Neurobiology of Disease最新文献

{"title":"Spinal cord reactive-antibodies identified by serological antigen selection show prognostic value in traumatic spinal cord injury patients","authors":"Astrid Pues ,&nbsp;Patrick Vandormael ,&nbsp;Tim Vangansewinkel ,&nbsp;Naomi Veeningen ,&nbsp;Sam Vanherle ,&nbsp;Charlotte C.M. van Laake-Geelen ,&nbsp;Erwin M.J. Cornips ,&nbsp;Dieter Peuskens ,&nbsp;Eveleen Buelens ,&nbsp;Jens Deckers ,&nbsp;Bart Depreitere ,&nbsp;Sven Bamps ,&nbsp;Marc J. Ruitenberg ,&nbsp;Angel Arevalo-Martin ,&nbsp;Daniel Garcia-Ovejero ,&nbsp;Lukas Grassner ,&nbsp;Orpheus Mach ,&nbsp;Iris Leister ,&nbsp;Judith Fraussen ,&nbsp;Veerle Somers","doi":"10.1016/j.nbd.2026.107306","DOIUrl":"10.1016/j.nbd.2026.107306","url":null,"abstract":"<div><div>Outcome prediction after traumatic spinal cord injury (SCI) remains challenging due to patient heterogeneity, highlighting the need for better prognostic tools. Neural tissue damage and blood–spinal cord barrier disruption expose the immune system to spinal cord proteins, eliciting autoantibody responses that may be beneficial or detrimental. This study aimed to identify the (auto)antibody profile of SCI patients, and examine the prognostic antibody biomarker potential.</div><div>A healthy and a SCI cDNA phage display library were screened for novel antibodies using SCI samples (<em>n</em> = 12/11). Antibody reactivity was validated using phage ELISA in 291 samples from 190 SCI patients collected at baseline (0–4 days post-injury [dpi]) and follow-up (15–30 dpi; 31–56 dpi). Correlations between antibody reactivity and clinical characteristics including SCI level, and American Spinal Injury Association impairment scale (AIS), were analysed. Immunofluorescent stainings were used to validate expression of two antigenic targets.</div><div>We identified antibodies against 6 novel autoantigens (University Hasselt [UH.] SCI.104/105/106/108/109/110). A panel of three antigens (UH.SCI.104/109/110) demonstrated increased antibody reactivity in 31.3% of SCI patients with AIS improvement versus 4.8% with no improvement, resulting in a positive likelihood ratio of 6.56. Patients with injuries above thoracic level 4 had significantly lower antibody reactivity against UH.SCI.105/110 compared to patients with lower lesions. Anti-UH.SCI.108/110 antibodies bound to astrocytes, in mouse spinal cord tissue and primary cell cultures, confirming disease-relevant reactivity.</div><div>Antibodies targeting the novel antigens demonstrated prognostic biomarker potential, supporting their future use in outcome prediction and patient stratification for SCI management and clinical trial design.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107306"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146119742","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":"Associations between diseases of the mouth and mental disorders: A scoping review of longitudinal studies","authors":"Sudan Prasad Neupane ,&nbsp;Ifeoma N. Onyeka ,&nbsp;Vibeke H. Bull ,&nbsp;Federico M. Daray","doi":"10.1016/j.nbd.2026.107285","DOIUrl":"10.1016/j.nbd.2026.107285","url":null,"abstract":"<div><h3>Background</h3><div>Mental disorders and oral health conditions frequently co-occur. We mapped and critically reviewed the literature on longitudinal associations between oral health conditions and mental disorders.</div></div><div><h3>Method</h3><div>MEDLINE, Embase and PsycInfo were searched for longitudinal studies published during the last 25 years. Two reviewers independently screened, reviewed full-text and extracted data before synthesizing the evidence. Associations between oral and mental disorders were illustrated as Sankey diagrams. The review protocol was pre-registered (<span><span>https://osf.io/vrpu9</span><svg><path></path></svg></span>).</div></div><div><h3>Findings</h3><div>From 165 included studies, we identified 118 studies investigating 35 independent associations between 16 oral exposures and 12 mental disorder outcomes. Another 42 studies investigated 32 associations between 17 mental disorder exposures and 14 oral outcomes. Five studies reported bidirectional associations. Most reports linked tooth loss to Alzheimer's disease/other dementias (18 studies) and cognitive impairment (15 studies), with periodontitis linked to Alzheimer's disease/other dementias (16 studies). Conversely, depression (10 studies), dementia (6 studies) and sleep disorder (5 studies) were attributed to temporomandibular disorders (TMD; 10 studies), periodontitis (8 studies) and caries (7 studies) outcomes. Depressive and anxiety disorders were linked bidirectionally with TMD and eating disorders.