Experimental Neurology最新文献

{"title":"Identification of Npas4 as a biomarker for CICI by transcriptomics combined with bioinformatics and machine learning approaches","authors":"Zhenyu He ,&nbsp;Huanhuan Ma ,&nbsp;Yu Zhang ,&nbsp;Liping Chen ,&nbsp;Yueling Pang ,&nbsp;Xiaoshan Ding ,&nbsp;Yanan Wang ,&nbsp;Yongqi Liu ,&nbsp;Ling Li ,&nbsp;Jiawei Li","doi":"10.1016/j.expneurol.2025.115290","DOIUrl":"10.1016/j.expneurol.2025.115290","url":null,"abstract":"<div><div>Chemotherapy is one of the most successful strategies for treating cancer. Unfortunately, up to 70 % of cancer survivors develop cognitive impairment during or after chemotherapy, which severely affects their quality of life. We first established a mouse model of CICI and combined bioinformatics, machine learning, and transcriptome sequencing to screen diagnostic genes associated with CICI. Relevant DEGs were screened by differential analysis, and potential biological functions of DEGs were explored by GO and KEGG analysis. WGCNA analysis was then used to find the most relevant modules for CICI. The diagnostic gene Npas4 was screened by combining the three machine learning methods; its diagnostic value was proved by ROC analysis, GSEA analyzed its potential biological function, and then we preliminarily explored the chemicals associated with Npas4. Our study found that Npas4 can be used as an early diagnostic gene for CICI, which provides a theoretical basis for further research.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115290"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144004971","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The cannabinoid receptor 1 mediates exercise-induced improvements of motor skill learning and performance in parkinsonian mouse","authors":"Talifu Zikereya ,&nbsp;Chuang Liu ,&nbsp;Longwei Wei ,&nbsp;Yinhao Wang ,&nbsp;Zhizhen Zhang ,&nbsp;Chuanliang Han ,&nbsp;Kaixuan Shi ,&nbsp;Wei Chen","doi":"10.1016/j.expneurol.2025.115289","DOIUrl":"10.1016/j.expneurol.2025.115289","url":null,"abstract":"<div><div>The endocannabinoid system (eCBs) modulates corticostriatal circuits through cannabinoid receptor 1 (CB1R). These circuits are crucial for encoding goal-directed and habitual learning behaviors and are implicated in the occurrence and progression of Parkinson's disease (PD). While exercise has been shown to enhance motor performance and reverse learning deficits in PD patients, the underlying molecular mechanisms remain unclear. We hypothesized that a treadmill training program could rescue changes in striatal plasticity and ameliorate early motor and cognitive deficits in mice subjected to an intrastriatal 6-hydroxydopamine injection. Our findings demonstrated that exercise training would improve motor performance and learning abilities in PD mice. Moreover, both immunofluorescence and reverse transcription polymerase chain reaction results suggested that corticostriatal activation decreased CB1R expression in the dorsomedial striatum of PD mice but increased expression in the substantia nigra pars reticulata following treadmill exercise. These results suggest that dysregulated CB1R expression is associated with the pathogenesis of Parkinsonism, highlighting the vital role of the CB1R in corticostriatal pathway functionality enhanced by exercise. Our results suggest the potential benefits of treadmill exercise in alleviating Parkinsonism, providing valuable insights into future potential treating strategies.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115289"},"PeriodicalIF":4.6,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-modified animal models of Parkinson's disease","authors":"Yong Peng ,&nbsp;Dai-yi Jiang ,&nbsp;Shun-yu Yao ,&nbsp;Xiuli Zhang ,&nbsp;Sugimoto Kazuo ,&nbsp;Jia Liu ,&nbsp;Miao-qiao Du ,&nbsp;Lan-xin Lin ,&nbsp;Quan Chen ,&nbsp;Hong Jin","doi":"10.1016/j.expneurol.2025.115287","DOIUrl":"10.1016/j.expneurol.2025.115287","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a neurodegenerative disorder that commonly occurs in older individuals and clinically manifests as resting tremors, bradykinesia, muscle stiffness, and impaired postural balance. From a genetic perspective, animal models using gene-editing