Alzheimer's Research & Therapy最新文献

{"title":"Design and application of a Tau seed amplification assay for screening inhibitors of Tau seeding.","authors":"Damian Gorski, Haley Evans, Tyler Allison, Carla Barria, Danielle Harrison, Victor Banerjee, Nicolas Mendez, Mohammad Shahnawaz, Sanne Kaalund, Jonas Folke, Susana Aznar, Paul Schultz, Fei Wang, Claudio Soto","doi":"10.1186/s13195-025-01855-y","DOIUrl":"10.1186/s13195-025-01855-y","url":null,"abstract":"<p><strong>Background: </strong>Tau protein aggregates are a key pathological hallmark of Alzheimer's disease (AD) and are closely associated with cognitive decline and neurodegeneration. It is proposed that tau aggregates faithfully propagate throughout the brain by self-templating their disease-associated conformation onto natively-folded tau monomers, thereby inducing their aggregation and incorporation into growing fibrils. As such, the inhibition or modulation of tau seeding and aggregation represents a viable therapeutic strategy for AD and other tauopathies.</p><p><strong>Methods: </strong>We have recently developed seed amplification assays (SAA) for the detection and amplification of small quantities of misfolded protein aggregates in various neurodegenerative diseases. In this article, we adapted the SAA technology to amplify the process of tau aggregation and seeding in AD brain samples. Using the Tau-SAA we screened two chemical libraries: one comprising over 20 suspected aggregation inhibitors and the other comprising over 200 FDA-approved, blood-brain barrier-permeable compounds from a commercial chemical library. We also performed secondary in vitro assays to confirm the activity of selected hits as well as determining the IC50 of the most active compounds.</p><p><strong>Results: </strong>Our Tau-SAA detects the presence of tau seeds even after a 100-million-fold dilution of the initial inoculum. Examination of 26 postmortem brain samples from AD and control cases confirmed that our assay is specific for AD brain tau seeds. Screening of 220 compounds showed that approximately 57% of suspected aggregation inhibitors and ~ 3% of CNS-penetrant compounds inhibited over 75% of AD brain-templated tau aggregation.</p><p><strong>Conclusions: </strong>In conclusion, our data suggests that Tau-SAA readily detects the presence of tau seeds in AD brains but not in controls, and that by amplifying AD brain tau seeds, the assay may serve as a valuable primary drug screening platform.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"214"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482674/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of APOE4 on Alzheimer's plasma biomarkers among Mexican Americans in the HABS-HD cohort.","authors":"J A Contreras, N E Ortega, K Espejo, V Aslanyan, J Pa","doi":"10.1186/s13195-025-01845-0","DOIUrl":"10.1186/s13195-025-01845-0","url":null,"abstract":"<p><strong>Background and objectives: </strong>The relationship between APOE4 status and plasma biomarkers previously shown to be related to Alzheimer's risk have not been carefully examined among Mexican Americans. This research is needed to elucidate disparities within the Alzheimer's field by evaluating key genetic factors in an underrepresented population. The present study deepens our understanding of the interaction between biological and genetic factors for these populations with greater incidence of Alzheimer's disease (AD) and helps address whether APOE4 confers similar risk of AD in Mexican Americans as previously reported in Non-Hispanic Whites.</p><p><strong>Methods: </strong>Cross-sectional data consisting of 792 Mexican American and 785 Non-Hispanic White participants from the Health & Aging Brain Study - Health Disparities (HABS-HD) with available plasma biomarkers and APOE4 genotype profiles were included in the present study. Linear regression models were used to test our hypotheses. APOE4-Race/ethnicity interaction term tested whether the biomarker levels differed between ethnic groups. Analyses were adjusted for age, gender, and education. Further analyses explored whether biomarker levels differed by APOE4 carrier status within racial/ethnic groups.</p><p><strong>Results: </strong>Among 1577 participants (59.5% women; mean age 66.4 ± 8.74 years), significant differences were observed across race/ethnic and APOE4 groups. Mexican Americans were younger (p < 0.001), had a higher proportion of women (p = 0.001), fewer years of education (p < 0.001), and lower MMSE scores (p < 0.001). Biomarker differences between Mexican Americans and Non-Hispanic Whites included variations in Aβ42/Aβ40 (p = 0.03) and p-tau181 (p < 0.001), but not in total tau, TNF-α, or NfL levels (all p > 0.12). Race/ethnicity-APOE4 interactions were significant for Aβ42/Αβ40, p-tau181, and total tau (all p < 0.05) but not for NfL or TNF-α. APOE4 associations with Aβ42/Aβ40 and p-tau181 were significant in NH White participants (all p < 0.001) but not among Mexican Americans.