Experimental Neurology最新文献

{"title":"Overexpression of colonic VIP ameliorates cognitive function and barrier system damage caused by sevoflurane anesthesia and surgery in aged rats with fragile brain functions","authors":"Huihui Liao ,&nbsp;Xinyi Wang ,&nbsp;Chenyi Yang ,&nbsp;Zixuan Wang ,&nbsp;Xing Liu ,&nbsp;Huan Liu ,&nbsp;Jingwei Zhang ,&nbsp;Huai Shen ,&nbsp;Haiyun Wang","doi":"10.1016/j.expneurol.2025.115328","DOIUrl":"10.1016/j.expneurol.2025.115328","url":null,"abstract":"<div><h3>Background</h3><div>Surgery and anesthesia may compromise fragile brain function in the elderly, potentially precipitating cognitive decline or Alzheimer's disease (AD) following perioperative neurocognitive disorder (PND). Vasoactive intestinal peptide (VIP) exhibits anti-inflammatory properties via the gut-brain axis. Nevertheless, whether VIP regulation enhances cognitive function in the fragile brains of aged rat and the underlying mechanisms remain to be elucidated.</div></div><div><h3>Methods</h3><div>A model of fragile brain function was established in elderly rats through bilateral common carotid artery ligation. Cognitive impairment induced by anesthesia and surgery was evaluated using behavioral assays, quantification of cognition-related protein levels, analysis of inflammatory markers, assessment of microglial polarization, and examination of intestinal mucosal and blood-brain barrier integrity. Adeno-associated virus (AAV) was employed to upregulate VIP expression in the colon, and subsequent alterations in the aforementioned parameters were recorded.</div></div><div><h3>Results</h3><div>Cognitive performance was evaluated through behavioral assays, while cognition-related protein levels were determined using Western blot analysis. Anesthesia and surgical interventions exacerbated cognitive deficits in rats with fragile brain function. VIP upregulation significantly ameliorated post-anesthesia and surgery cognitive deficits, normalized cognition-related protein expression, attenuated the inflammatory response, and promoted the repair of both intestinal mucosal and blood-brain barriers.</div></div><div><h3>Conclusion</h3><div>These findings indicate that VIP upregulation mitigates anesthesia- and surgery-induced cognitive impairment and its progression in aged rats with fragile brain function a, primarily by modulating the inflammatory response and preserving the gut and blood-brain barrier integrity. This study offers valuable insights potential preventive strategies against cognitive decline.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115328"},"PeriodicalIF":4.6,"publicationDate":"2025-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144208077","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":"Sex-dependent blood-brain barrier alterations following repeated mild blast traumatic brain injury at varying inter-injury intervals","authors":"Gopal V. Velmurugan ,&nbsp;Sushant Prajapati ,&nbsp;Sarah Tran ,&nbsp;Carter Miller ,&nbsp;Benjamin Burke ,&nbsp;W. Brad Hubbard","doi":"10.1016/j.expneurol.2025.115325","DOIUrl":"10.1016/j.expneurol.2025.115325","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic brain injury (TBI) is a worldwide epidemic and a major cause of disability, morbidity, and mortality. TBI is a major risk factor for the development of late-life dementia, especially Alzheimer's Disease, and other neurological conditions, such as epilepsy. The most prevalent form of TBI is mild TBI (mTBI), which is characterized by cognitive and psychological deficits as well as metabolic and vascular mechanisms of neuropathobiology. mTBI can be induced by either impact or blast insults and multiple mTBIs can result in worsened outcomes. There is a need to understand pathological impairments in the blood-brain barrier (BBB) following mTBI.