technologies offer distinct advantages in replicating the pathophysiological traits of PD, while also functionally exploring potential treatment targets. In this review, we highlight the available gene- modified animal models related to various mechanisms of PD, including abnormal expression of alpha-synuclein protein, dysfunction of the autophagy-lysosome system, abnormalities in the ubiquitin-proteasome system, and mitochondrial dysfunction. We further discuss their respective strengths, limitations, and prospects, aiming to provide the most up to date information for the application of PD animal models and the advancement of anti-PD drugs.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115287"},"PeriodicalIF":4.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143913024","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosome-based therapies and biomarkers in stroke: Current advances and future directions","authors":"Naresh Poondla ,&nbsp;Ali Babaeizad ,&nbsp;Mohsen Sheykhhasan ,&nbsp;Christopher J. Barry ,&nbsp;Hamed Manoochehri ,&nbsp;Hamid Tanzadehpanah ,&nbsp;Hanie Mahaki ,&nbsp;Sharafaldin Al-Musawi","doi":"10.1016/j.expneurol.2025.115286","DOIUrl":"10.1016/j.expneurol.2025.115286","url":null,"abstract":"<div><div>Stroke is a challenging neurological condition caused by interrupted blood flow to the brain and presents substantial global health concerns due to its prevalence and limited treatment options. Exosomes, tiny vesicles released by cells, are gaining attention for their potential in targeted drug delivery and as diagnostic and therapeutic biomarkers for stroke. This article outlines recent advances in exosome-based drug delivery systems and examines their application in managing stroke.</div><div>Stroke presents with diverse symptoms depending on the brain region affected, and current treatments primarily aim to restore blood flow and manage risk factors. Exosomes exhibit a unique structure and composition and contain bioactive molecules. Their ability to cross the blood-brain barrier and target specific cells makes them promising candidates for precise drug delivery in stroke therapy.</div><div>Exosomes contribute extensively to stroke pathophysiology and present considerable therapeutic promise by promoting neuroprotection and assisting in brain repair mechanisms. They can be engineered to carry various therapeutic substances, such as small molecules, enabling highly specific targeted delivery. Furthermore, the molecular compositions of exosomes reflect the pathological changes observed in stroke, indicating their potential use as biomarkers for early diagnosis, monitoring of disease progression, and creating individualized treatment strategies.</div><div>Despite promising developments, challenges remain in optimizing exosome production, purification, and cargo loading. Further investigations into their biological mechanisms and clinical validation are crucial for translating their potential into tangible benefits for patients. This article highlights recent advances and future prospects in exosome research, underscoring their application as novel diagnostic and therapeutic tools in stroke management.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115286"},"PeriodicalIF":4.6,"publicationDate":"2025-05-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143986642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibiting mitochondrial excessive fission alleviates the neuronal damage in Parkinson's disease via regulating PGC-1α mediated mitochondrial biogenesis","authors":"Jingwei Ma ,&nbsp;Yang Yang ,&nbsp;Caixia Zang ,&nbsp;Qiuzhu Chen ,&nbsp;Yueqi Jiang ,&nbsp;Yirong Dong ,&nbsp;Jinrong Wang ,&nbsp;Ning Zhou ,&nbsp;Xing Yang ,&nbsp;Fangfang Li ,&nbsp;Xiuqi Bao ,&nbsp;Dan Zhang","doi":"10.1016/j.expneurol.2025.115288","DOIUrl":"10.1016/j.expneurol.2025.115288","url":null,"abstract":"<div><div>Mitochondrial excessive fission is one of representative pathological features and a principal element triggering the neuronal damage in Parkinson's disease (PD). Inhibiting mitochondrial excessive fission benefits the pathology of PD through promoting mitochondrial biogenesis, but the detailed mechanism has not been