Aging and Disease最新文献

{"title":"Extracellular Vesicle-Mediated microRNA Signaling in Osteosarcopenia: Emerging Insights into Age-Related Bone-Muscle Crosstalk.","authors":"Srijan Chatterjee, Jae Gyu Kim, Yeon-Hee Lee, Seungyi Cha, Minwook Kim, Chiranjib Chakraborty, Hongsik Cho, Sang-Soo Lee","doi":"10.14336/AD.2026.1034","DOIUrl":"https://doi.org/10.14336/AD.2026.1034","url":null,"abstract":"<p><p>Osteosarcopenia combines low bone strength with sarcopenia and increases the risks of falls, fractures, disability, and death. Recent reviews have catalogued extracellular vesicle (EV)-associated microRNAs in muscle-bone crosstalk, but intracellular microRNA function, EV association, experimentally administered EVs, and physiological tissue-to-tissue transfer are often discussed together. This focused narrative review applies an author-defined, non-validated four-tier framework to separate these inference levels using prespecified criteria for tissue-of-origin tracing, EV characterization, cargo perturbation, recipient validation, and in vivo phenotype. Within the studies reviewed, miR-125a-5p is the most complete preclinical muscle-to-bone candidate pathway, but its Tier-A assignment is provisional and supports causality only in the reported mouse models; it does not establish an exclusive single-cargo mechanism or human physiological transfer. Other muscle-cell EV microRNAs provide mechanistic but less complete evidence. No equivalent physiological bone-to-muscle EV-microRNA pathway meets Tier A; bone marrow stromal cell-derived EV miR-486-5p represents an experimentally administered therapeutic product rather than endogenous bone-to-muscle signaling. Most included studies concern related muscle or bone conditions or mechanistic models rather than directly defined osteosarcopenia. Human studies are small and heterogeneous, and none combines rigorous tissue-of-origin assignment, a prespecified osteosarcopenia phenotype, paired bone and muscle outcomes, and external validation. EV biomarkers and RNA/EV therapies therefore remain investigational. This evidence-based asymmetry, rather than another catalogue of candidate microRNAs, distinguishes the present review and defines priorities for tissue-specific tracing, cargo-specific rescue, independent human validation, and prospective tests of clinical utility.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164871","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":"Lysosomal Competence in Skeletal Muscle Aging: Autophagic Flux, Measurement Gaps, and Human Translation.","authors":"Oyungerel Dogsom, Jae Gyu Kim, Yeon-Hee Lee, Holger Jahr, Sang-Soo Lee","doi":"10.14336/AD.2026.1047","DOIUrl":"https://doi.org/10.14336/AD.2026.1047","url":null,"abstract":"<p><p>Age-related deterioration of skeletal muscle contributes to loss of mobility, frailty, and disability. Altered autophagy-lysosome competence has been proposed as a mechanism linking impaired proteostasis, mitochondrial damage, inflammation, and regenerative failure to sarcopenia. Chronological muscle aging and clinically defined sarcopenia overlap, but evidence from healthy aging, frailty, disuse, cachexia, obesity, or chronic disease cannot be treated as interchangeable. This narrative review examines how lysosomal acidification, degradative capacity, biogenesis, and turnover influences autophagic flux in aging muscle and evaluates the strength of evidence across experimental models and human studies. Genetic and pharmacological studies show that severe disruption of autophagy or specific lysosomal functions can cause myofiber damage, mitochondrial impairment, defective regeneration, and weakness. However, direct evidence that lysosomal acidification, fusion, hydrolase activity, membrane integrity, recycling, cargo degradation, or completed autophagic flux is impaired in aging human muscle remains limited. Much of the human literature relies on static abundance of LC3-II, SQSTM1/p62, lysosomal proteins, or transcriptional signatures, which cannot distinguish increased autophagosome formation from impaired degradation. We therefore separate causal experimental evidence from human associations and focus on V-ATPase, TMEM175, LAMP proteins, TFEB/TFE3, lysophagy, and crosstalk with mitophagy and the ubiquitin-proteasome system. Exercise improves clinically relevant outcomes in older adults, but mediation through completed autophagic flux has not been established. Recent trials of metformin and once-weekly sirolimus did not improve prespecified functional outcomes in the tested populations and regimens, whereas urolithin A produced endpoint-specific signals while missing key primary outcomes.