</p><p><strong>Conclusion: </strong>These findings will significantly contribute to understanding potential differences in the role of APOE4 and AD plasma biomarkers among Mexican Americans. This research has the potential to enhance preventive care and early diagnosis for populations with a higher incidence of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"208"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482669/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197828","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut microbiota characterization in ageing, mild cognitive impairment, and Alzheimer's disease in the context of mediterranean lifestyle in a Spanish population.","authors":"Cristian Cabrera, Nerea Carrión, David Mateo, Paloma Vicens, Andrés Pinzón, Luis Heredia, Eva Forcadell-Ferreres, Maria Pino, Beatriz Yerga, Josep Zaragoza, Mikel Vicente-Pascual, Alfons Moral, Trini Arco, Margarita Arjó, Esther Martínez, Sònia Galvez, Maria José Lozano, Margarita Torrente","doi":"10.1186/s13195-025-01862-z","DOIUrl":"10.1186/s13195-025-01862-z","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"211"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482474/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197592","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of adherence to a healthy sleep pattern with the dementia risk in the UK biobank.","authors":"Tao Wei, Jie Chang, Yiwei Zhao, Aonan Li, Wei Sun, Xiaoduo Liu, Hongjia Liu, Yi Xing, Zhibin Wang, Yi Tang","doi":"10.1186/s13195-025-01864-x","DOIUrl":"10.1186/s13195-025-01864-x","url":null,"abstract":"<p><strong>Background: </strong>Existing evidence highlights associations between sleep behaviors and dementia risk; however, the impact of adhering to a healthy sleep pattern on dementia risk remains unclear.</p><p><strong>Methods: </strong>Of 406,364 UK Biobank participants aged 40-64, we excluded those who had withdrawn, had incomplete sleep data, or had dementia at baseline, yielding a final sample of 333,014. Participants were enrolled between 2006 and 2010, with follow-up extending from recruitment to dementia diagnosis, death, loss to follow-up, or the censoring date (December 2022), whichever came first. Incident dementia was identified using hospital inpatient and death records, along with primary care data, with cases diagnosed at a mean age of 70.0 years (standard deviation [SD]: 5.6). Sleep-related questionnaire items from the UK Biobank were summarized into five sleep behaviors: sleeping 7-8 h daily, early chronotype, absence of frequent insomnia, no snoring, and no frequent daytime sleepiness. Each behavior meeting the healthy criterion was assigned one point, resulting in a total range from 0 to 5, with higher scores indicating better adherence to a healthy sleep pattern. Cox proportional hazards models were used to assess the association between healthy sleep patterns and dementia risk, adjusting for demographics, lifestyle factors, and medical history. A subset of 33,401 participants underwent brain magnetic resonance imaging (MRI) scans during the 9.4-year median period between sleep assessment and imaging. The imaging analysis included total brain volume, gray matter volume, white matter volume, hippocampal volume, and white matter hyperintensities (WMH).</p><p><strong>Results: </strong>During a median follow-up of 13.8 years, 3,035 incident dementia cases were recorded, including 1,304 Alzheimer's disease (AD) cases and 597 vascular dementia (VD) cases. A higher adherence to a healthy sleep pattern was associated with a lower dementia risk. Each 1-point increase in the healthy sleep score corresponded to a 7% reduction in dementia risk (Hazard Ratio [HR] = 0.93, 95% Confidence Interval [CI]: 0.89-0.96). Compared to participants with a score of 0-1, those with a score of 5 had a significantly lower risk of dementia (HR = 0.75, 95% CI: 0.61-0.92). Benefits were more pronounced in adults aged 40-55 years than those aged 56-64 years (p for interaction < 0.001). Adherence to a healthy sleep pattern was associated with increased grey matter volume and decreased WMH volume (all p < 0.05). Mediation analysis indicates that preserving grey and white matter integrity partially mediated the dementia-risk-lowering benefit (p < 0.05).