Neurobiology of Disease最新文献

{"title":"The alternative complement pathway drives neuroinflammation and neurodegeneration in mouse models of glaucoma and optic nerve injury.","authors":"Cindy Hoppe, Ryo Mukai, Nasrin Refaian, Margarete Karg, Shintaro Shirahama, Maleeka Shrestha, Yinjie Guo, Amarachi Nwogu, Drenushe Krasniqi-Vanmeter, Volha V Malechka, Bruce R Ksander, Kip Connor, Meredith Gregory-Ksander","doi":"10.1016/j.nbd.2025.107119","DOIUrl":"10.1016/j.nbd.2025.107119","url":null,"abstract":"<p><p>Glaucoma is a leading cause of irreversible blindness worldwide, characterized by progressive retinal ganglion cell (RGC) loss and optic nerve degeneration. Although elevated intraocular pressure (IOP) is a major risk factor, disease progression can occur despite normal IOP, highlighting the need for neuroprotective strategies beyond IOP reduction. Neuroinflammation has been implicated in glaucomatous neurodegeneration through complement system activation via the classical and lectin pathways. However, the role of the alternative pathway (AP), which functions as an amplification loop for central complement component 3 (C3) activation, in glaucoma is unclear. In this study, we investigated the role of the AP in glaucoma using a microbead-induced mouse model of glaucoma in mice deficient in either complement factor B (Cfb^-/-), to selectively block the AP, or in C3 (C3^-/-) to block all three complement pathways. Our results indicate the AP is critical for glaucoma development, and blocking this pathway resulted in significant neuroprotection, preventing loss of RGCs, axons, and visual acuity, which coincided with reduced glial activation and inflammation. Blocking the AP provided comparable neuroprotection to blocking all three complement pathways, indicating that the AP amplification loop is an essential component of destructive neuroinflammation in glaucoma. Furthermore, blocking the AP also conferred neuroprotection in the optic nerve crush model, suggesting a broader role for the AP in optic neuropathies. These findings establish the AP as a key driver of complement-mediated neurodegeneration in glaucoma and highlight the therapeutic potential of targeting the AP in glaucoma and other neurodegenerative diseases.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107119"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145176982","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":"Demyelination-induced glutamatergic imbalance mediates hippocampal Hyperexcitability.","authors":"Alyssa M Anderson, Moyinoluwa Ajayi, Carrie R Jonak, Shane Desfor, Joselyn Soto, Adrian Akhuetie, Devang Deshpande, Andrew Lapato, Devin K Binder, Seema K Tiwari-Woodruff","doi":"10.1016/j.nbd.2025.107125","DOIUrl":"10.1016/j.nbd.2025.107125","url":null,"abstract":"<p><p>Chronic demyelination is a hallmark of multiple sclerosis (MS) and is associated with increased seizure susceptibility. In this study, we used the cuprizone (CPZ) diet induced demyelination model to investigate the progression of hippocampal demyelination and its impact on seizure activity and neurotransmitter dysregulation. Using EEG recordings, immunohistochemistry, Western blotting, ELISA, Golgi staining, and NanoString transcriptomics, we found progressive hippocampal demyelination accompanied by a striking increase in seizure incidence, from 38 % at 6 weeks to 88 % by 12 weeks. Structural degeneration of the CA1 pyramidal layer was marked by reduced dendritic arborization and loss of parvalbumin interneurons. Hippocampal glutamate levels increased as early as 3 weeks and remained elevated, with values (∼2.2 μM) reaching excitotoxic thresholds, along with astrocyte reactivity (glial fibrillary acidic protein) and downregulation of astrocytic glutamate transporter-1, and glutamate aspartate Transporter-1 and modification of aquaporin-4 in CA1. Stratum pyramidal and stratum radiatum region-specific alterations in glutamate transporters and related enzymes (glutamine synthetase, glutamic acid decarboxylase 67, vesicular glutamate transporter 1), further supported neurotransmitter imbalance. Transcriptomic profiling revealed widespread downregulation of myelin, neuronal, astrocytic, glutamatergic, and GABAergic genes at 6 weeks, with partial recovery by 12 weeks. Together, these findings establish a mechanistic link between chronic hippocampal demyelination, glutamate dysregulation, and epileptogenesis offering potential molecular targets for therapeutic intervention in MS-associated epilepsy.