</div></div><div><h3>Methods</h3><div>To model repeated mild blast traumatic brain injury (rmbTBI), male and female rats (<em>N</em> = 6/group) were exposed to repeated low-level, 11 psi static peak overpressure blast waves using the McMillan blast device. rmbTBI was produced with either 1 h or 24 h inter-injury interval. Sham animals undergo all procedures except for the blast. Animals performed open field and elevated plus maze (EPM) behavior tests before euthanasia at 7d post-rmbTBI. Hemibrains were taken separately for immunohistochemistry and western blot analysis. Brain capillaries were isolated from fresh brain tissue and taken for immunofluorescent (IF) staining.</div></div><div><h3>Results</h3><div>To examine BBB-specific deficits, pericyte (PDGFRβ), tight junction (TJ) protein (zonula occludens-1 (ZO1), occludin and Claudin-5), astrocytic end-feet (AQP4), and BBB integrity (SMI-71) markers were analyzed at 7d post-rmbTBI. Deficits in cortical AQP-4 and SMI-71 levels were observed in male rmbTBI-24 h group compared to sham while female rmbTBI groups displayed no deficits in these markers compared to sham. There were deficits in TJ markers in both male rmbTBI groups that were not apparent in female-derived capillaries. Western blot analysis demonstrates that PDGFRβ is significantly decreased in male rmbTBI-24 h animals but not male rmbTBI-1 h or female rmbTBI animals. Male rmbTBI-1 h group displayed lower levels of GFAP and higher levels of IBA-1 in the cortex as compared to sham; female rmbTBI groups displayed similar levels of cortical GFAP and IBA-1 as sham. Male rmbTBI and female 1 h-interval rmbTBI groups displayed significantly higher closed arm entrances during EPM as compared to respective sham groups.</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate that rmbTBI produces robust on-going deficits in BBB and glial outcomes that correspond with behavioral abnormalities in male animals. The extent of these outcomes is dependent upon inter-injury interval. Female rmbTBI animals display anxiety-related behavior that is not driven by BBB-related impairments.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115325"},"PeriodicalIF":4.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198565","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":"Endothelial LRP1 activation mitigates microthrombosis after traumatic brain injury in mice","authors":"Ruicheng Yan ,&nbsp;Jiyang Wang ,&nbsp;Jinpeng Wu ,&nbsp;Xiancheng Qiu ,&nbsp;Lei Yang ,&nbsp;Jieru Yang ,&nbsp;Yong Jiang ,&nbsp;Jianhua Peng","doi":"10.1016/j.expneurol.2025.115324","DOIUrl":"10.1016/j.expneurol.2025.115324","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) remains a pressing global health challenge, with microthrombosis emerging as a key pathological contributor to secondary brain damage. Through tissue disruption and multifaceted molecular cascades, TBI induces cerebral microthrombi formation, reducing local cerebral blood flow (CBF) and worsening neurological outcomes. However, effective strategies targeting this thrombotic complication are lacking, underscoring an urgent need for novel therapeutic approaches. Low-density lipoprotein receptor-related protein 1 (LRP1), a multifunctional receptor involved in vascular homeostasis, plays a central role in endothelial regulation, yet its therapeutic potential in post-TBI thrombosis remains underexplored. In this study, we systematically investigated the protective effects of LRP1 activation against TBI-induced microthrombosis using both in vivo and in vitro approaches. A murine TBI model was established via controlled cortical impact (CCI), followed by administration of the LRP1 agonist SP16. Behavioral assessments, immunohistochemistry, and immunoblotting revealed that TBI induced marked microthrombosis and endothelial hypercoagulability. SP16 treatment significantly reduced microthrombus burden, restored CBF perfusion, improved neurological recovery, and downregulated endothelial coagulation factors. Importantly, endothelial-specific LRP1 knockdown aggravated coagulation factor expression under pathological conditions. Mechanistically, SP16-mediated neuroprotection was at least partly dependent on endothelial LRP1 activation. These findings highlight LRP1 as a promising therapeutic target and position SP16 as a viable translational candidate for mitigating thrombotic complications and functional deficits following