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149164729","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":"Mouse Models for Aging Research: Mechanistic Utility, Translational Relevance, and Practical Model Selection.","authors":"Cassandra Coleman, Holly Thomas, Shenfeng Qiu, E Angela Murphy, Daping Fan","doi":"10.14336/AD.2026.0565","DOIUrl":"https://doi.org/10.14336/AD.2026.0565","url":null,"abstract":"<p><p>Aging is a complex biological process characterized by the progressive decline of physiological and cognitive function, increased vulnerability to disease, and eventual mortality. Laboratory mice have been used as models for aging research due to their genetic tractability, short lifespan, and physiological similarities to humans. However, no single mouse model fully recapitulates the complexity of organismal aging, and substantial differences exist in the biological processes, aging hallmarks, and translational relevance represented by individual models. Consequently, selecting an appropriate model requires careful consideration of the specific aging mechanisms and research objectives. This review provides a comparative overview of six broad categories of murine aging models, highlighting their mechanisms, advantages, and limitations. Natural aging models such as C57BL/6, BALB/c, FVB/N, and SAMP8 mice most closely recapitulate physiological aging, while accelerated models such as Klotho⁻/⁻, Ercc1⁻/Δ, and Lmna^G609G offer mechanistic insights into genetic pathways of senescence. Chemically induced models, such as those induced by D-galactose and paraquat administration, provide rapid and cost-effective approaches to mimic oxidative stress-related aging phenotypes. Telomere and senescence models, such as the Terc⁻/⁻, p16^INK4a-reporter, and INK-ATTAC mice, allow for visualization and direct manipulation of cellular senescence. Metabolic and mitochondrial models (Polg^mut/mut \"mutant\" mice and Sod^-/- mice) link mitochondrial DNA instability and oxidative stress to various conditions associated with aging, including sarcopenia, presbycusis, anemia, and reduced fertility. Dietary and environmental models allow for lifestyle-related aging modeling through high fat diets, irradiation, dietary restriction, and chronic stress exposure. Modeled mechanisms include altered metabolism, cellular senescence, and immune system effects. Together, these models form a versatile toolkit for investigating cellular, organismal, and systemic aspects of aging, and serve as platforms for anti-aging drug development.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149163876","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":"Functional Hemodynamic Assessment in Intracranial Atherosclerotic Disease: From Anatomical Stenosis to μQFR-Guided Precision Medicine.","authors":"Kangjie Fan, Shanshan Cao, Yandi Qiao, Zhenhua Zhang, Qiang Li","doi":"10.14336/AD.2026.0793","DOIUrl":"https://doi.org/10.14336/AD.2026.0793","url":null,"abstract":"<p><p>Intracranial atherosclerotic stenosis (ICAS) is the leading cause of ischemic stroke worldwide, especially in Asians. Current risk stratification depends mainly on the degree of anatomical narrowness. Growing evidence indicates a significant separation between lumen stenosis and lesion-specific hemodynamic impairment. This phenomenon highlights the limitations of anatomy-based assessment alone. In this context, researchers began to adopt a physiologically oriented assessment strategy. This strategy is seen as a promising approach to improve individualized ICAS diagnosis and guide treatment decision-making. The Murray's law-based quantitative flow ratio (μQFR) is a novel angiography-derived functional index that enables rapid, wire-free, and nonhyperemic assessment of translesional hemodynamic impairment using digital subtraction angiography (DSA). Originally translated from coronary functional imaging, the μQFR has recently been adapted for intracranial circulation evaluation and has shown strong agreement with invasive pressure-derived indices. Emerging studies further reveal that the μQFR is correlated with downstream cerebral hypoperfusion, ischemic injury on diffusion-weighted imaging (DWI), collateral circulation status, and long-term cerebrovascular outcomes. In this review, we summarize the technical principles underlying the μQFR; critically evaluate the current evidence supporting its validation and prognostic value in ICAS; and discuss its relationship with invasive physiology, cerebral perfusion imaging, collateral compensation, and computational flow modeling. We further propose that the μQFR should not be viewed merely as an alternative to anatomical stenosis grading but rather as part of integrated cerebrovascular physiology-guided precision treatment. Overall, the μQFR represents a promising step toward functional hemodynamic stratification in ICAS and may serve as a practical biomarker linking focal stenotic physiology to tissue-level ischemic vulnerability.