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107125"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177042","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 potential role of misfolded wild-type SOD1 protein in sporadic amyotrophic lateral sclerosis (ALS): a review of the evidence.","authors":"Thomas R Marlow, Katie M Bowden, Mark O Collins, Pamela J Shaw","doi":"10.1016/j.nbd.2025.107124","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107124","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterised by the selective loss of motor neurons in the motor cortex, brainstem and spinal cord. In 1993, the first ALS-linked gene mutations were identified in the Cu,Zn superoxide dismutase (SOD1) gene, which account for approximately 20 % of familial ALS cases. The mechanism of toxicity in this subset of patients is thought to arise from a gain-of-toxic function from the protein's propensity to misfold and aggregate into cytoplasmic inclusions. Immunohistochemical studies have shown that misfolded wildtype SOD1 (wtSOD1) is also detected in the motor neurons and glial cells of ALS patients without SOD1 mutations. It is proposed that disrupted, or aberrant, posttranslational modifications cause wtSOD1 to adopt a toxic conformation similar to that of the mutant protein. Subsequent mechanistic studies have shown that this misfolded wtSOD1 can disrupt cellular function and lead to motor neuron death through pathways similar to those observed in mutant SOD1-ALS. Given the limited neuroprotective treatments currently available that can effectively slow or reverse disease progression, targeting a pathogenic mechanism that features in both familial and sporadic ALS cases represents a promising therapeutic approach for a broader patient population. This review examines the growing body of evidence that supports or challenges the role of misfolded wtSOD1 in the pathophysiology of sporadic ALS and explores the potential implications of this mechanism in disease progression. Understanding how misfolded wtSOD1 contributes to disease pathogenesis provides new opportunities for developing more widely available treatments for this devastating disease.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107124"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145177045","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":"α7 nicotinic acetylcholine receptor and depression: Mechanistic insights and therapeutic prospects","authors":"Canmao Wang ,&nbsp;Danna Gan ,&nbsp;Zixi Hong ,&nbsp;Haixing Feng ,&nbsp;Yufan Wu ,&nbsp;Guanghui Xu ,&nbsp;Tianrong Xun ,&nbsp;Xixiao Yang","doi":"10.1016/j.nbd.2025.107122","DOIUrl":"10.1016/j.nbd.2025.107122","url":null,"abstract":"<div><div>Depression is a highly prevalent and disabling psychiatric disorder worldwide, yet current treatments are limited by delayed onset and suboptimal response rates. The α7 nicotinic acetylcholine receptor (α7 nAChR), a ligand-gated cation channel within the central cholinergic system, is highly expressed in emotion-regulating regions including the hippocampus and prefrontal cortex, where it modulates neurotransmitter release, synaptic plasticity, and neuroinflammation. Accumulating preclinical evidence indicates that α7 nAChR activation may exert antidepressant-like effects by modulating monoaminergic neurotransmission, enhancing brain-derived neurotrophic factor (BDNF) expression, attenuating microglial activation and proinflammatory cytokine release, and engaging gut–brain-axis pathways. Nevertheless, heterogeneous findings, target-engagement hurdles, and a paucity of adequately powered clinical studies have limited translation to the clinic. This review systematically summarizes the structural features, mechanistic insights, and therapeutic advances of α7 nAChR in depression, with the aim of providing a theoretical basis and future directions for targeted interventions and novel drug discovery.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107122"},"PeriodicalIF":5.