</div></div><div><h3>Interpretation</h3><div>Prevention and early management of oral and mental disorders may mitigate their reciprocal risk, thereby lowering the overall disease burden.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107285"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146080744","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":"Pharmacological manipulation of nested oscillations in human iPSC-derived 2D neuronal networks","authors":"Deborah Pré ,&nbsp;Christian Cazares ,&nbsp;Alexander T. Wooten ,&nbsp;Haowen Zhou ,&nbsp;Isabel Onofre ,&nbsp;Ashley Neil ,&nbsp;Todd Logan ,&nbsp;Ruilong Hu ,&nbsp;Jan H. Lui ,&nbsp;Bradley Voytek ,&nbsp;Anne G. Bang","doi":"10.1016/j.nbd.2026.107281","DOIUrl":"10.1016/j.nbd.2026.107281","url":null,"abstract":"<div><div>Dynamically coupled neural networks are fundamental to human cognition and behavior and are disrupted in neurodevelopmental disorders. The formation and dissolution of functional networks is thought to be driven by synchronized oscillatory bursts across large populations of neurons. The mechanisms driving the emergence of these rhythms, known as oscillogenesis, are not well understood, particularly in the human brain. Using multi-electrode arrays, we investigated oscillogenesis in human induced pluripotent stem cell 2D neural cultures at different developmental stages and under pharmacological challenges. We found that cultures exhibited nested oscillations that were reduced by GABAA receptor blockade and emerged earlier when the proportion of GABAergic neurons was increased. Pharmacological manipulations of voltage-gated potassium channels and cholinergic receptors modulated the pattern of nested oscillations. These results reveal the capacity of these 2D cultures to model oscillogenesis, and underscore the need for their continued refinement, paving the way for linking systems-level neural networks to human cognition and disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107281"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146053176","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":"New perspective on neurodegenerative diseases: Focusing on the interaction between autophagy and oxidative stress and targeted strategies","authors":"Jiaqin Jin ,&nbsp;Qiuyu Cen ,&nbsp;Huage Wang ,&nbsp;Yin Xin ,&nbsp;Jing Feng ,&nbsp;Yanru Cui ,&nbsp;JiaYu Li ,&nbsp;Zilong You ,&nbsp;Fangyuan Jing ,&nbsp;Yang Yu ,&nbsp;Yingbo Qiu ,&nbsp;Rizhao Pang ,&nbsp;Junyu Wang ,&nbsp;Anren Zhang","doi":"10.1016/j.nbd.2026.107283","DOIUrl":"10.1016/j.nbd.2026.107283","url":null,"abstract":"<div><div>Autophagy is a highly conserved lysosome-dependent degradation process that plays a crucial role in maintaining neuronal homeostasis and adaptation during stress by eliminating misfolded proteins, damaged organelles, and pathogens. Oxidative stress, triggered by an imbalance between reactive oxygen speciesreactive oxygen species:ROS (ROS) production and antioxidant defenses, contributes to disease pathogenesis through mechanisms such as lipid peroxidation, protein carbonylation, and mitochondrial DNA damage. Recent studies reveal that autophagy and oxidative stress interact via a dynamic bidirectional regulatory network to modulate neurodegenerative pathology: ROS activate autophagy by regulating signaling pathways and modifying autophagy-associated proteins, while moderate autophagic activity selectively clears ROS-generating components and activates antioxidant pathways. Dysregulation of autophagy or excessive ROS accumulation can disrupt this equilibrium, leading to cell death and disorders such as neurodegenerative diseases, cancer, and aging-related pathologies. They reciprocally serve as “pressure signals” and “clearance targets”, synergistically maintaining cellular homeostasis. This review synthesizes insights from current studies to systematically analyze the complex cross-talk between autophagy and oxidative stress in neurodegeneration and evaluates emerging therapeutic strategies targeting this interplay, including autophagy modulators, antioxidants, phytochemicals, and nanomaterials. These advancements offer novel perspectives for developing neuroprotective therapies through therapeutic modulation of the autophagy-oxidative stress axis. Finally, we summarize key challenges in the field and propose potential directions for future research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107283"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146030447","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 auxiliary GABAB receptor subunit KCTD16 in pain modulation","authors":"Daniel Vasconcelos ,&nbsp;Mario Heles ,&nbsp;Pavel Adamek ,&nbsp;Anirban Bhattacharyya ,&nbsp;Adolf