</p><p><strong>Conclusions: </strong>Adherence to a healthy sleep pattern is associated with both a reduced risk of dementia and greater white matter integrity, underscoring the role of improving overall sleep behaviors to support brain structure and lower dementia risk.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"213"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12481806/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197529","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"petBrain: a new pipeline for amyloid, Tau tangles and neurodegeneration quantification using PET and MRI.","authors":"Pierrick Coupé, Boris Mansencal, Floréal Morandat, Sergio Morell-Ortega, Nicolas Villain, Jose V Manjón, Vincent Planche","doi":"10.1186/s13195-025-01839-y","DOIUrl":"10.1186/s13195-025-01839-y","url":null,"abstract":"<p><strong>Introduction: </strong>Quantification of amyloid plaques (A), neurofibrillary tangles (T₂), and neurodegeneration (N) using PET and MRI is critical for Alzheimer's disease (AD) diagnosis and prognosis. Existing pipelines face limitations regarding processing time, tracer variability handling, and multimodal integration.</p><p><strong>Methods: </strong>We developed petBrain, a novel end-to-end processing pipeline for amyloid-PET, tau-PET, and structural MRI. It leverages deep learning-based segmentation, standardized biomarker quantification (Centiloid, CenTauR, HAVAs), and simultaneous estimation of A, T₂, and N biomarkers. It is implemented in a web-based format, requiring no local computational infrastructure and software usage knowledge.</p><p><strong>Results: </strong>petBrain provides reliable, rapid quantification with results comparable to existing pipelines for A and T₂, showing strong concordance with data processed in ADNI databases. The staging and quantification of A/T₂/N by petBrain demonstrated good agreements with CSF/plasma biomarkers, clinical status and cognitive performance.</p><p><strong>Discussion: </strong>petBrain represents a powerful open platform for standardized AD biomarker analysis, facilitating clinical research applications.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"209"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482854/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197820","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disentangling phonology from phonological short-term memory in Alzheimer's disease phenotypes.","authors":"Shalom K Henderson, Ajay Halai, Kamen A Tsvetanov, Thomas E Cope, Karalyn E Patterson, James B Rowe, Matthew A Lambon Ralph","doi":"10.1186/s13195-025-01856-x","DOIUrl":"10.1186/s13195-025-01856-x","url":null,"abstract":"<p><strong>Background: </strong>Impaired phonological short-term memory is a core feature of the logopenic variant of primary progressive aphasia (lvPPA), but it is not clear whether a core phonological processing deficit is also present.</p><p><strong>Methods: </strong>We asked three questions: (i) beyond short-term memory impairment, do lvPPA patients have an impairment within phonology itself?; (ii) is their performance in working memory and naming reflective of this phonological impairment?; and (iii) is their repetition performance related to structural and functional differences in key language-dominant regions? We compared non-word and word repetition and short-term memory performance in patients with typical Alzheimer's disease (tAD), lvPPA per consensus criteria, and others who previously satisfied definitions of lvPPA but had progressed with multi-domain cognitive impairments (lvPPA+).</p><p><strong>Results: </strong>Bayesian analyses revealed no group differences in phonological tasks of word and non-word repetition. We found very strong evidence for an effect of self-reported hearing loss on word and non-word repetition, but not multi-syllabic word/phrase repetition. A comparison of phonological versus working memory and naming tasks produced either no evidence or evidence for no correlation. Beyond the expected grey matter reductions in patients relative to controls, there was anecdotal evidence for an association between non-word repetition and functional connectivity between dorsal premotor and posterior superior temporal gyrus regions in patients.