clarified. In our study, we revealed that inhibiting mitochondrial excessive fission by Mdivi-1, the dynamin related protein 1 (DRP1) inhibitor, increased the expression and nuclear translocation of peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α), as well as its downstream transcriptional factors, nuclear respiratory factor 1/2 (NRF1/2) and mitochondrial transcription factor A (TFAM), and therefore promoted mitochondrial biogenesis. Suppression of mitochondrial excessive fission alleviated dopaminergic synaptic injury, neuronal apoptosis and motor dysfunction, while inhibiting PGC-1α attenuated these ameliorative effects in both <em>in-vitro</em> and <em>in-vivo</em> PD models. Mechanistic study showed that inhibiting mitochondrial excessive fission facilitated the expression of PGC-1α, NRF1 and TFAM by activation of Ca²⁺/calmodulin-dependent serine/threonine kinase II (CaMKII)/cAMP-response element binding protein (CREB) pathway. Inhibiting mitochondrial excessive fission also activated AMP-activated serine/threonine kinase (AMPK)/Sirtuin1 (Sirt1) pathway, and then phosphorylated and deacetylated PGC-1α by post-translational modifications. In conclusion, inhibiting mitochondrial excessive fission could promote mitochondrial biogenesis through activation of PGC-1α and therefore rescue the impaired dopaminergic neurons, which provided evidence for targeting mitochondrial excessive fission for the treatment of PD and new drug developments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115288"},"PeriodicalIF":4.6,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143948857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heat shock proteins in cerebral ischemia-reperfusion injury: Mechanisms and therapeutic implications","authors":"Anliu Zhao ,&nbsp;Guangming Zhang ,&nbsp;Huayuan Wei,&nbsp;Xu Yan,&nbsp;Jiali Gan,&nbsp;Xijuan Jiang","doi":"10.1016/j.expneurol.2025.115284","DOIUrl":"10.1016/j.expneurol.2025.115284","url":null,"abstract":"<div><div>Cerebral ischemia-reperfusion injury (CIRI) remains a significant challenge in ischemic stroke treatment. Heat shock proteins (HSPs), a cadre of molecular chaperones, have emerged as pivotal regulators in this pathological cascade. This review synthesizes the latest research on HSPs in CIRI from 2013 to 2024 focusing on their multifaceted roles and therapeutic potential. We explore the diverse cellular functions of HSPs, including regulation of oxidative stress, apoptosis, necroptosis, ferroptosis, autophagy, neuroinflammation, and blood-brain barrier integrity. Key HSPs, such as HSP90, HSP70, HSP32, HSP60, HSP47, and small HSPs, are investigated for their specific mechanisms of action in CIRI. Potential therapeutic strategies targeting HSPs, including HSP inhibitors, traditional Chinese medicine components, and gene therapy, are discussed. This review provides a comprehensive understanding of HSPs in CIRI and offers insights into the development of innovative neuroprotective treatments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115284"},"PeriodicalIF":4.6,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143901962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SDF2L1 downregulation mediates high glucose-caused Schwann cell dysfunction by inhibiting nuclear import of TFEB and CREB via KPNA3","authors":"Tingting Jin ,&nbsp;Fan Li ,&nbsp;Wandi Wei ,&nbsp;Qiuli Li ,&nbsp;Yue Gao ,&nbsp;Chao Yuwen ,&nbsp;Yuanyuan Sun ,&nbsp;Wenhui Li ,&nbsp;Lin Zhu ,&nbsp;Jun Hao","doi":"10.1016/j.expneurol.2025.115273","DOIUrl":"10.1016/j.expneurol.2025.115273","url":null,"abstract":"<div><div>Schwann cells dysfunction is a key contributor to diabetic peripheral neuropathy (DPN), affecting both neurons and blood vessels. However, the precise mechanisms underlying high glucose-induced Schwann cells dysfunction are still not fully elucidated. In the present study, we investigated the expression, function and molecular mechanisms of SDF2L1 in Schwann cells using diabetic mice, <em>SDF2L1</em> KO mice, rat Schwann cell (RSC96) and primary rat Schwann cell (PRSC). The RNA-seq of high glucose-treated RSC96 cells revealed an evident downregulation of SDF2L1 at both 48 and 72 h. The inhibition of high glucose