Alzheimer's Research & Therapy最新文献

{"title":"Linking oxysterols and different stages of mild cognitive impairment: insights from gut metabolites and N6-methyladenosine.","authors":"Wenjing Feng, Mengwei Ju, Tao Wang, Shanshan Cui, Kexin Yang, Zhiting Guo, Miao Liu, Jiaxuan Tao, Huiyan Yu, Rong Xiao","doi":"10.1186/s13195-025-01743-5","DOIUrl":"10.1186/s13195-025-01743-5","url":null,"abstract":"<p><strong>Background: </strong>Oxysterols, gut metabolites, and N6-methyladenosine (m6A) are extensively implicated in the pathogenesis of cognitive dysfunction, while their alterations in different stages of mild cognitive impairment (MCI) have not been elucidated. Therefore, this study was conducted to explore the associations of oxysterols, gut metabolites, and m6A methylation profiles in early MCI (EMCI) and late MCI (LMCI) individuals.</p><p><strong>Methods: </strong>Liquid chromatography-mass spectrometry, untargeted metabolomic analysis, and m6A mRNA Epitranscriptomic Microarray were used to detect the characteristics of serum oxysterols (n = 35/group), fecal gut metabolites (n = 30/group), and m6A in whole blood (n = 4/group) respectively. The concentration of serum β-amyloid (Aβ) was detected with ELISA (n = 25/group). The gene expression of amyloid precursor protein (APP) and its key enzyme β-secretase (BACE1) in whole blood were measured by quantitative real-time PCR (n = 25/group).</p><p><strong>Results: </strong>EMCIs and LMCIs, especially LMCIs, exhibited poorer performance in almost all global and multidimensional cognitive tests. Serum 27-hydroxycholesterol (27-OHC) and 24S-hydroxycholesterol (24S-OHC) were elevated in EMCI and LMCI groups. Changes in gut metabolites occurred mainly in the EMCI group, in which several gut metabolites, including Procyanidin dimer B7 and Phorbol myristate, were significantly decreased. The m6A methylation landscape of EMCIs and LMCIs obviously differed from Controls. Hypomethylated mRNAs accounted for the majority and were mainly accompanied by downregulated mRNAs, which was consistent with the downregulated expression of the m6A writer methyltransferase-like 4 (METTL4). 27-OHC and 24S-OHC combined with various gut metabolites significantly distinguished between MCI subgroups from healthy controls (EMCI/Control: AUC = 0.877; LMCI/Control: AUC = 0.952). Heatmap revealed the correlation between Phorbol myristate and differentially m6A-methylated mRNAs. Differentially expressed gut metabolites and methylated mRNAs were commonly enriched in 34 KEGG metabolic pathways, including cholesterol metabolism and neurodegenerative disease-related pathways.</p><p><strong>Conclusions: </strong>Our study explored the altered oxysterols, gut metabolites, and m6A methylation and their associations in different stages of MCI. The potential function of aberrant gut metabolites in oxysterols and m6A methylation driving MCI progression warrants further mechanistic investigation.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"102"},"PeriodicalIF":7.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070570/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961890","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":"Development and validation of a novel predictive model for dementia risk in middle-aged and elderly depression individuals: a large and longitudinal machine learning cohort study.","authors":"Xuan Xiao, Yihui Li, Qiaoboyang Wu, Xinting Liu, Xu Cao, Maiping Li, Jianjing Liu, Lianggeng Gong, Xi-Jian Dai","doi":"10.1186/s13195-025-01750-6","DOIUrl":"10.1186/s13195-025-01750-6","url":null,"abstract":"<p><strong>Background: </strong>Depression serves as a prodromal symptom of dementia, and individuals with depression exhibit a significantly higher risk of developing dementia. The aim of this study is to develop and validate a novel dementia risk prediction tool among middle-aged and elderly individuals with depression based on machine learning algorithms.</p><p><strong>Methods: </strong>This study included 31,587 middle-aged and elderly individuals with depression who did not have a diagnosis of dementia at baseline from a large UK population-based prospective cohort. A rigorous variable selection strategy was employed to identify risk and protective factors of dementia from an initial pool of 190 candidate variables, ultimately retaining 27 variables. Eight distinct data analysis strategies were utilized to develop and validate the dementia risk prediction model. The DeLong's test was applied to compare the statistical differences between different models.