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079310","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":"Loss of Newborn Neuron Function Promotes Aβ Accumulation in an Alzheimer's Disease Mouse Model.","authors":"Risako Tamura, Riki Kawabata, Chenxu Lei, Haowei Li, Daiki Hayashi, Masashide Seki, Yutaka Suzuki, Tatsuhiro Hisatsune","doi":"10.14336/AD.2026.0713","DOIUrl":"https://doi.org/10.14336/AD.2026.0713","url":null,"abstract":"<p><p>Whether the loss of adult hippocampal newborn neuron (NBN) function contributes to Alzheimer's disease (AD) amyloid pathology remains unclear. Adult NBNs regulate dentate gyrus (DG) circuitry, and their decline has been observed during AD progression. To investigate their role, we generated NBN-APP mice by crossing APPswe/PS1dE9 mice with NBN-TeTX mice. Importantly, in vivo microdialysis in the DG molecular layer prior to plaque formation demonstrated that the loss of NBN function for 4 weeks, starting at 3 months of age (early phase), elevated soluble Aβ levels (p < 0.001). At this early phase, we also observed increased Aβ deposition in the lateral entorhinal cortex (p < 0.001). Furthermore, to evaluate chronic cumulative pathology, we extended the loss of NBN function to 8 weeks starting at 5 months of age (late phase), which resulted in enhanced Aβ plaque deposition in the DG molecular layer, widespread glial activation and inflammatory responses throughout the hippocampus, alongside cognitive alterations. Together, these findings demonstrate that the loss of NBN function consistently induces Aβ accumulation across both early and late phases, and is associated with glial activation, highlighting its contribution to AD pathology.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079349","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":"Gut Microbial Function and Immune Aging: An Evidence-Graded Framework Linking Microbial Metabolites to Healthspan and Age-Related Disease.","authors":"Dong-Sheng He, Fei Liao, Hai-Lin Chen, Qi Zhang, Min-Xue Wei, Dong-Ming Guo","doi":"10.14336/AD.2026.0884","DOIUrl":"https://doi.org/10.14336/AD.2026.0884","url":null,"abstract":"<p><p>This narrative review examines how the metabolic output of the intestinal microbiota, rather than its taxonomic composition alone, relates to immune aging and to clinically meaningful geroscience outcomes. We organise the evidence around four questions: which microbial features are reproducibly associated with older age, which host pathways plausibly mediate their effects, how strong the evidence is for each mechanistic step, and what this implies for intervention. Three points structure the synthesis. First, the microbiota of older adults is not a single \"dysbiotic\" state: much of the reported difference between younger and older cohorts is attributable to frailty, multimorbidity, polypharmacy, residential setting, diet, physical activity, bowel transit and geography rather than to chronological age, and healthy-longevity phenotypes frequently diverge from the frail-elderly phenotype. Second, the dominant mediators-short-chain fatty acids (SCFAs), bile acids, tryptophan and polyphenol derivatives, polyamines and trimethylamine N-oxide (TMAO)-are context-dependent rather than uniformly protective or harmful, their host effects varying with local versus systemic concentration, receptor distribution, immune state, hepatic and renal clearance, and measurement platform. Third, most human data are cross-sectional; causal inference rests largely on rodent transfer experiments whose translational relevance to human healthspan is unresolved. We therefore label the evidence type supporting each major claim, compare cardiometabolic, neurodegenerative, hepatic, musculoskeletal and oncological domains, and appraise microbiota-targeted interventions with attention to strain, dose and formulation specificity, replication failure, endpoint heterogeneity, and safety in frail or immunocompromised older adults. We conclude by proposing an evidence-graded framework mapping defined microbial functions onto discrete features of immune aging and onto validated geroscience endpoints, and by identifying the designs required to move from association to intervention. The causal and clinical evidence base remains limited, and changes in microbiome composition should not be equated with gains in healthspan.