Melichar ,&nbsp;Rostislav Turecek ,&nbsp;Jiri Palecek","doi":"10.1016/j.nbd.2026.107286","DOIUrl":"10.1016/j.nbd.2026.107286","url":null,"abstract":"<div><div>Chronic pain affects nearly 10% of the global population and remains a major clinical challenge due to the limited efficacy and adverse effects of current therapies. In this study, we identify the potassium channel tetramerization domain protein KCTD16 as a key modulator of GABA_B receptor mediated inhibition of nociceptive transmission. Immunohistochemical analysis revealed prominent KCTD16 expression in dorsal horn and dorsal root ganglion (DRG) neurons, consistent with a role in spinal nociceptive processing. KCTD16 knockout (KO) mice exhibited increased mechanical thresholds relative to wild-type (WT) littermates, while thermal sensitivity remained unchanged; this phenotype persisted following carrageenan-induced inflammation. The GABA_B receptor agonist Baclofe<strong>n</strong> produced strong analgesic effects in WT mice under both basal and inflammatory conditions, whereas its anti-allodynic efficacy was significantly reduced in KO animals. Whole-cell patch-clamp recordings from dorsal horn neurons showed comparable baseline miniature excitatory and lower inhibitory postsynaptic currents (mEPSCs and mIPSCs) for KCTD16^−/−. However, following inflammation, Baclofen-induced suppression of excitatory transmission was potentiated in WT but markedly attenuated in KO neurons. Light-evoked synaptic inhibitory currents and calcium imaging of cultured DRG neurons further demonstrated enhanced Baclofen sensitivity in WT cells. These findings indicate that KCTD16 plays a critical role in presynaptic modulation of inhibitory control in the spinal dorsal horn, affecting the balance between the excitation and inhibition in nociceptive circuits. Collectively, these results demonstrate that KCTD16 modulates GABA_B receptor-dependent inhibitory control of nociceptive signaling and highlight the GABA_B receptor-KCTD16 complex as a promising new molecular target for effective pain treatments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107286"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065586","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":"Artificial intelligence and machine learning in neurodegenerative disease management: A 21st century paradigm","authors":"Shaik Basha ,&nbsp;Pranavi KS ,&nbsp;Ahana Chattopadhyay ,&nbsp;Aparna Ramakrishna Pai ,&nbsp;Krishna Kishore Mahato","doi":"10.1016/j.nbd.2026.107307","DOIUrl":"10.1016/j.nbd.2026.107307","url":null,"abstract":"<div><div>Neurodegenerative diseases represent a major and growing clinical challenge due to their progressive nature, biological heterogeneity, and limited therapeutic options. Recent advances in artificial intelligence (AI) have introduced new analytical strategies for extracting clinically relevant information from complex biomedical data, offering complementary tools to established diagnostic and research approaches. This review provides a critical and method-comparative synthesis of AI applications in neurodegenerative diseases, with emphasis on studies published between 2022 and 2025. Rather than cataloging algorithms, the review evaluates how specific AI methodologies are selected, implemented, and validated across diverse data modalities, including molecular profiles, neuroimaging, biosensors, speech, gait, and electronic health records. Across Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders, the reviewed evidence indicates that AI-based models can support early risk stratification, disease characterization, and monitoring when applied within clearly defined analytic and clinical contexts. Importantly, performance gains are shown to depend strongly on data quality, feature representation, validation design, and alignment between model architecture and biological signal, rather than on algorithmic complexity alone. Emerging paradigms, including multimodal integration and next-generation AI frameworks, are discussed in relation to their methodological contributions rather than clinical readiness. By systematically comparing analytical strategies and highlighting sources of variability across studies, this review underscores the importance of methodological transparency, uncertainty-aware evaluation, and biological interpretability. Collectively, the work positions AI as an enabling and adjunctive analytical framework that can enhance neurodegenerative disease research and clinical decision support when deployed with rigor and caution, providing a balanced perspective on current capabilities and future