Background</h3> <p>Parkinson's disease (PD) is a neurodegenerative disorder that worsens progressively. Different pathological mechanisms are involved in the progression of PD, including the loss of dopaminergic (DA) neurons and exacerbated oxidative damage in the nigrostriatal path. Da-Bu-Yin-Wan combined with Qian-Zheng-San is called Bu-Yin-Qian-Zheng Formula (BYQZF), which is a prescription for PD used in traditional Chinese medicine, but its neuroprotective effects and mechanisms are not well understood.</p> </section> <section> <h3> Purpose</h3> <p>The purpose of this study was to explore how BYQZF can activate the Keap1/Nrf2/HO-1 pathway to effectively lessen oxidative damage, providing insights into its potential anti-PD effects.</p> </section> <section> <h3> Methods</h3> <p>The chemical constituents and pharmacokinetics of BYQZF were analyzed by ultraperformance liquid chromatography in tandem with mass spectrometry (UPLC-MS/MS). Then, we evaluated the toxicity and safety of BYQZF treatment. After establishing MPTP-induced PD mouse models and the administration of BYQZF treatment, PD-like behaviors were assessed through the pole test, rotarod test and open field experiment. DA neuron loss and apoptosis in the nigrostriatal path were detected via immunofluorescence and western blotting analysis. Oxidative stress levels and the dissociation state of Keap1-Nrf2 in these brain areas were assessed by ELISA, immunofluorescence Co-IP, RT-qPCR, and western blot analysis. We constructed Nrf2-knockdown PD cell models. The transcriptional and Nrf2 protein expression levels were determined using both real-time quantitative PCR and western blot analysis. We further assessed cellular viability, intracellular ATP content, apoptotic cell ratio, as well as the expression levels of CAT and GSH following MPP<sup>+</sup>, and BYQZF exposure.</p> </section> <section> <h3> Results</h3> <p>The chemical constituents of BYQZF were systematically characterized using UPLC-MS/MS technology. The results of pharmacokinetic evaluation suggested that the pathological conditions of PD significantly affected the pharmacokinetic behavior of BYQZF in vivo. BYQZF treatment ultimately improved the movement disorders in MPTP-induced PD mice, by alleviating the damage of dopaminergic neurons within the nigrostriatal path. In addition, BYQZF reduced the damage caused by oxidative stress by decreasing the 8-OHdG level and increasing the CAT, GSH/GSSG, HO-1, NQO1, and GCLM levels. Further, BYQZF treatment advanced the dissociation of Keap1 and Nrf2 and the nucle
{"title":"Da-Bu-Yin-Wan and Qian-Zheng-San Alleviate Parkinson's Disease by Activating the Keap1/Nrf2/HO-1 Pathway to Positively Regulate Oxidative Stress","authors":"Huimin Zhu, Zijian Liu, Jing Feng, Die Hu, Xia Li, Zhenyu Guo, Xueying Zhu, Cong Gai","doi":"10.1002/cns.70681","DOIUrl":"10.1002/cns.70681","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Parkinson's disease (PD) is a neurodegenerative disorder that worsens progressively. Different pathological mechanisms are involved in the progression of PD, including the loss of dopaminergic (DA) neurons and exacerbated oxidative damage in the nigrostriatal path. Da-Bu-Yin-Wan combined with Qian-Zheng-San is called Bu-Yin-Qian-Zheng Formula (BYQZF), which is a prescription for PD used in traditional Chinese medicine, but its neuroprotective effects and mechanisms are not well understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>The purpose of this study was to explore how BYQZF can activate the Keap1/Nrf2/HO-1 pathway to effectively lessen oxidative damage, providing insights into its potential anti-PD effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The chemical constituents and pharmacokinetics of BYQZF were analyzed by ultraperformance liquid chromatography in tandem with mass spectrometry (UPLC-MS/MS). Then, we evaluated the toxicity and safety of BYQZF treatment. After establishing MPTP-induced PD mouse models and the administration of BYQZF treatment, PD-like behaviors were assessed through the pole test, rotarod test and open field experiment. DA neuron loss and apoptosis in the nigrostriatal path were detected via immunofluorescence and western blotting analysis. Oxidative stress levels and the dissociation state of Keap1-Nrf2 in these brain areas were assessed by ELISA, immunofluorescence Co-IP, RT-qPCR, and western blot analysis. We constructed Nrf2-knockdown PD cell models. The transcriptional and Nrf2 protein expression levels were determined using both real-time quantitative PCR and western blot analysis. We further assessed cellular viability, intracellular ATP content, apoptotic cell ratio, as well as the expression levels of CAT and GSH following MPP<sup>+</sup>, and BYQZF exposure.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The chemical constituents of BYQZF were systematically characterized using UPLC-MS/MS technology. The results of pharmacokinetic evaluation suggested that the pathological conditions of PD significantly affected the pharmacokinetic behavior of BYQZF in vivo. BYQZF treatment ultimately improved the movement disorders in MPTP-induced PD mice, by alleviating the damage of dopaminergic neurons within the nigrostriatal path. In addition, BYQZF reduced the damage caused by oxidative stress by decreasing the 8-OHdG level and increasing the CAT, GSH/GSSG, HO-1, NQO1, and GCLM levels. Further, BYQZF treatment advanced the dissociation of Keap1 and Nrf2 and the nucle","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686966/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated.