</p><p><strong>Conclusions: </strong>Our results indicated that, in the absence of self-reported hearing loss, patients did not exhibit impairments in tasks tapping \"pure\" phonological processing. Our results suggest that instead of having a core phonological impairment, lvPPA patients have a working memory/buffering impairment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"206"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482198/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cerebral amyloid-β, glucose metabolism and hippocampal volume in major depression with and without suspected non-Alzheimer pathophysiology (SNAP).","authors":"Min-Jung Wu, Ing-Tsung Hsiao, Kun-Ju Lin, Yi-Ming Wu, Kuan-Yi Wu","doi":"10.1186/s13195-025-01858-9","DOIUrl":"10.1186/s13195-025-01858-9","url":null,"abstract":"<p><strong>Background: </strong>Major depressive disorder (MDD) can encompass suspected non-Alzheimer's disease pathophysiology (SNAP), characterized by negative cerebral Amyloid-β (Aβ) and positive neurodegeneration (ND) biomarkers. Relationships among cerebral Aβ deposition, glucose metabolism, and hippocampal volume in SNAP and non-SNAP MDD groups remain unclear.</p><p><strong>Methods: </strong>We conducted cross-sectional analyses of 136 MDD patients (enrolment age ≥ 50 years), classified into SNAP (n = 71) and non-SNAP (n = 65) groups. Dual-phase ¹⁸F-florbetapir (AV45) PET/MR scans provided early-phase (as a proxy for glucose metabolism) and late-phase (reflecting Aβ deposition) images. Bilateral adjusted hippocampal volume (HVa) was measured using MRI. Partial correlations and multiple regression analyses examined the associations among Aβ deposition, metabolism, HVa, and depression-related variables.</p><p><strong>Results: </strong>In the non-SNAP MDD, greater Aβ deposition was associated with reduced glucose metabolism and smaller HVa, while HVa positively correlated with metabolism. Glucose metabolism partially mediated the relationship between Aβ deposition and both hippocampal atrophy and cognition function. In the SNAP MDD group, lower Aβ deposition was associated with lower glucose metabolism. While more lifetime depressive episodes were related to smaller HVa, depression severity showed a positive correlation with HVa. Additional subgroup analyses stratified by age and Aβ/ND status were also conducted.</p><p><strong>Conclusions: </strong>These findings suggest distinct biological patterns in SNAP and non-SNAP MDD. Age- and biomarker (Aβ/ND)-stratified analyses yielded consistent Aβ-metabolism-atrophy profiles; however, the biomarker-stratified results should be interpreted with caution due to limited sample sizes. Notably, the non-SNAP group comprises biologically heterogeneous subgroups, which may obscure important distinctions and limit the interpretability of pooled findings. These results underscore the need for subgroup-specific approaches to better elucidate the pathophysiology of MDD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"207"},"PeriodicalIF":7.6,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482320/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145197626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Cerebral small vessel disease in memory center patients with dementia with lewy bodies and Alzheimer's disease.","authors":"Giulia Bommarito, Alessandra Griffa, Patrik Michel, Caroline Hall, Chiabotti Paolo Salvioni, Silvia Pistocchi, Yasser Alemán-Gómez, Daniel Damian, Mario Jreige, John O Prior, Vincent Dunet, Olivier Rouaud, Patric Hagmann, Gilles Allali","doi":"10.1186/s13195-025-01853-0","DOIUrl":"10.1186/s13195-025-01853-0","url":null,"abstract":"","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"204"},"PeriodicalIF":7.6,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12482051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145190754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ap1s1 reduction in the aging brain heightens neuronal vulnerability to amyloid-β and oxidative stress in Alzheimer's pathogenesis.","authors":"Xuehan Yang, Xinru Geng, Zhuoyan Xu, Yang Xu, Hao Han, Qiang Zhang, Honglian Jin, Yuxin Wang, Bin Sun, Ming Zhang, Siwei Zhang, Li Chen","doi":"10.1186/s13195-025-01861-0","DOIUrl":"10.1186/s13195-025-01861-0","url":null,"abstract":"<p><p>Alzheimer's Disease (AD), a progressive neurodegenerative disorder, is characterized by cognitive decline and memory impairment. Brain aging is indisputably the most significant risk factor for AD. Given that aging is a fundamental driving force behind the onset of AD, identifying the aging - regulated genes that contribute to AD development is of utmost importance. Such genes might hold the key to preventing AD or delaying the transition from normal aging to the disease state. In the present study, a comprehensive bioinformatic analysis was conducted on brain transcriptomic datasets obtained from