TBI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115324"},"PeriodicalIF":4.6,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144198564","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":"Overexpression of thioredoxin 1 contributes to neuroprotection through ATM activation and pentose phosphate pathway modulation after traumatic brain injury","authors":"Lei Meng ,&nbsp;Bingyi Song ,&nbsp;Xuan Shi ,&nbsp;Aojie Duan ,&nbsp;Dengfeng Lu ,&nbsp;Yubo Ren ,&nbsp;Yu Zhang ,&nbsp;Renjie Shou ,&nbsp;Haiying Li ,&nbsp;Zhong Wang ,&nbsp;Jiangang Liu ,&nbsp;Zongqi Wang ,&nbsp;Xiaoou Sun","doi":"10.1016/j.expneurol.2025.115326","DOIUrl":"10.1016/j.expneurol.2025.115326","url":null,"abstract":"<div><h3>Background</h3><div>Traumatic brain injury (TBI) induces oxidative stress, leading to secondary injury and neuronal apoptosis. The thioredoxin (Trx) system, a key regulator of redox homeostasis, and the pentose phosphate pathway (PPP), the primary source of NADPH, play critical roles in mitigating oxidative damage. This study investigates the neuroprotective effects of Trx1 in modulating oxidative stress through the Trx1-ATM-PPP axis.</div></div><div><h3>Methods</h3><div>Adenovirus-mediated Trx1 overexpression was performed in a controlled cortical impact (CCI) mouse model four weeks prior to injury. Neuronal apoptosis, G6PD activity, NADPH levels, and ATM phosphorylation (P-ATM) were evaluated post-CCI. Behavioral deficits were assessed one week post-injury. In vitro, primary neurons were subjected to scratch injury and analyzed for Trx1 effects on P-ATM, G6PD, and NADPH.</div></div><div><h3>Results</h3><div>Trx1 overexpression significantly reduced neuronal apoptosis in vivo and in vitro. P-ATM levels were elevated following CCI, and Trx1 overexpression further enhanced P-ATM without altering total ATM expression. G6PD activity and NADPH levels were significantly increased in the Trx1-overexpression group, indicating upregulation of PPP flux. Behavioral assessments revealed improvements in exploratory behavior, anxiety, and memory in CCI mice with Trx1 overexpression.</div></div><div><h3>Conclusion</h3><div>Trx1 mitigates secondary injury in TBI by enhancing PPP flux through ATM phosphorylation, promoting NADPH production and reducing oxidative stress. These findings identify the Trx1-ATM-PPP axis as a potential therapeutic target for TBI treatment.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115326"},"PeriodicalIF":4.6,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144191703","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":"Prenatal arsenic exposure causes cognitive dysfunction in offspring through KDM5-regulated reprogramming of autophagy in developing brain, an effect attenuated by alpha-ketoglutarate","authors":"Zhongyue Wang ,&nbsp;Hailan Wang ,&nbsp;Xiaoshan Peng ,&nbsp;Bowen Fan ,&nbsp;Jingshu Zhang ,&nbsp;Qizhan Liu","doi":"10.1016/j.expneurol.2025.115323","DOIUrl":"10.1016/j.expneurol.2025.115323","url":null,"abstract":"<div><div>Prenatal exposure to arsenic has lasting health effects on the developing fetus, including an increased risk of neurological damage in the offspring during adulthood. Epigenetics may be involved in the pathogenic process, but the underlying mechanisms remain unclear. Autophagy, which is involved in nearly all steps of neurodevelopment, is regulated by histones and can be inherited across generations. In the study, we investigated the effects of prenatal arsenic exposure on cognitive function in offspring mice. Dams were exposed to 0, 0.2, 2, or 20 ppm arsenic or to a mixture of 20 ppm arsenic and 1 % α-ketoglutatate (α-KG) through drinking water during pregnancy. Our data showed that prenatal arsenic exposure led to memory impairment in adult male offspring, but not in females. RNA sequencing (RNA-seq) was used to explore differences in gene expression. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses highlighted changes in the activity of lysine demethylase 5 (KDM5) and autophagy pathways. Subsequent experiments revealed that arsenic downregulated the levels of α-KG, reduced the levels of KDM5 activity in the brains of male offspring at postnatal day (PND) 1, and led to elevated levels of trimethylation marks on histone 3 lysine 4 (H3K4me3). Furthermore, H3K4me3 facilitated the transcription of <em>Beclin1</em> mRNA and increased its expression, resulting in excessive neuronal autophagy. As a cofactor required for KDM5 activity, α-KG, supplemented prenatally, restored KDM5 activity in the brains of offspring and reversed these changes. The results show that supplementation with α-KG during pregnancy, via restoring KDM5 activity, blocks prenatal arsenic exposure-induced cognitive dysfunction in adult male offspring through reprogramming of autophagic processes in developing brain. Our findings provide new insights into the neurodevelopmental damage caused by prenatal arsenic exposure.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115323"},"PeriodicalIF":4.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186894","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":"Intraoperative ultrasound monitoring of spinal cord swelling and parenchymal changes in a porcine model of thoracic spinal cord injury","authors":"Madeleine Amy Bessen ,&nbsp;Oana Claudia Marian ,&nbsp;Ryan L. O'Hare Doig ,&nbsp;Annabel Sorby-Adams ,&nbsp;Christine Diana Gayen ,&nbsp;Lola May Kaukas ,&nbsp;Anna Victoria Leonard ,&nbsp;Claire Frances Jones","doi":"10.1016/j.expneurol.2025.115320","DOIUrl":"10.1016/j.expneurol.2025.115320","url":null,"abstract":"<div><div>Tools for monitoring traumatic spinal cord injury (SCI) severity and progression are limited. Ultrasound (US) imaging may be suitable but requires improved understanding of post-SCI spinal cord changes observed on US. Using serial US images in a clinically relevant porcine model of SCI, this study: (1) determined temporal changes to the spinal cord and subarachnoid space over 24-h post-SCI; and, (2) quantitatively compared US to magnetic resonance imaging (MRI) and histology at 24-h post-SCI. Ten anesthetised females pigs received a thoracic contusion SCI across three injury groups, and midsagittal B-mode US images were obtained hourly from baseline over 24 h. At 24-h, T2-weighted MRI was performed and spinal cord tissue was harvested for histology. Spinal cord and dura diameters were extracted from US. Greyscale distribution parameters of spinal cord parenchyma were assessed on US and MRI. The following US-based parameters were used to assess injury progression: spinal cord swelling, subarachnoid occlusion, dural distension, and parenchymal echogenicity (median and interquartile range [IQR] of the greyscale distribution). On US, for all animals, parenchymal echogenicity (median and IQR) increased rapidly within 2-h, subarachnoid occlusion occurred by 13-h, and maximal spinal cord swelling occurred by 23-h, accompanied by dura distension up to 10 %. Increased US median echogenicity was correlated with histologically measured intraparenchymal haemorrhage and tissue loss, but not with MRI signal changes. These findings support the use of intraoperative US as an objective, real-time, tool for assessing SCI progression.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"392 ","pages":"Article 115320"},"PeriodicalIF":4.6,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144186893","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 role of LINGO-1 in regulating CB1R/TrkB signalling and GABAergic interneurons in Alzheimer's disease pathogenesis","authors":"Qi He ,&nbsp;Lin Jiang ,&nbsp;Feng-Lei Chao ,&nbsp;Chun-Ni Zhou ,&nbsp;Lei Zhang ,&nbsp;Yu-Ning Zhou ,&nbsp;Yi-Ying Wang ,&nbsp;Yu-Hui Deng ,&nbsp;Jing Tang ,&nbsp;Yanmin Luo ,&nbsp;Xin Liang ,&nbsp;Jing Li ,&nbsp;Yi Zhang ,&nbsp;Yong Tang","doi":"10.1016/j.expneurol.2025.115319","DOIUrl":"10.1016/j.expneurol.2025.115319","url":null,"abstract":"<div><div>Leucine-rich repeat and immunoglobulin-like domain-containing nogo receptor-interacting protein 1 (LINGO-1) is a neuronal system-specific transmembrane protein that is highly expressed in the brains of patients with Alzheimer's disease (AD), and our previous findings showed that LINGO-1 antagonism can improve cognitive function and protect hippocampal GABAergic interneurons in AD model mice. However, the specific mechanism