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145157025","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":"K_V7.2 channel dysfunction delays neuronal maturation and undermines early network development in a hiPSC model of KCNQ2-DEE.","authors":"Filip Rosa, Stephan Theiss, Susanne Krepp, Heidi Loeffler, Dulini C Mendis, Stefanie Klingenstein, Stefan Liebau, Sarah Weckhuysen, Michael Alber, Steven Petrou, Holger Lerche, Snezana Maljevic, Thomas V Wuttke","doi":"10.1016/j.nbd.2025.107120","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107120","url":null,"abstract":"<p><p>KCNQ2 developmental and epileptic encephalopathy (KCNQ-DEE), is caused predominantly by dominant-negative loss-of-function variants in the KCNQ2 gene, leading to neonatal-onset epileptic seizures and profound neurodevelopmental impairment. Using patient induced pluripotent stem cells (iPSC)-derived neurons and complementary murine model, we found that dominant-negative KCNQ2 variants leading to diminished M-current cause depolarized resting membrane potential, reduced action potential generation and fragmented early network oscillations, all indicative of delayed neuronal development. These effects were most pronounced at immature developmental stages and replicated by pharmacological M-current inhibition, highlighting a critical role for Kv7.2 during early neuronal maturation. Notably, our data challenge the prevailing view that KCNQ2-DEE symptoms are solely driven by hyperexcitability. Instead, we reveal a biphasic pattern in which loss of M-current delays the acquisition of basic functional properties in developing neurons, with potential consequences for synaptogenesis and cortical circuit formation. These findings provide a plausible cellular mechanism for the early-onset developmental delay observed in KCNQ2-DEE patients, even when seizures are effectively controlled. They raise the possibility that seizure-suppressing therapies such as carbamazepine may disrupt the development of immature networks, but further work is needed to assess clinical relevance.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107120"},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150167","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":"Considering Big tau as a novel and specific biomarker for spinal motor neuron pathology","authors":"Itzhak Fischer","doi":"10.1016/j.nbd.2025.107118","DOIUrl":"10.1016/j.nbd.2025.107118","url":null,"abstract":"<div><div>Big tau is an isoform of tau that includes the large 4 A exon, resulting in an extended projection domain and an overall increase in apparent molecular weight from 40 to 65 kDa to 95–110 kDa. Its expression is highly restricted to the peripheral and autonomic nervous systems and select regions of the central nervous system. Although the precise function of Big tau remains unclear, we have proposed that the expanded projection domain of low molecular weight (LMW) tau by 250 amino acids of exon 4a and its structural properties may enhance axonal transport in long-projecting neurons and confer resistance to aggregation.</div><div>Here, we propose a clinical perspective based on the properties of Big tau: the selective expression of Big tau in spinal motor neurons, but not in upper motor neurons or other spinal neuronal populations, is likely to make Big tau a specific biomarker for spinal motor neuron pathology. This expression pattern may be particularly valuable for tracking disease prognosis and progression in conditions such as amyotrophic lateral sclerosis (ALS) and related disorders, to identify when degeneration advances to lower motor neurons. Big tau could thus serve as a more specific biomarker to neurofilament or LMW tau proteins or can be used in combination with other biomarkers to enhance the specificity and sensitivity.</div><div>This hypothesis can be readily tested using existing samples and assays applied to cerebrospinal fluid (CSF) and blood samples from patients. If validated through clinical studies, Big tau may provide clinicians with a new tool to better diagnose and monitor a variety of motor neuron degenerative disorders. To accelerate research in this area, I offer to share experimental data and an inventory of polyclonal antibodies specific to Big tau to the research community to enable further investigation of Big tau as a clinical biomarker.