Purpose
This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms.
Methods
We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APPswe/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints Baihui (GV20), Guanyuan (CV4), and Zusanli (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity.
Results
Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice.
Conclusion
Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.
{"title":"Electroacupuncture Prevents Against AD-Like Phenotypes in APP/PS1 Mice: Investigation of the Mechanisms From Cerebral Microangiopathy","authors":"Chen Yang, Baobao Li, Shaojie Yang, Xuncui Wang, Guoqi Zhu, Jingji wang","doi":"10.1002/cns.70696","DOIUrl":"10.1002/cns.70696","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Electroacupuncture (EA) has been widely used in Alzheimer's disease (AD) treatment. However, its underlying mechanisms remain poorly elucidated.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>This study aimed to investigate the effects of EA on AD-like phenotypes and explore the mechanisms.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We first evaluated AD-like behaviors and cerebral blood flow (CBF) changes in APP<sub>swe</sub>/PS1dE9 (APP/PS1) mice at different ages. Subsequently, the therapeutic effects of EA at acupoints <i>Baihui</i> (GV20), <i>Guanyuan</i> (CV4), and <i>Zusanli</i> (ST36), as well as sunitinib, a PDGFRβ-specific inhibitor, on AD-like phenotypes in APP/PS1 mice were investigated. CBF was monitored by laser speckle imaging, and hippocampal synaptic ultrastructure and microvascular morphology were examined by transmission electron microscopy (TEM). Western blot was performed to measure related protein expression. Finally, functional ultrasound (fUS) imaging was used to assess changes in brain-wide functional connectivity.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Compared with age-matched wild-type (WT) mice, 6- and 9-month-old APP/PS1 mice exhibited significant cognitive decline, while all age groups (3-, 6-, and 9-month-old) of APP/PS1 mice showed significantly reduced CBF. APP/PS1 mice showed elevated expression of microvascular markers in both the hippocampus and cortex. EA significantly ameliorated AD-like behaviors and prevented CBF reduction as well as microvascular deformation in 6-month-old APP/PS1 mice compared with non-treatment group. TEM and western blot analysis revealed damaged synaptic structure and reduced synaptic proteins in APP/PS1 mice, all of which were markedly alleviated by EA treatment. In addition, EA treatment downregulated the aberrantly elevated expression of PDGFRβ and CD31, enhanced the levels of tight junction proteins (Occludin, Claudin-5, and ZO-1) and glucose transporter 1 (GLUT1), and suppressed the expression of inflammatory proteins. Of note, intervention with sunitinib also improved AD-like behaviors in APP/PS1 mice. Remarkably, fUS imaging results showed that EA enhanced the functional connection between hippocampal regions of APP/PS1 mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Our data demonstrates that EA ameliorates AD-like phenotypes, potentially through preventing microangiopathy.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712734","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood.
Method
In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing.
Results
Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia–astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair.
Conclusions
Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation.