directions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107307"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146125881","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":"Hippocampal glial alterations are associated with Lamin B1 dysregulation and abnormal nuclear morphology in a rat model of fragile X syndrome","authors":"Alessandro Rava ,&nbsp;Alessandro Feo ,&nbsp;Giulia Bagnato ,&nbsp;Valentina D’Oria ,&nbsp;Marco Pezzullo ,&nbsp;Stefania Petrini ,&nbsp;Valeria Buzzelli ,&nbsp;Fabrizio Ascone ,&nbsp;Melania Di Trapano ,&nbsp;Barbara Peruzzi ,&nbsp;Viviana Trezza","doi":"10.1016/j.nbd.2026.107304","DOIUrl":"10.1016/j.nbd.2026.107304","url":null,"abstract":"<div><div>Fragile X syndrome (FXS) is the most common inherited intellectual disability and the leading monogenic cause of autism spectrum disorders (ASD). Although the pathological mechanisms underlying this neurodevelopmental disorder are challenging, recent studies have increasingly highlighted the involvement of glial cells in the pathogenesis of both ASD and FXS. Microglia and astrocytes are critical for brain development and homeostasis; thus, understanding glial dysfunction in both the developing and adult brain in these disorders may reveal novel therapeutic targets beyond the neuro-centric perspective. In this study, we demonstrated that the loss of function of Fmrp leads to phenotypic changes in both microglia and astrocytes within the hippocampus of the recently validated <em>Fmr1-</em>^<em>∆</em><em>exon 8</em> rat model of FXS without a significant induction of pro-inflammatory cytokines. For the first time, we also provide evidence that these non-inflammatory changes in glia are associated with dysmorphic nuclei and a reduced expression of Lamin B1, a key component of the nuclear envelope and an important modulator of brain development and aging, in the hippocampus of young adult <em>Fmr1-</em>^<em>∆</em><em>exon 8</em> rats.</div><div>Collectively, our findings strengthen existing evidence of the glial contribution to FXS and identify Lamin B1 loss and nuclear abnormalities as potential early markers of hippocampal pathology, providing a novel potential molecular target which should be furtherly considered.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107304"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132585","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":"Novel extracellular vesicle release pathway facilitated by toxic superoxide dismutase 1 oligomers","authors":"Brianna Hnath ,&nbsp;Srinivasan Ekambaram ,&nbsp;Nikolay V. Dokholyan","doi":"10.1016/j.nbd.2026.107309","DOIUrl":"10.1016/j.nbd.2026.107309","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that results in paralysis and death within three to five years. Mutations in over forty different proteins have been linked to ALS, raising debate over whether ALS is a single disease or multiple disorders with similar symptoms. Mutations in Cu,Zn superoxide dismutase 1 (SOD1) are found in only 2–3% of ALS cases, yet misfolded SOD1 appears in both sporadic (sALS) and familial (fALS) patients. Furthermore, mutations in TDP-43 or FUS increase levels of misfolded SOD1 on extracellular vesicles (EVs). Small EVs isolated from ALS patient samples have been shown to cause death of wild-type motor neurons and myotubes, supporting the theory that EVs play a role in spreading disease. We hypothesize that the previously identified toxic trimeric SOD1 spreads via EVs in ALS and influences the distribution of other ALS-related proteins, suggesting a common mechanism. To test this, we isolate EVs from motor neuron-like cells expressing mutations that stabilize trimers. We then perform a sandwich enzyme-linked immunosorbent assay (ELISA) using a CD9 capture antibody to measure whether misfolded SOD1 and 17 other ALS-related proteins increase or decrease on EVs with trimer stabilization. We identify which EV release pathway is affected by trimeric SOD1 using endocytosis and exocytosis inhibitors and analyze altered protein interaction pathways through co-immunoprecipitation and mass spectrometry proteomics. Our results show that VAPB, VCP, and Stathmin-2 increase on EVs when trimers are stabilized. The common pathway linking these ALS-associated proteins and SOD1 appears to involve multiple mechanisms, including the Caveolae endocytosis pathway, pointing to a novel hybrid EV release pathway in ALS. Overall, our findings show that trimeric SOD1 influences EV cargo and spread in ALS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107309"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146132523","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-specific deletion of LRRC8A causes neurological dysfunction but not chronic white matter