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107118"},"PeriodicalIF":5.6,"publicationDate":"2025-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145150195","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":"Stimulation of Purkinje cell firing reverses early onset spatial navigation deficits in a spinocerebellar ataxia type 6 mouse model","authors":"Michelle Grömmke ,&nbsp;Hannah Schulte ,&nbsp;Candy D.C. Theis ,&nbsp;Lena Nonnweiler ,&nbsp;Melanie D. Mark","doi":"10.1016/j.nbd.2025.107109","DOIUrl":"10.1016/j.nbd.2025.107109","url":null,"abstract":"<div><div>Spinocerebellar ataxia type 6 (SCA6) is a hereditary neurodegenerative disease that manifests in a late onset and progressive impairment of motor coordination, balance and speech as well as cerebellar and brainstem atrophy. It is caused by a polyglutamine expansion in the <em>CACNA1A</em> gene which bicistronically encodes the α1A-subunit of the P/Q-type voltage-gated calcium channel and the transcription factor α1ACT. The lack of treatments for SCA6 patients emphasizes the necessity to investigate the underlying pathomechanisms and its impact on cognition. In this study we found that SCA6 mice demonstrate spatial navigation deficits which precede their motor deficiencies. This resulted in a concomitant Purkinje cell (PC) dysfunction, exhibited by a disruption in their PC spontaneous simple spike firing rates and regularity of firing. PC dysfunction was further confirmed by elevated numbers of axonal swellings found in the PC proximal axons throughout the cerebellum. More importantly, we were able to partially rescue irregular PC firing and spatial navigation deficits using a stimulatory Gq-protein coupled designer receptor exclusively activated by a designer drug (Gq-DREADD), further indicating that PC dysfunction contributes to SCA6 cognitive abnormalities in spatial navigation.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":""},"PeriodicalIF":5.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145098807","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":"Astrocyte-microglia crosstalk in the hippocampus mediates cognitive impairments induced by chronic intermittent hypoxia.","authors":"Zhen-Huan Wu, Ming-Rui Zhai, Yu-Rong Wang, Long Ren, Jie Pan, Lei Xiao, Yue-Hua Liu","doi":"10.1016/j.nbd.2025.107117","DOIUrl":"10.1016/j.nbd.2025.107117","url":null,"abstract":"<p><p>Obstructive sleep apnea (OSA), characterized by chronic intermittent hypoxia (CIH), is a common systemic disease with a high-risk factor for developing cognitive impairment. However, the possible mechanism(s) underlying the cognitive function impairment in CIH remain largely unknown. In this study, our results reveal that 8-week CIH reliably induces significant cognitive impairment, synaptic deficits, and pronounced microglial activation characterized by excessive synaptic phagocytosis. Pharmacological depletion of microglia using PLX5622 ameliorated these CIH-induced impairments. Furthermore, CIH enhanced the interaction between activated astrocytes and microglia, accompanied by upregulation of complement C3 in astrocytes and C3aR in microglia. Notably, blocking C3aR with SB290157 attenuated microglial overactivation, reduced aberrant synaptic engulfment, and improved cognitive performance in CIH-exposed mice. Collectively, these findings demonstrate that C3/C3aR-mediated astrocyte-microglia crosstalk contributes to CIH-induced cognitive dysfunction by activating microglia to excessive phagocytosis of synapses.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107117"},"PeriodicalIF":5.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138212","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":"Cerebellar dysfunction in a mouse model of childhood-onset manganese-induced dystonia parkinsonism.","authors":"Alexander N Rodichkin, Amanda M Brown, Pavani Devabathini, Jennifer L McGlothan, Si Chen, Ajith Pattammattel, Yong S Chu, Tao Lin, Daniel D Pontow, Karam Abilmouna, Ritishka Kapoor, Sarah E Hardin, Yulia Pushkar, Roy V Sillitoe, Tomás R Guilarte","doi":"10.1016/j.nbd.2025.107115","DOIUrl":"10.1016/j.nbd.2025.107115","url":null,"abstract":"<p><p>Humans with pathogenic variants of the manganese (Mn) transporter gene SLC39A14 exhibit highly elevated brain Mn concentrations and childhood-onset dystonia-parkinsonism. Here we show that Slc39a14-knockout (KO) mice, a preclinical model of the disease with elevated Mn