</p><p><strong>Results: </strong>During a median follow-up of 7.98 years, 896 incident dementia cases were identified among study participants. In model development employing an 8:2 data split (fivefold cross-validation for training), the Adaboost classifier achieved the optimal performance (AUC 0.861 ± 0.003), followed by XGBoost (AUC 0.839 ± 0.005) and CatBoost (AUC 0.828 ± 0.007) classifiers. To facilitate community generalization and clinical applicability, we develop a simplified model through a forward feature subset selection algorithm, retaining 12 variables. The simplified model maintained robust performance, with AdaBoost achieving the highest discriminative ability (AUC 0.859 ± 0.002), followed by XGBoost (AUC 0.835 ± 0.001) and CatBoost (AUC 0.821 ± 0.005). The DeLong's test revealed no statistically significant difference in AUC values between models using 12 and 27 variables (p = 0.278). For practical implementation, we deployed the optimal model to a web application for visualization and dementia risk assessment, named DRP-Depression.</p><p><strong>Conclusions: </strong>We developed a practical and easy-to-promote risk prediction model based on machine learning algorithms, and deployed it to a web application to provide a new and convenient tool for dementia risk prediction in the middle-aged and elderly individuals with depression.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"103"},"PeriodicalIF":7.9,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12070709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143963947","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":"Soluble SorLA in CSF, a novel biomarker to explore disrupted trafficking of SorLA protein in Alzheimer disease.","authors":"Romain Castelot, Aline Zarea, David Wallon, Anne Rovelet-Lecrux, Catherine Schramm, Muriel Quillard-Muraine, Anne Beaume, Frédéric Blanc, Olivier Bousiges, Julien Dumurgier, Maïté Formaglio, Gwenael Leguyader, Sylvain Lehmann, Cecilia Marelli, Matthieu Martinet, Leonor Nogueira, Jérémie Pariente, Isabelle Quadrio, Adeline Rollin-Sillaire, Susanna Schraen, Gaël Nicolas, Magalie Lecourtois","doi":"10.1186/s13195-025-01748-0","DOIUrl":"https://doi.org/10.1186/s13195-025-01748-0","url":null,"abstract":"<p><strong>Background: </strong>The SorLA protein, encoded by the Sortilin-related receptor 1 (SORL1) gene, is a major player in Alzheimer's disease (AD) pathophysiology. Functional studies demonstrated that SorLA deficiency results in increased production of Aβ peptide, and thus a higher risk of AD. SorLA can be subject to proteolytic shedding at the cell surface, leading to the release of the soluble ectodomain of the protein (sSorLA) in the extracellular space. Recently, we demonstrated that a large proportion (~25%) of rare SORL1 missense variants found in AD patients alter SorLA trafficking along the constitutive secretory pathway, resulting in reduced delivery of SorLA to the plasma membrane and thus a loss of function. Here, we aimed to determine if CSF levels of sSORLA in AD patients carrying SORL1 rare variants that impact or not the trafficking of the protein can be used as a novel biomarker to explore disrupted trafficking of SorLA protein in AD.</p><p><strong>Methods: </strong>A total of 151 participants were categorized into 5 study groups: controls without any neurodegenerative disease (n=30), patients suffering from Fronto-Temporal Lobar Degeneration (FTLD, n=34), AD patients not carrying a SORL1 rare variant (AD ^{SORL1 WT}, n=40), AD patients carrying SORL1 trafficking-defective variants or a protein-truncating variant (PTV) (AD^{SORL1 TD}, n=16), and AD patients carrying a SORL1 variant with no evidence of trafficking defect (AD ^{SORL1 nTD,} n=31). Thirty-three unique rare variants of SORL1 were included for this study: 3 PTVs, 13 missense variants that impact SorLA protein trafficking in in vitro cellular assays, and 17 variants with no detectable effect on SorLA protein trafficking. We measured amounts of cleaved sSorLA by western blot in CSF samples.</p><p><strong>Results: </strong>We found significantly decreased levels of sSorLA in AD^{SORL1 TD}, compared to all other groups. According to ROC curve analysis, levels of sSorLA showed good performances to distinguish AD^{SORL1 TD} patients from other AD patients (AUC=0.89 [95%CI: 0.81-0.97]).</p><p><strong>Conclusions: </strong>Our results suggest that differential levels of sSorLA in CSF could be used as a novel marker to explore disrupted trafficking of SorLA protein in Alzheimer disease. This could help solve some proportion of variants of uncertain significance in SORL1.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"100"},"PeriodicalIF":7.9,"publicationDate":"2025-05-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12057124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959898","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":"\"It seems enormously valuable to me.