both aging individuals and those with Alzheimer's disease. Among the shared differentially expressed genes, eight genes were found to be downregulated in both aging and AD datasets. Notably, reduced expression of adaptor protein complex 1 sigma 1 subunit (Ap1s1) was validated across multiple mouse models with varying degree of dementia, including aged mice, senescence-accelerated SAMP8 mice, 5xFAD amyloidosis mice, as well as cellular models, including senescent Neuro-2a (N2a) cells, and Aβ-treated or expressing N2a neurons. Functional studies revealed that Ap1s1 knockdown induced cellular senescence without directly impairing viability. However, Ap1s1 silencing exacerbated neuronal vulnerability to oxidative stress (H₂O₂) and Aβ toxicity, manifesting as Golgi-dispersion and reduced survival. Proteomic profiling following Ap1s1 depletion implicated dysregulation of rRNA modifications in the nucleus and cytosol, Golgi-associated vesicle biogenesis. These findings position Ap1s1 as a critical aging-related gene at the nexus of brain aging and AD pathogenesis, whose decline may predispose neurons to Alzheimer's-related insults. As such, Ap1s1 may represent a potential therapeutic target for mitigating aging-related cognitive decline and delaying the onset of AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"203"},"PeriodicalIF":7.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12434918/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145068878","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Intestinal epithelial Dicer1 regulates gut microbiome and Alzheimer's pathology in App-knock-in mice.","authors":"Wenlin Hao, Qinghua Luo, Ilona Magdalena Szabo, Gilles Gasparoni, Sascha Tierling, Wenqiang Quan, Hsin-Fang Chang, Gang Wu, Julia Schulze-Hentrich, Yang Liu","doi":"10.1186/s13195-025-01849-w","DOIUrl":"10.1186/s13195-025-01849-w","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) patients and animal models exhibit an altered gut microbiome that is associated with pathological changes in the brain. Intestinal miRNA enters bacteria and regulates bacterial metabolism and proliferation. This study aimed to investigate whether the manipulation of miRNA could alter the gut microbiome and AD pathologies.</p><p><strong>Methods: </strong>The enzyme producing miRNA was deleted in App-knock-in mice by conditional knock-out of Dicer1 gene in intestinal epithelial cells. 16S rDNA sequencing/microbiome analysis was performed in both the gut and brain. Barrier integrity, inflammatory activation and T cell differentiation in the gut were analyzed by measuring transcripts of relevant marker genes. AD-associated pathologies in the brain, including amyloid pathology, neuroinflammation and synaptic impairment, were investigated by immunohistochemistry, ELISA, quantitative Western blot, mRNA-sequencing/transcriptomic analysis, real-time PCR and behavior tests. To investigate the mechanisms controlling Aβ level, β- and γ-secretase activities, protein levels of LRP1 and ABCB1 in isolated blood microvessels, CD68 immunofluorescence around Aβ deposits and transcription of neprilysin and IDE genes in the brain were analyzed.</p><p><strong>Results: </strong>Deletion of Dicer1 in intestinal epithelial cells of App-knock-in mice reduced the absolute number and altered the composition of bacteria in both the gut and brain, and inhibited inflammatory activation in the gut, but had no effect on the differentiation of CD4-positive T lymphocytes. It lowered Aβ load in the brain, possibly by inhibiting β-secretase activity, and increasing the expression of LRP1 and ABCB1 at the blood-brain barrier. Deletion of intestinal Dicer1 increased Il-10 transcription and decreased Ccl-2 transcription in the brain tissue. Transcriptomic analysis further showed that Dicer1 deletion reduced transcription of Ndufa2 and Ndufa5 genes. In behavior tests, deletion of intestinal Dicer1 induced anxiety symptoms without improving cognitive function in AD mice.</p><p><strong>Conclusions: </strong>Deletion of Dicer1 in intestinal epithelial cells modulates the microbiome in both the gut and brain, and AD pathologies in the brain of App-knock-in mice. Future studies should focus on the identification of AD-specific miRNAs in the gut that can be therapeutically utilized to alter the gut microbiome and prevent AD progression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"202"},"PeriodicalIF":7.6,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12418706/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145028771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}