underlying these effects is not clear. In this study, an adeno-associated virus (AAV) was used to directly interfere with hippocampal LINGO-1 in vivo, and LINGO-1 antagonists, cannabinoid type 1 receptor (CB1R) agonists, and CB1R antagonists were used to treat mouse hippocampal neurons (HT22 neurons) in vitro. We found that overexpressing hippocampal LINGO-1 in normal young mice impaired spatial learning and memory and reduced hippocampal CB1R protein levels, whereas silencing hippocampal LINGO-1 in AD model mice had the opposite effect. Additionally, antagonizing LINGO-1 increased CB1R/tyrosine kinase receptor B (TrkB) signalling and rescued CB1R- rich cholecystokinin-GABAergic (CCK-GABAergic) interneurons in HT22 neurons transduced with an APP/PS1-expressing virus. Competitive inhibition of LINGO-1 and CB1R was observed, and antagonizing LINGO-1 reversed the changes in HT22 neurons caused by the inhibition of CB1R, such as the decreases in the protein levels of doublecortin (DCX), TrkB, and phosphorylated TrkB (p-TrkB). These findings provide an important scientific basis for further exploration of the mechanism by which LINGO-1 regulates cognitive function and hippocampal GABAergic interneurons in AD model mice.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115319"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180681","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 role of astrocyte-derived extracellular vesicles in cellular microenvironment remodeling after spinal cord injury: A study based on quantitative proteomics analysis","authors":"Zhenghuan Zhu ,&nbsp;Yi Xu ,&nbsp;Kejie Wang ,&nbsp;Xu Xu ,&nbsp;Yu Song ,&nbsp;Baizhen Zhao ,&nbsp;Wenge Ding ,&nbsp;Jinbo Liu ,&nbsp;Zhiwen Song","doi":"10.1016/j.expneurol.2025.115321","DOIUrl":"10.1016/j.expneurol.2025.115321","url":null,"abstract":"<div><div>After spinal cord injury (SCI), astrocytes (AS), the most abundant glial cells in the central nervous system, closely interact with other nerve cells. The precise mechanism by which astrocytes remodel the cellular microenvironment (CME) remains unclear; however, the extracellular vesicles (EVs) they release may facilitate communication between cells by transporting biological macromolecules. This study aimed to elucidate the role of astrocyte-derived EVs in modulating CME after SCI. An <em>in vitro</em> model of reactive astrocytes (RA) was developed under simulated SCI conditions, followed by proteomic analysis of EVs isolated from RA and AS. Differential protein expression was assessed using quantitative proteomics, complemented by gene set enrichment analysis to elucidate the associated biological functions. Our results indicate that AS-EVs provide neuroprotective benefits by attenuating microglial activation, decreasing neuronal apoptosis, promoting axonal growth, and facilitating the maturation of oligodendrocyte precursor cells, thereby improving motor function recovery in murine models. Conversely, RA-EVs exhibited deleterious effects, exacerbating inflammation and impeding functional recovery. C<img>C Motif Chemokine Ligand 7 (CCL7) was identified as a critical secretory protein mediating these adverse effects. These findings elucidate the neuroprotective and regenerative mechanisms mediated by astrocyte-derived EVs, highlighting the therapeutic potential of CCL7-targeted interventions in promoting recovery after SCI.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115321"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144167583","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":"Osteocalcin modulates Abeta42 aggregation to aid in amyloid reduction in mouse models of Alzheimer's disease","authors":"Viji Vijayan ,&nbsp;Ibrar Ahmad Siddique ,&nbsp;Sakshi Gupta ,&nbsp;Evanka Madan Chopra ,&nbsp;Navya Raj ,&nbsp;Avadhesha Surolia ,&nbsp;Sarika Gupta","doi":"10.1016/j.expneurol.2025.115322","DOIUrl":"10.1016/j.expneurol.2025.115322","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by overexpression of amyloid-beta in the brain, particularly the toxic Abeta-42 form. Recent studies have identified osteocalcin, a peptide traditionally associated with bone, to