\" Perspectives of Dutch (potential) carriers of genetic FTD on onset-predictive biomarker testing.","authors":"Charlotte H Graafland, Harro Seelaar, Jessica L Panman, Lize C Jiskoot, Tjitske Kleefstra, Jackie M Poos, Edo Richard, Maartje H N Schermer, John C van Swieten, Laura Donker Kaat, Eline M Bunnik","doi":"10.1186/s13195-025-01749-z","DOIUrl":"https://doi.org/10.1186/s13195-025-01749-z","url":null,"abstract":"<p><strong>Background: </strong>Onset-predictive biomarker tests (OPBT) in genetic frontotemporal dementia (FTD) may be used to recruit mutation carriers into preventive clinical trials before symptoms manifest. This would require disclosure of OPBT results to potential participants. This study investigates the perspectives of Dutch presymptomatic mutation carriers and individuals at 50% risk of genetic FTD on disclosure of OPBT results. It focuses on their willingness to receive OPBT results, what impacts they foresee from disclosure, and their preferences for the process of disclosure.</p><p><strong>Methods: </strong>Semi-structured interviews were conducted with presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD (n = 25), who had received genetic counselling or participate in a longitudinal cohort study. The interview transcripts were analysed using thematic inductive analysis.</p><p><strong>Results: </strong>Main themes were: willingness to undergo biomarker testing, foreseen impact of test results, preferences regarding biomarker test features, and understanding of biomarker testing. Most participants would be willing to receive OPBT results in the context of clinical trial recruitment. Participants would also be willing to receive OPBT results without access to clinical trial participation, as they perceived utility from these results. They would use positive OPBT results to prepare for the future, e.g. by planning for care, drawing up advance care directives, retiring early, and spending final healthy years well. At the same time, they thought positive OPBT results might also have negative psychological impacts on self-image or social dynamics with others. Implications of positive OPBT results for self-image as healthy or ill differed between participants. Negative OPBT results would provide relief and not lead to life changes.</p><p><strong>Conclusions: </strong>Dutch presymptomatic mutation carriers and individuals at 50% risk of developing genetic FTD tend to be willing to receive OPBT results. The results would allow for participation in a clinical trial and preparation for onset through personal life planning. At the same time, disclosure of OPBT results might have negative psychological consequences. This study provides valuable input for developing ethical guidance and an appropriate counselling process to ensure responsible disclosure of OPBT results with clinical trial recruitment.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"99"},"PeriodicalIF":7.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054206/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143957062","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":"Assessment of the relationship between synaptic density and metabotropic glutamate receptors in early Alzheimer's disease: a multi-tracer PET study.","authors":"Elaheh Salardini, Ryan S O'Dell, Em Tchorz, Nabeel B Nabulsi, Yiyun Huang, Richard E Carson, Christopher H van Dyck, Adam P Mecca","doi":"10.1186/s13195-025-01739-1","DOIUrl":"https://doi.org/10.1186/s13195-025-01739-1","url":null,"abstract":"<p><strong>Background: </strong>The pathological effects of amyloid β oligomers (Aβo) may be mediated through the metabotropic glutamate receptor subtype 5 (mGluR5), leading to synaptic loss in Alzheimer's disease (AD). Positron emission tomography (PET) studies of mGluR5 using [¹⁸F]FPEB indicate a reduction of receptor binding that is focused in the medial temporal lobe in AD. Synaptic loss due to AD measured through synaptic vesicle glycoprotein 2A (SV2A) quantification with [¹¹C]UCB-J PET is also focused in the medial temporal lobe, but with clear widespread reductions is commonly AD-affected neocortical regions. In this study, we used [¹⁸F]FPEB and [¹¹C]UCB-J PET to investigate the relationship between mGluR5 and synaptic density in early AD.</p><p><strong>Methods: </strong>Fifteen amyloid positive participants with early AD and 12 amyloid negative, cognitively normal (CN) participants underwent PET scans with both [¹⁸F]FPEB to measure mGluR5 and [¹¹C]UCB-J to measure synaptic density. Parametric distribution volume ratio (DVR) images using equilibrium methods were generated from dynamic images. For [¹⁸F]FPEB PET, DVR was calculated using equilibrium methods and a cerebellum reference region. For [¹¹C]UCB-J PET, DVR was calculated with a simplified reference tissue model - 2 and a whole cerebellum reference region.