concentrations in the CB, express deficits in physiological tremor implicating cerebellar (CB) dysfunction. Imaging of intracellular Mn in Purkinje cells (PCs) using synchrotron-based X-ray fluorescence microscopy confirmed highly elevated Mn concentrations in the PCs of Slc39a14-KO mice. To determine biological pathways altered in the CB of Slc39a14-KO mice relative to wildtype (WT), we performed RNA sequencing and discovered significant upregulation of pathways and genes regulating immune response and cell death. To substantiate these findings, we performed quantitative autoradiography of the neuroinflammation biomarker Translocator Protein 18 kDa (TSPO) which was significantly increased in the CB of Slc39a14-KO mice relative to WT. The latter findings were confirmed via immunostaining with the microglial marker Iba-1, revealing widespread microglia activation and clustering in the CB cortex. Immunostaining for cleaved caspase-3 (cCASP3), a marker of apoptosis, showed increased number of PCs with positive immunolabeling for cCASP3 in Slc39a14-KO mice relative to WT. Degeneration of PCs was confirmed by Hematoxylin and Eosin (H&E) staining. Lastly, functional electrophysiological assessment of CB neurocircuitry revealed a marked decrease in firing rates of cerebellar nuclei (CN) neurons and increased variability of PC simple spikes firing. Collectively, these findings show, for the first time, Mn-induced PC degeneration and dysfunctional CB circuitry in Slc39a14-KO mice providing additional evidence for the pathological underpinnings of the dystonia-like movements, balance, and gait abnormalities in SLC39A14 mutation carriers.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107115"},"PeriodicalIF":5.6,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145138244","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":"Regional differences in astrocytic Aquaporin-4 protein levels and distribution in aging and Alzheimer's disease in down syndrome","authors":"Cherie A. Stringer ,&nbsp;Haley K.S. Miyasato ,&nbsp;Kevin A. Camey ,&nbsp;Krina A. Ghadia ,&nbsp;Elizabeth J. Andrews ,&nbsp;Phong T. Ngo ,&nbsp;Jesse R. Pascual ,&nbsp;Sierra T. Wright ,&nbsp;Justine A. Silva ,&nbsp;Brianna M. Gawronski ,&nbsp;Lourdes Gonzalez ,&nbsp;Kevin A. Wood ,&nbsp;Michael J. Phelan ,&nbsp;Florence Lai ,&nbsp;Frederick A. Schmitt ,&nbsp;Jordan P. Harp ,&nbsp;Adam M. Brickman ,&nbsp;Patrick J. Lao ,&nbsp;Mark E. Mapstone ,&nbsp;Julia K. Kofler ,&nbsp;Elizabeth Head","doi":"10.1016/j.nbd.2025.107114","DOIUrl":"10.1016/j.nbd.2025.107114","url":null,"abstract":"<div><div>Aquaporin-4 (AQP4) is implicated in Alzheimer's disease (AD) pathology through its role in astrocytic function, cerebrovascular integrity, and beta-amyloid (Aβ) clearance. Impaired Aβ clearance in AD is linked to changes in AQP4 distribution; however, the role of AQP4 in AD associated with Down Syndrome (DS) is poorly understood. This study investigates AQP4 protein levels, its relationship with Aβ deposition, and distribution patterns in DS. Using human post-mortem brain sections from the frontal and occipital cortex, we analyzed AQP4 and Aβ levels in samples from neurotypical controls, DS, DS with AD (DSAD), and late onset AD (LOAD). Protein levels and distribution were assessed using immunohistochemistry and immunofluorescence with quantitative imaging tools. AQP4 protein levels were higher with age in both neurotypical control and DS groups, but not in the LOAD group. AQP4 and Aβ were positively correlated with age in the frontal cortex of all groups. AQP4 and Aβ were positively correlated with each other after adjusting for age in the frontal cortex in both the control and DS groups which was not observed in the occipital cortex. In the frontal cortex of both DS and DSAD, AQP4 was more frequently distributed to the soma and proximal branches and less to astrocytic endfeet compared to the control group, consistent with previous reports of impaired glymphatic clearance and perivascular regulation. These findings support a relationship between altered AQP4 protein levels and distribution, Aβ accumulation, and region-specific vulnerability in DS and AD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107114"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131622","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}