on SDF2L1 expression was further confirmed at the levels of mRNA and protein in RSC96 and PRSC cells. Again, reduced SDF2L1 expression was also observed in the sciatic nerves of both type 1 and 2 diabetic mice. Functional exploration revealed that SDF2L1 knockdown in RSC96 cells suppressed the expression of LC3-II, P62, BDNF, NGF and IGF. <em>In vivo SDF2L1</em> KO also decreased these proteins expression in the sciatic nerve of C57BL/6 J mice, along with the reduced nerve conduction velocity and action potential amplitude. Then, proteomics analyses and biological experiments demonstrated that SDF2L1 knockdown significantly decreased KPNA3 expression in RSC96 cells. Overexpression of KPNA3 ameliorated the decreases in LC3-II, P62, BDNF, NGF and IGF caused by SDF2L1 downregulation <em>in vitro</em>. Moreover, KPNA3 affected the nuclear import of transcription factors TFEB and CREB in RSC96 cells. Next, KPNA3 overexpression reversed <em>SDF2L1</em> KO-reduced the nuclear aggregation of TFEB and CREB, and the expression of LC3, P62, BDNF and NGF <em>in vivo.</em> Collectively, these findings suggest that decreased SDF2L1 inhibits cell autophagy and neurotrophin expression by impeding the nuclear import of TFEB and CREB <em>via</em> KPNA3 downregulation in high glucose-treated Schwann cells.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115273"},"PeriodicalIF":4.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143904464","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neuroprotective roles of SGLT2 and DPP4 inhibitors: Modulating ketone metabolism and suppressing NLRP3 inflammasome in T2D induced Alzheimer's disease","authors":"A Young Sim ,&nbsp;Jong Youl Kim ,&nbsp;Yong-ho Lee ,&nbsp;Jong Eun Lee","doi":"10.1016/j.expneurol.2025.115271","DOIUrl":"10.1016/j.expneurol.2025.115271","url":null,"abstract":"<div><div>Sodium-glucose cotransporter 2 inhibitor (SGLT2-i) and dipeptidyl peptidase-4 inhibitor (DPP4-i) are known to ameliorate Alzheimer's disease (AD)-like pathology and cognitive decline through distinct mechanisms. In this study, we investigated how these antidiabetic drugs elevate ketone levels and subsequently reduce amyloid-β (Aβ) and tau pathology via the NLR family pyrin domain containing 3 (NLRP3) inflammasome pathway in microglia, using a type 2 diabetes (T2D)-AD mouse model.</div><div>Male C57BL/6 mice were fed a high-fat diet and injected with low doses of streptozotocin to establish a T2D-AD model. The mice were then treated with either SGLT2-i or DPP4-i. Our results revealed that both the inhibitors markedly enhanced brain ketone metabolism by upregulating key metabolic enzymes and transporters. They also reduced neuroinflammation by suppressing the expression of pro-inflammatory cytokines, such as IL-1β, and increasing the expression of the anti-inflammatory cytokine IL-4. A critical mechanism for this anti-inflammatory effect involved the inhibition of the expression of the NLRP3 inflammasome, a key driver of neuroinflammation. Notably, SGLT2-i appeared to inhibit NLRP3 inflammasome expression by disrupting the pTau-CX3C1 interaction, whereas DPP4-i exerted its effects through the Aβ-TLR4-NF-κB pathway.</div><div>Moreover, our results showed that both the inhibitors promoted a shift in microglial activation from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, as indicated by the changes in CD206 and CD86 expression.</div><div>These findings suggest that SGLT2-i and DPP4-i provide neuroprotective benefits through multiple mechanisms, including enhanced ketone metabolism, reduced neuroinflammation, and modulation of microglial activity in T2D-AD mouse model. This research offers a scientific basis for considering these inhibitors as potential therapeutic agents for neurodegenerative diseases, particularly in cognitive impairment patients with metabolic dysfunction.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115271"},"PeriodicalIF":4.