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079404","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":"Lipid Networks in Osteoarthritis: Context-Dependent Drivers, Hallmarks of Aging, and Clinical Translation.","authors":"Nijiao Qin, Xiwei Fan, Yaxin Tan, Miao He, Indira Prasadam, Antonia Rujia Sun, Xiaoxin Wu, Ross Crawford, Yanping Wang, Qichen Long, Guozhi Xiao, Xinzhan Mao","doi":"10.14336/AD.2026.0752","DOIUrl":"https://doi.org/10.14336/AD.2026.0752","url":null,"abstract":"<p><p>Osteoarthritis (OA) is an age-related condition affecting the entire joint. Abnormal lipid regulation may act as a trigger for disease onset, or result from inflammation or mechanical injury; alternatively, it may merely manifest as a detectable signal without any direct mechanistic significance. Given that causality cannot be determined based on abundance alone, we propose a compartment-cell temporal framework: pathogenic effects may arise when lipid composition, flux or localisation exceed the tissue's adaptive capacity. Experimental evidence plays a causal role for certain cholesterol and fatty acid pathways, whilst human lipid research remains at the stage of exploring associations. Lipid stress, through dysregulation of organelles such as the endoplasmic reticulum and mitochondria, converges with common features of joint ageing-including cellular senescence, mitochondrial dysfunction, imbalances in autophagy and proteostasis, inflammation, and alterations in signalling-and may reconcile previous conflicting findings in areas such as apolipoprotein E and fatty acid oxidation. At the translational level, weight loss and metabolic management are feasible short-term strategies, and the prospects for lipid stratification are promising; however, testing has not yet met clinical diagnostic standards, and lipid nanoparticles have not yet been established as a therapeutic method. At present, they should be regarded as delivery vehicles; challenges such as joint preservation, deep tissue delivery, and safety still need to be overcome, and validation in human tissue is required. In summary, lipid research contributes to the classification and treatment of OA, but a strict distinction must be made between the maturity of causal evidence and mere correlation.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079397","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":"Lower Epigenetic Age Acceleration in Older Adults with Preserved Global Cognitive Performance.","authors":"Felipe Salech, Carlos Marquez, Paulina Correa-Burrows, Rodrigo Saguez, Daniela P Ponce, Carol San Martin, Christian Gonzalez-Billault, María Isabel Behrens, Cecilia Albala","doi":"10.14336/AD.2026.0311","DOIUrl":"https://doi.org/10.14336/AD.2026.0311","url":null,"abstract":"<p><p>Epigenetic clocks estimate biological age, yet evidence linking decelerated epigenetic aging to healthy cognitive performance in community-dwelling older adults is limited. Cross-sectional study within the population-based ALEXANDROS cohort (Santiago, Chile). Healthy Cognitive Agers (HCA) were participants aged ≥80 years who consistently maintained a MMSE score =30 across all cohort assessments. Controls were cognitively normal peers from the same cohort (MMSE 28.5 ± 2.9). Epigenetic age was estimated using the Horvath, GrimAge, and PhenoAge clocks. Epigenetic age acceleration (EAA) was calculated as residuals from regressing control-calibrated epigenetic age on chronological age. DNA methylation-derived telomere length (DNAmTL, kb) was also assessed. Eighty community-dwelling older adults were included (40 HCA and 40 controls). HCA exhibited substantially lower control-calibrated EAA than controls across all clocks, including Horvath (-13.55 ± 5.28 vs 0.00 ± 4.34 years; p < 0.001; Cohen's d = -2.80), PhenoAge (-9.72 ± 8.37 vs 0.00 ± 4.56 years; p < 0.001; Cohen's d = -1.44), and GrimAge (-3.16 ± 3.08 vs 0.00 ± 4.14 years; p < 0.001; Cohen's d = -0.87). HCA also exhibited substantially longer DNAm-derived telomere length (6.39 ± 0.27 vs 5.39 ± 0.21 kb; p < 0.001; Cohen's d = 4.15). Preserved cognitive performance in late life, based primarily on persistent MMSE performance, is associated with a decelerated biological aging profile in community-dwelling older adults. Although longitudinal studies are required to clarify temporality, these findings are consistent with the hypothesis that DNA methylation-derived epigenetic markers may help characterize healthy cognitive aging trajectories.