{"title":"Decoding the Therapeutic Effects of Acupuncture in Hemorrhagic Stroke Using Single-Cell RNA Sequencing","authors":"Chen Ruan, Jia Du, Wentao Zhang, Jiacheng Song, Peipei Feng, Jiajun Shi, Kelang Lou, Yuqiang Lu, Xinwei Li, Zhongwei Guo, Hao Liu","doi":"10.1002/cns.70689","DOIUrl":"10.1002/cns.70689","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acupuncture has been proposed as a therapeutic intervention for stroke recovery, yet the underlying molecular mechanisms remain poorly understood.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>In this study, we used a mouse model of hemorrhagic stroke induced by autologous blood injection to investigate the effects of acupuncture on post-stroke recovery at the cellular and molecular levels, utilizing single-cell RNA sequencing.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our findings revealed that acupuncture modulates the gene expression of microglia, astrocytes, and oligodendrocytes, three major glial cell types, which may contribute to the improvement of stroke-induced phenotypes. Notably, we identified a potential role of the APOE-TREM2 signaling axis, with ligand-binding interactions enhancing microglia activation and promoting their neuroprotective functions. These findings also suggested that acupuncture may promote microglia–astrocyte interactions, leading to enhanced neuroinflammation resolution and tissue repair.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study provided new insights into the cellular mechanisms underlying acupuncture's therapeutic effects in stroke recovery and highlighted the potential of targeting glial cell-mediated pathways, including APOE-TREM2, as a strategy for improving post-stroke rehabilitation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686964/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Feiyu Ma, Yi Bai, Na Li, Xiangyu Cai, Ruicong Xu, Xiang Cao
Introduction
Microglia, the resident immune cells of the central nervous system, rapidly activate after ischemic stroke and actively communicate with neurons, astrocytes, endothelial cells, and infiltrating peripheral immune cells. As ischemic stroke remains a major cause of death and long-term disability worldwide, growing evidence highlights that microglia-driven communication—through direct cell–cell contact, soluble factors, and extracellular vesicles—plays a central role in regulating neuroinflammation and shaping disease progression. A clearer understanding of these communication networks may help identify new therapeutic strategies targeting glial function.
Methods
This review summarizes recent advances in understanding microglial states after ischemic stroke and their communication with neural and peripheral immune cells. Literature was collected from PubMed and Web of Science, with attention to mechanisms involving direct cell–cell interaction, cytokine and chemokine signaling, extracellular vesicle communication, and newly described tunneling structures. Key regulatory processes at different pathological stages are compared.
Results
Experimental and clinical evidence shows that microglia display dynamic and heterogeneous activation patterns after ischemic stroke. Through diverse communication pathways, they influence neuronal survival, synaptic remodeling, inflammatory responses, and blood–brain barrier integrity. Soluble mediators—including cytokines, chemokines, and damage-associated molecular patterns—shape both local and systemic immune reactions, while extracellular vesicles regulate neuroinflammation and tissue repair by transferring bioactive molecules. Recently reported microglial tunneling structures further increase the complexity of intercellular communication. Together, these pathways determine the progression of ischemic injury and recovery.
Conclusions
Microglia act as central coordinators of communication among neurons, glial cells, and immune cells during ischemic stroke, thereby influencing disease severity and functional outcome. Clarifying microglia-mediated communication mechanisms may help guide the development of targeted immunomodulatory treatments. Continued research will be important for advancing these findings toward clinical translation.
小胶质细胞是中枢神经系统的常驻免疫细胞，在缺血性卒中后迅速激活，并积极与神经元、星形胶质细胞、内皮细胞和浸润性外周免疫细胞进行交流。缺血性中风仍然是世界范围内死亡和长期残疾的主要原因，越来越多的证据表明，小胶质细胞驱动的通讯——通过直接的细胞-细胞接触、可溶性因子和细胞外囊泡——在调节神经炎症和塑造疾病进展中起着核心作用。更清楚地了解这些通讯网络可能有助于确定针对胶质细胞功能的新治疗策略。方法：本文综述了缺血性脑卒中后小胶质细胞状态及其与神经和外周免疫细胞的联系的最新进展。文献收集自PubMed和Web of Science，重点关注细胞间直接相互作用、细胞因子和趋化因子信号传导、细胞外囊泡通讯以及新近描述的隧道结构等机制。比较不同病理阶段的关键调控过程。结果：实验和临床证据表明，缺血性脑卒中后小胶质细胞表现出动态和异质性的激活模式。通过不同的通讯途径，它们影响神经元存活、突触重塑、炎症反应和血脑屏障完整性。可溶性介质——包括细胞因子、趋化因子和损伤相关的分子模式——塑造局部和全身免疫反应，而细胞外囊泡通过转移生物活性分子来调节神经炎症和组织修复。最近报道的小胶质隧道结构进一步增加了细胞间通讯的复杂性。总之，这些途径决定了缺血性损伤的进展和恢复。结论：缺血性卒中时，小胶质细胞作为神经元、胶质细胞和免疫细胞之间通讯的中枢协调者，从而影响疾病的严重程度和功能结局。阐明小胶质细胞介导的通讯机制可能有助于指导靶向免疫调节治疗的发展。持续的研究对于将这些发现推向临床翻译将是重要的。