</p><p><strong>Results: </strong>A strong positive correlation between mGluR5 and synaptic density was present in the hippocampus for participants with AD (r = 0.81, p < 0.001) and in the CN group (r = 0.74, p = 0.005). In the entorhinal cortex, there was a strong positive correlation between mGluR5 and synaptic density in the AD group (r = 0.85, p < 0.001), but a weaker non-significant correlation in the CN group (r = 0.36, p = 0.245). Exploratory analyses indicated more widespread significant positive correlations between synaptic density and mGluR5 within regions, as well as significant positive correlations between synaptic density in the temporal lobe and mGluR5 across a broader set of regions commonly affected by AD.</p><p><strong>Conclusions: </strong>Our findings suggest that mGluR5 reduction in AD is closely linked to synaptic loss. Longitudinal studies are needed to clarify causality, deepen understanding of AD pathogenesis, and aid in developing novel biomarkers and treatments.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"98"},"PeriodicalIF":7.9,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12054321/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955163","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":"Prognostic value of plasma biomarkers for informing clinical trial design in mild-to-moderate Alzheimer's disease.","authors":"Yuqi Qiu, Diane M Jacobs, Karen Messer, David P Salmon, Cheryl L Wellington, Sophie Stukas, Carolyn Revta, James B Brewer, Gabriel C Léger, Brianna Askew, Lia Donahue, Stephen Kaplita, Vladimir Coric, Irfan A Qureshi, Howard H Feldman","doi":"10.1186/s13195-025-01745-3","DOIUrl":"https://doi.org/10.1186/s13195-025-01745-3","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence supports the diagnostic and prognostic utility of plasma biomarkers in Alzheimer's disease (AD), particularly in early disease stages. We sought to extend these findings by evaluating the prognostic value of plasma biomarkers in a clinical trial of mild-to-moderate AD.</p><p><strong>Methods: </strong>Post-hoc analyses investigated whether baseline concentrations of plasma biomarkers (Aβ42/Aβ40, T-tau, P-tau181, NfL, and GFAP) predicted change in ADAS-Cog11, CDR-SB, and volumetric MRI among participants in T2 Protect AD, a negative 48-week, phase-2, placebo-controlled trial of troriluzole in mild-to-moderate AD. All trial participants met diagnostic criteria for probable AD. Baseline concentrations of, and 48-week changes in, plasma biomarkers were assessed for association with 48-week change in outcomes using linear regression. Combinations of baseline biomarkers that best predicted change on the ADAS-Cog11 and CDR-SB were identified using least absolute shrinkage and selection operator (LASSO) regression. Biomarker-informed sample size calculations were modeled.</p><p><strong>Results: </strong>Of 350 trial participants, 319 had all requisite biomarker and clinical outcome data for inclusion in these analyses (mean age 71.5, SD = 8.03; 58.6% female). Higher plasma NfL at baseline predicted worsening scores on the ADAS-Cog11 (effect size (ES) = 1.42, 95%CI = [0.43, 2.41], p = 0.026) and CDR-SB (ES = 0.42, 95%CI = [0.10, 0.73], p = 0.048). LASSO regression revealed that worsening on the ADAS-Cog11 was best predicted by the combination of baseline plasma NfL, T-tau, and Aβ42/40 ratio, whereas baseline NfL alone best predicted worsening on CDR-SB. Higher baseline NfL predicted increasing ventricular volume (ES = 1.30cm³, 95%CI = [0.43, 2.17], p = 0.018) and decreasing mid-temporal cortical volume (ES = -0.47, 95%CI = [-0.74, -0.20], p = 0.003). Increasing NfL over the 48-week trial was associated with worsening on CDR-SB but not ADAS-Cog11. Modeling of biomarker-informed power calculations revealed that including high NfL as a trial entry criterion could substantially reduce requisite trial sample size.</p><p><strong>Conclusions: </strong>Elevated baseline plasma NfL predicted more rapid clinical decline and MRI volume loss. Furthermore, increasing plasma NfL concentration over time was associated with worsening on the CDR-SB. Plasma NfL is an easily accessible biomarker that may enhance the design of clinical trials in mild-to-moderate AD.</p><p><strong>Trial registration: </strong>The T2 Protect AD trial was registered as NCT03605667 on clinicaltrials.gov on 2018-07-27.