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143900338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biphasic changes in hippocampal granule cells after traumatic brain injury","authors":"Joanna Danielewicz ,&nbsp;Nerea Llamosas ,&nbsp;Irene Durá ,&nbsp;Danillo Barros de Souza ,&nbsp;Serafim Rodrigues ,&nbsp;Juan Manuel Encinas-Pérez ,&nbsp;Diego Martin Mateos","doi":"10.1016/j.expneurol.2025.115281","DOIUrl":"10.1016/j.expneurol.2025.115281","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) leads to a wide range of long-lasting physical and cognitive impairments. Changes in neuronal excitability and synaptic functions in the hippocampus have been proposed to underlie cognitive alterations. The dentate gyrus (DG) acts as a “gatekeeper” of hippocampal information processing and as a filter of excessive or aberrant input activity. In this study, we investigated the effects of controlled cortical impact, a model of TBI, on the excitability of granule cells (GCs) and spontaneous excitatory postsynaptic currents (sEPSCs) in the DG at three time points, 3 days, 15 days and 4 months after the injury in male and female mice. Our results indicate that changes in the short term are related to intrinsic properties, while changes in the long term are more related to input and synaptic activity, in agreement with the notion that TBI-related pathology courses with an acute phase and a later long-term secondary phase. A biphasic response, a reduction in the shorter term and an increase in the long term, was found in TBI neurons in the frequency of sEPSCs. These changes correlated with a loss of complexity in the pattern of the synaptic input, an alteration that could therefore play a role in the chronic and recurrent TBI-associated hyperexcitation.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115281"},"PeriodicalIF":4.6,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143905867","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypercholesterolemia drives microglial dysfunction and weakens response to amyloid plaques","authors":"Sarah Kaye ,&nbsp;Andrew Gold ,&nbsp;Da Lin ,&nbsp;Min Chen ,&nbsp;Jiangjiang Zhu ,&nbsp;Jie Gao","doi":"10.1016/j.expneurol.2025.115272","DOIUrl":"10.1016/j.expneurol.2025.115272","url":null,"abstract":"<div><div>Hypercholesterolemia is a recognized comorbidity of Alzheimer's disease (AD), yet its mechanistic connection to AD pathology, particularly its impact on microglial function and amyloid-beta (Aβ) dynamics remains unclear. To investigate this, we utilized the APP^NL-G-F (AK) mouse model, which develops robust Aβ pathology, and the APP^NL-G-F;LDLR^−/− (AL^KO) model, which combines Aβ pathology with LDL receptor deficiency to induce hypercholesterolemia under a Western diet (WD). These models were designed to study the combined effects of genetic predisposition and dietary factors on AD progression. At six months of age, mice were maintained on a control diet or switched to a WD for two months to induce hypercholesterolemia. Our findings demonstrate that hypercholesterolemia suppresses microglial responses to Aβ plaques, evidenced by reduced clustering and activation of microglia around plaques. The combination of WD and LDLR deficiency synergistically diminished the expression of disease-associated microglia markers, resulting in reduced Aβ plaque compactness. Mechanistically, RNA sequencing revealed hypercholesterolemia impaired microglial mitochondrial function, reduced protein synthesis, and heightened neuroinflammation. Lipidomic profiling revealed significant changes in the microglial lipidome, including elevated ceramides, hexosylceramides, and lysophosphatidylcholine, along with reduced N-acylethanolamines, reflecting a pro-inflammatory and metabolically stressed microglial state. Behavioral analyses further revealed that both WD and LDLR deficiency independently and synergistically impaired cognitive performance and increased anxiety-like behaviors in AD mice. Together, this study highlights the role of hypercholesterolemia in exacerbating AD pathology by disrupting microglial function, altering lipid metabolism, and impairing cognitive function, and suggests that pharmacological management of hypercholesterolemia could slow AD progression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"390 ","pages":"Article 115272"},"PeriodicalIF":4.6,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143891277","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}