{"title":"Cellular Communication Networks Mediated by Microglia in Ischemic Stroke","authors":"Feiyu Ma, Yi Bai, Na Li, Xiangyu Cai, Ruicong Xu, Xiang Cao","doi":"10.1002/cns.70687","DOIUrl":"10.1002/cns.70687","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Introduction</h3>\u0000 \u0000 <p>Microglia, the resident immune cells of the central nervous system, rapidly activate after ischemic stroke and actively communicate with neurons, astrocytes, endothelial cells, and infiltrating peripheral immune cells. As ischemic stroke remains a major cause of death and long-term disability worldwide, growing evidence highlights that microglia-driven communication—through direct cell–cell contact, soluble factors, and extracellular vesicles—plays a central role in regulating neuroinflammation and shaping disease progression. A clearer understanding of these communication networks may help identify new therapeutic strategies targeting glial function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This review summarizes recent advances in understanding microglial states after ischemic stroke and their communication with neural and peripheral immune cells. Literature was collected from PubMed and Web of Science, with attention to mechanisms involving direct cell–cell interaction, cytokine and chemokine signaling, extracellular vesicle communication, and newly described tunneling structures. Key regulatory processes at different pathological stages are compared.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Experimental and clinical evidence shows that microglia display dynamic and heterogeneous activation patterns after ischemic stroke. Through diverse communication pathways, they influence neuronal survival, synaptic remodeling, inflammatory responses, and blood–brain barrier integrity. Soluble mediators—including cytokines, chemokines, and damage-associated molecular patterns—shape both local and systemic immune reactions, while extracellular vesicles regulate neuroinflammation and tissue repair by transferring bioactive molecules. Recently reported microglial tunneling structures further increase the complexity of intercellular communication. Together, these pathways determine the progression of ischemic injury and recovery.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Microglia act as central coordinators of communication among neurons, glial cells, and immune cells during ischemic stroke, thereby influencing disease severity and functional outcome. Clarifying microglia-mediated communication mechanisms may help guide the development of targeted immunomodulatory treatments. Continued research will be important for advancing these findings toward clinical translation.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12690164/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145712710","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shamseddin Ahmadi, Shiler Khaledi, Kimia Ahmadi, Kambiz Hassanzadeh
Main Problems
The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.
Methods
This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.
Results
Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood–brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.
Conclusions
Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.
{"title":"Amyloid Beta in Alzheimer's Disease: Mechanisms, Biomarker Potential, and Therapeutic Targets","authors":"Shamseddin Ahmadi, Shiler Khaledi, Kimia Ahmadi, Kambiz Hassanzadeh","doi":"10.1002/cns.70688","DOIUrl":"10.1002/cns.70688","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Main Problems</h3>\u0000 \u0000 <p>The accumulation of amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs) composed of Tau protein is two characteristic brain pathologies in Alzheimer's disease (AD). However, the Aβ hypothesis has recently faced challenges due to the limited clinical efficacy of anti-Aβ antibodies, such as aducanumab and lecanemab.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>This comprehensive review highlights recent advances and debates regarding the pathophysiology of Aβ peptides and plaques in AD, as well as their use as biomarkers and drug targets.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Aβ aggregation is primarily driven by an imbalance between its generation from amyloid precursor protein (APP) and its clearance from the brain, processes influenced by various risk factors. The toxicity of amyloid plaques is affected by the accumulation of different Aβ species with varying lengths and post-translational modifications of Aβ. Additionally, pathways including neuroinflammation, blood–brain barrier deterioration, autophagy and mitochondrial dysfunction, lipid raft changes, and oxidative stress have pivotal roles in AD. Therefore, a clear map of Aβ's upstream regulators and downstream effectors is crucial for developing effective diagnostics and treatments for AD.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Incorporating new research findings and ongoing debates surrounding the Aβ cascade hypothesis is crucial for improving early diagnosis and for guiding the development of effective treatments for AD.</p>\u0000 </section>\u0000 </div>","PeriodicalId":154,"journal":{"name":"CNS Neuroscience & Therapeutics","volume":"31 12","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12686972/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145706874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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