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"97"},"PeriodicalIF":7.9,"publicationDate":"2025-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12046789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953655","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":"Early presentation of spastic paraparesis in individuals carrying PSEN1 mutations: a clinical and genetic analysis.","authors":"Kang-Yang Jih, Ting-Rong Hsu, Jong-Ling Fuh, Tse-Hao Lee, Yung-Shuan Lin, Shih-Yu Fang, Yi-Chu Liao, Yi-Chung Lee","doi":"10.1186/s13195-025-01744-4","DOIUrl":"https://doi.org/10.1186/s13195-025-01744-4","url":null,"abstract":"<p><strong>Background: </strong>Mutations in the presenilin 1 gene (PSEN1) are well-known causes of early-onset familial Alzheimer's disease, but they can also present with atypical phenotypes such as pure spastic paraparesis. This study aims to investigate the clinical and genetic features of PSEN1 variants in patients mainly manifested with hereditary spastic paraparesis (HSP)-like phenotypes.</p><p><strong>Methods: </strong>Mutational analysis was performed in 242 unrelated Taiwanese patients with clinically suspected HSP using a targeted resequencing panel covering the entire coding regions of PSEN1, along with 76 genes associated with HSP and 55 genes linked to HSP-like phenotypes.</p><p><strong>Results: </strong>Two of the 242 patients (0.8%) were found to carry the pathogenic PSEN1 variants (p.P284S and p.F386S). In addition to the two probands, six affected family members were further identified to have the pathogenic PSEN1 variants. Six of these eight patients (75%) presented with spastic paraparesis as their initial symptom, one suffered from cognitive decline, and another manifested with personality change. The average age of symptom onset was 40.1 ± 4.8 years. Except for one patient, cognitive decline developed in all subjects before the last follow-up. For the patient carrying the PSEN1 p.P284S variant, amyloid deposition in bilateral lateral temporal, frontal, precuneus, and parietal regions was evident by amyloid PET, but no hippocampus atrophy was found on brain MRI. For the three patients carrying the PSEN1 p.F386S variant, brain atrophy with dilated ventricles were noted in the patient initially presented with personality changes, but normal MRI findings in the other two patients manifested with spastic paraparesis.</p><p><strong>Conclusions: </strong>Spastic paraparesis can be the initial and isolated clinical presentation of PSEN1 mutations. We identified eight patients from two families carrying a pathogenic PSEN1 variant, all but one carriers have developed cognitive symptoms. PSEN1 related spastic paraparesis usually has a later age of onset compared to other common hereditary spastic paraparesis subtypes, and the family history of early onset dementia might be obscure. Our findings suggested that PSEN1 variants are a rare cause of spastic paraparesis but should be considered especially in those with a later age of onset.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"96"},"PeriodicalIF":7.9,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12042469/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143959702","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":"Repetitive prefrontal tDCS activates VTA dopaminergic neurons, resulting in attenuation of Alzheimer's Disease-like deficits in Tg2576 mice.","authors":"Maria Luisa De Paolis, Gilda Loffredo, Paraskevi Krashia, Livia La Barbera, Annalisa Nobili, Emma Cauzzi, Lucy Babicola, Matteo Di Segni, Roberto Coccurello, Stefano Puglisi-Allegra, Emanuele Claudio Latagliata, Marcello D'Amelio","doi":"10.1186/s13195-025-01736-4","DOIUrl":"https://doi.org/10.1186/s13195-025-01736-4","url":null,"abstract":"<p><strong>Background: </strong>Emerging evidence implicates early dysfunction of dopaminergic neurons in the Ventral Tegmental Area (VTA) as a key contributor to Alzheimer's Disease (AD) pathophysiology. Specifically, the VTA dopaminergic neurodegeneration and the consequent reduction of dopamine (DA) in mesocorticolimbic targets are associated with the onset of cognitive impairments and neuropsychiatric-like manifestations in AD animal models. Moreover, decreased midbrain volume and functional VTA disconnection are identified as predictors of accelerated progression from Mild Cognitive Impairment to AD-dementia in clinical populations. Given these findings, interventions capable of directly modulating VTA activity and augmenting DA release, despite the ongoing neurodegeneration, may hold therapeutic potential for mitigating DA-related deficits in AD. This study aims at evaluating the therapeutic potential of prefrontal transcranial Direct Current Stimulation (tDCS) in the Tg2576 mouse model of AD, exhibiting early VTA dopaminergic neurodegeneration.