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079391","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":"Repurposing MitoQ10 as a Therapeutic for Established Alzheimer's Disease Pathology.","authors":"Mohit Kumar, Sudipta Ray, Susmita Sil","doi":"10.14336/AD.2026.0946","DOIUrl":"https://doi.org/10.14336/AD.2026.0946","url":null,"abstract":"<p><p>Alzheimer's Disease (AD) is characterized by progressive amyloid accumulation, neuroinflammation, and neuronal loss, yet therapies targeting amyloid alone provide limited clinical benefit. Here, we evaluated whether pharmacological targeting of mitochondrial redox dysfunction using MitoQ10 (MitoQ), a mitochondria-targeted antioxidant, could modify AD pathology and behavioral deficits in symptomatic 5XFAD mice. Four-month-old 5XFAD mice received oral MitoQ for four months, and behavioral, histological, and biochemical analyses were performed at eight months of age. MitoQ administration significantly improved novelty-related exploration, attenuated hyper-locomotor activity, and broadly suppressed amyloid pathology, including pan-Aβ, oligomeric Aβ species, fibrillar plaques, and mature amyloid deposits across the cortex, hippocampus, thalamus, and amygdala. MitoQ also attenuated astrocyte and microglial reactivation, reduced pathological pTau622, and preserved neuronal integrity. Restoration of mitochondrial homeostasis was reflected by increased PDH-positive mitochondrial particle area, reduced oxidative DNA damage, and normalization of mitochondrial clearance via restoration of mitophagy-associated quality-control markers. Collectively, these findings show that MitoQ administration was associated with improvement in mitochondrial redox- and quality-control-related indices, accompanied by reductions in amyloid burden, gliosis, and neuronal injury in animals with established AD pathology. These findings support mitochondrial redox homeostasis as a therapeutically relevant target that may influence multiple pathological features of AD and provide a preclinical rationale for further evaluation of MitoQ as a potential therapeutic strategy for AD. Given that MitoQ has been evaluated in clinical studies in other conditions, the present preclinical findings support further investigation of its translational potential in AD; however, its safety and efficacy in individuals with AD require direct clinical evaluation.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079430","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":"Targeting isoD7 Neoepitope in Aβ for Alzheimer's Disease Immunotherapy.","authors":"Irina L Grigorova, Kseniya B Varshavskaya, Elena V Kuzubova, Lidiia A Koltunova, Elizaveta A Kolobova, Alexandra I Radchenko, Kirill D Chaprov, Viktor V Grishchenko, Irina Yu Petrushanko, Mikhail V Korokin, Vladimir A Mitkevich, Olga I Kechko, Alexander A Makarov","doi":"10.14336/AD.2026.0695","DOIUrl":"https://doi.org/10.14336/AD.2026.0695","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, neuroinflammation and cognitive impairment. During AD pathogenesis, Aβ undergoes several post-translational modifications, the most common of which is the isomerization of aspartic acid (isoD7-Aβ), a modification that contributes to the disease development. Passive immunization with isoD7-Aβ-specific antibodies reduced cognitive impairment and amyloid deposition in 5xFAD mice. However, therapeutic application of anti-Aβ antibodies has important limitations, emphasizing the need for alternative approaches. Here, we evaluated the efficacy of isoD7-Aβ_1-16-targeting immunization compared with Aβ_1-16-targeting immunization on AD pathogenesis in APP/PS1 mice. Both isoD7-Aβ_1-16 and Aβ_1-16, conjugated with ovalbumin, induced Aβ_1-16 - specific memory B cells and IgG in mice. However, only isoD7-Aβ_1-16 conjugate promoted B cell and IgG response to the neoepitopes on isoD7-Aβ_1-16. In the Y-maze test, only APP/PS1 mice immunized with isoD7-Aβ_1-16 at 3 months of age retained spatial memory as they aged, in contrast to APP/PS1 mice immunized with Aβ_1-16 at the same age. Immunization with both isoD7-Aβ_1-16 and Aβ_1-16 significantly reduced amyloid burden, lowered microglial and astrocyte activation. Furthermore, we assessed the effect of immunization in APP/PS1 mice at a later stage of AD pathogenesis, at 6 months of age. Even at the stage of advanced disease, immunization with isoD7-Aβ_1-16 strongly impeded the formation of amyloid plaques and reduced brain-wide microglial and astrocyte activation, in contrast to immunization with Aβ_1-16. Our results indicate the promise of targeting isoD7-Aβ for active AD immunotherapy, both for preventing the development of the pathology at its early stage and for ceasing the advanced AD pathogenesis.</p>","PeriodicalId":7434,"journal":{"name":"Aging and Disease","volume":" ","pages":""},"PeriodicalIF":9.6,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149079347","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}