edema","authors":"Sven Kerst ,&nbsp;Leoni Hoogterp ,&nbsp;Marjolein Breur ,&nbsp;Gemma M. van Rooijen-van Leeuwen ,&nbsp;Marianna Bugiani ,&nbsp;Rajan Sah ,&nbsp;Huibert D. Mansvelder ,&nbsp;Marjo S. van der Knaap ,&nbsp;Rogier Min","doi":"10.1016/j.nbd.2026.107313","DOIUrl":"10.1016/j.nbd.2026.107313","url":null,"abstract":"<div><div>Volume-regulated anion channels (VRACs) are central to cell volume homeostasis. They mediate swelling-induced efflux of chloride and organic osmolytes to drive regulatory volume decrease. In the brain, VRACs have been proposed to play a key role in astrocytic volume regulation. Genetic defects in astrocytic VRAC modulating proteins (MLC1, GlialCAM, Aquaporin-4, GPRC5B) cause the leukodystrophy Megalencephalic leukoencephalopathy with subcortical cysts (MLC), characterized by chronic white matter edema and myelin vacuolization. Disrupted VRAC activity in MLC-patient-derived lymphoblasts and primary astrocytes from MLC mice further supports a pathogenic link between defective VRAC activity and MLC. Here, we studied the physiological and pathological consequences of astrocyte-specific removal of the essential VRAC subunit LRRC8A. In contrast to established MLC mouse models, astrocyte specific <em>Lrrc8a</em> knockout mice had normal brain water content, no myelin vacuolization, and preserved expression of MLC-related proteins. At a late age they developed a mildly ataxic gait and displayed increased severity of kainate-induced seizures. Two-photon imaging in acute brain slices revealed that astrocytes lacking LRRC8A show normal volume recovery and chloride dynamics upon high potassium-induced cell swelling. Together, these findings demonstrate that astrocyte LRRC8A is not essential for volume regulation <em>in situ</em> and that its loss alone is insufficient to cause the chronic white matter edema typical of MLC. The mild neurological deficits indicate a physiological role for astrocyte LRRC8A, but MLC pathology likely arises from broader dysregulation of the astrocytic protein complex coordinating ion and water homeostasis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107313"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146137787","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":"A Novel APP p.V742L variant in a patient with ischemic small vessel disease enhances FE65 signalling","authors":"Bas J.B. Voesenek ,&nbsp;Julie W. Rutten ,&nbsp;Monique P.C. Mulder ,&nbsp;Hailiang Mei ,&nbsp;Esther A.R. Nibbeling ,&nbsp;Ellis S. van Etten ,&nbsp;Willeke M.C. van Roon-Mom ,&nbsp;Saskia A.J. Lesnik Oberstein ,&nbsp;Elena Daoutsali ,&nbsp;Ronald A.M. Buijsen","doi":"10.1016/j.nbd.2026.107280","DOIUrl":"10.1016/j.nbd.2026.107280","url":null,"abstract":"<div><div>Pathogenic variants in the amyloid precursor protein gene (<em>APP</em>) have been linked to Alzheimer's disease and intracerebral haemorrhage resulting from cerebral amyloid angiopathy. In these disorders, variants are generally located within or surrounding the amyloid-beta domain of <em>APP</em> and mostly increase the production or aggregation properties of the toxic amyloid-beta peptide. Here, we report a novel APP p.V742L variant in the APP intracellular domain (AICD) in a patient with a clinical and neuroradiological ischemic small vessel disease phenotype and a positive family history. We investigate the functional consequences of the variant on AICD function.</div><div>We obtained patient fibroblasts through a skin biopsy and applied immunocytochemistry to examine the subcellular localization of APP. Subsequently, 3’ mRNA sequencing was deployed to investigate changes in gene expression. Finally, the effect of the variant on the binding of FE65 to AICD was investigated using co-immunoprecipitation followed by western blot.</div><div>Localization of APP p.V742L to lysosomes was increased, without affecting lysosomal motility. Transcriptome analysis showed altered expression of AICD target genes as well as dysregulation of genes relevant to the ischemic stroke phenotype. Finally, APP p.V742L was associated with an increased interaction with FE65, its most important intracellular binding partner.</div><div>Taken together, our data demonstrate that the APP p.V742L variant enhances the interaction of the AICD with FE65, resulting in dysregulation of gene transcription. This study illustrates the diverse roles of APP in brain disorders, and suggests ischemic small vessel disease as a novel APP-associated phenotype.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"220 ","pages":"Article 107280"},"PeriodicalIF":5.6,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146065626","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}