modulate cognitive function in the AD brain. Osteocalcin exists in two forms: the undercarboxylated (uOC) and carboxylated (cOC) forms. This study investigates the role of uOC in modulating Abeta42 aggregation and its potential therapeutic implications for AD. Administration of uOC, but not cOC, improved both spatial learning and exploratory behavior of 5xFAD transgenic Alzheimer mice. Further investigation showed that uOC reduced the level of insoluble Abeta42 in the brain and increased the level of soluble Abeta42. There was increase in mRNA levels of CD36 in uOC treated 5xFAD transgenic brain alongside upregulation of neuroprotectants like Adipoq and Ahsg (fetuin). We explored the mechanisms underlying the influence of uOC on Aβ42 dynamics and understood that uOC interacts with Glu residues to form non-toxic early tube-like intermediates (A-O) before advancing to late mature Abeta42 fibrils. These intermediates enable Abeta42 uptake by glial cells by upregulating the cell surface expression of CD36 and reducing TNF-alpha production. Collectively, the study sheds light on the fact that uOC modulates Abeta42 dynamics and this interaction is warranted for Abeta42 uptake and clearance. The study provides a novel dimension for the treatment of amyloid disorders like AD.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115322"},"PeriodicalIF":4.6,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180852","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":"Intracerebroventricular phospho-tau immunotherapy alleviates cortical phospho-tau burden and motor phenotype in a neuron-specific P301S tauopathy mouse","authors":"S. Kemppainen ,&nbsp;M. Aramburu-Núñez ,&nbsp;H. Koivisto ,&nbsp;A. Posado-Fernández ,&nbsp;M.R. Felix-Garcia ,&nbsp;K. Nurminen ,&nbsp;S. Häkli ,&nbsp;E. Abelli-Deulofeu ,&nbsp;M. Kaisto ,&nbsp;A. Custodia ,&nbsp;L. van Olst ,&nbsp;R.-M. Willman ,&nbsp;P. Mäkinen ,&nbsp;P.O. Miettinen ,&nbsp;M. Schouten ,&nbsp;Ramón Iglesias-Rey ,&nbsp;A. Kamermans ,&nbsp;H. Martiskainen ,&nbsp;T. Rauramaa ,&nbsp;H.E. de Vries ,&nbsp;H. Tanila","doi":"10.1016/j.expneurol.2025.115315","DOIUrl":"10.1016/j.expneurol.2025.115315","url":null,"abstract":"<div><div>Pathological tau accumulation disrupts neuronal function, leading to neurodegeneration and dementia in tauopathies, such as Alzheimer's disease and frontotemporal dementia. Despite the progression of several anti-tau therapies to clinical trials, no disease-modifying treatments for tauopathies exist. Tau hyperphosphorylation is a key factor in pathology progression. Among all tau phosphorylation sites targeted in preclinical passive immunization studies, the classic AT8 pathological tau phosphorylation sites have remained understudied. Thus, we investigated the potential of immunotherapy against phosphorylated tau (pTau) in a P301S mouse model of tauopathy. We administered a new monoclonal B6 antibody that targets tau phosphorylation sites at serine 202, threonine 205 and serine 208 either systemically for 3 months or locally into the cerebral ventricles for 1 or 2 months via an osmotic minipump. Systemic administration failed to reach the brain effectively, and subsequently, was not able to alleviate the progressive motor impairment seen in this tauopathy mouse model. By contrast, intraventricular administration improved motor function in earlier stages of pathology but had a lesser effect in later stages. The local administration for 8 weeks reduced the number of pTau positive neurons in cortex and hippocampus. Our findings indicate that targeting the classical pathological tau phosphorylation sites can ameliorate tau pathology and improve function in a mouse tauopathy model. These results add to growing evidence supporting the efforts in developing tau-targeting immunotherapies for neurodegenerative diseases associated with pathological tau deposits.</div></div>","PeriodicalId":12246,"journal":{"name":"Experimental Neurology","volume":"391 ","pages":"Article 115315"},"PeriodicalIF":4.6,"publicationDate":"2025-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144126927","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}