</p><p><strong>Methods: </strong>Repeated tDCS was applied to assess its ability to activate VTA DA neurons. We also evaluated tDCS effects on synaptic plasticity, cognitive and non-cognitive behaviours and AD-related pathology. Hippocampal DA release and Nucleus Accumbens (NAc) DA transporter (DAT) expression were measured. With immunohistochemistry we examined microglial density and morphological complexity at different disease stages. Additionally, intracellular amyloid-β (Aβ) levels and plaque burden were evaluated to determine the impact of tDCS on AD pathology.</p><p><strong>Results: </strong>Prefrontal tDCS enhanced the activity of VTA dopaminergic neurons, leading to increased hippocampal DA release and higher DAT levels in the NAc. The enhanced DA outflow is associated with restored CA3-CA1 synaptic plasticity and improvements in recognition memory and motivational behaviours. tDCS reduced microglial numbers and morphological complexity in Tg2576 mice at both pre-plaque stage (7-months) and at an advanced stage characterized by plaque accumulation (12-months). Notably, tDCS also decreased Aβ plaque burden, although no changes in intracellular Aβ levels were observed in younger Tg2576 mice.</p><p><strong>Conclusions: </strong>These findings highlight the multifaceted therapeutic potential of prefrontal tDCS in targeting key AD pathophysiological hallmarks, including dopaminergic dysfunction, synaptic impairments, neuroinflammation and plaque deposition. As a non-invasive neuromodulatory approach, prefrontal tDCS emerges as a promising early intervention strategy to complement existing AD treatments, with the potential to improve patient outcomes and quality of life.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"94"},"PeriodicalIF":7.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039073/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953657","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 autocrine motility factor receptor delays the pathological progression of Alzheimer's disease via regulating the ubiquitination-mediated degradation of APP.","authors":"Jingjing Zhang, Congcong Liu, Jing Liu, Yuting Cui, Yuli Hou, Qiao Song, Xiaomin Zhang, Xiaoling Wang, Qian Zhang, Min Cao, Wenchao Wang, Peichang Wang, Yaqi Wang","doi":"10.1186/s13195-025-01741-7","DOIUrl":"https://doi.org/10.1186/s13195-025-01741-7","url":null,"abstract":"<p><strong>Background: </strong>The ubiquitin-proteasome system (UPS) is responsible for most protein degradation and its malfunction is normally observed in neurodegenerative diseases, including Alzheimer's disease (AD). The autocrine motility factor receptor (AMFR) is an E3 ubiquitin ligase that resides on the endoplasmic reticulum membrane and is involved in various essential biological processes. However, the role of AMFR in AD is still unidentified.</p><p><strong>Methods: </strong>Behavioral experiments, including open-field test (OFT), novel object recognition test (NORT) and morris water maze test (MWMT) were conducted after adeno-associated virus (AAV) microinjection into AD model mice. Western blot, co-immunoprecipitation (Co-IP), qPCR and ubiquitination assay were used to analyze AMFR mediated ubiquitination degradation of amyloid precursor protein (APP). ELISA was employed to evaluate changes in amyloidogenic cleavage products of APP following upregulation or downregulation of AMFR in neural cells and analyze AMFR levels in serum and cerebrospinal fluid (CSF) of AD patients.</p><p><strong>Results: </strong>The progressive decline in AMFR levels was found not only in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) mice but also in the CSF and serum of patients with AD. Moreover, the interaction of AMFR and APP was observed both in hippocampal tissues and brain neurons. In addition, AMFR promoted the K11-linked polyubiquitination of APP to speed up its proteasomal degradation, resulting in decreased Aβ production. Importantly, AMFR overexpression largely rescued the cognitive and synaptic deficits in APP/PS1 mice.</p><p><strong>Conclusions: </strong>Taken together, our results demonstrated that AMFR reduced Aβ production and alleviated cognitive impairment by promoting the ubiquitination-mediated degradation of APP. This study indicated that AMFR could have the potential to be a therapeutic target of early-stage AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"95"},"PeriodicalIF":7.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12039061/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143955767","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":"Clinical phenotypes of Alzheimer's disease: investigating atrophy patterns and their pathological correlates.","authors":"Niels Reijner, I Frigerio, M M A Bouwman, B D C Boon, N Guizard, T Jubault, J J M Hoozemans, A J M Rozemuller, F H Bouwman, F Barkhof, E Gordon, W D J van de Berg, L E Jonkman","doi":"10.1186/s13195-025-01727-5","DOIUrl":"https://doi.org/10.1186/s13195-025-01727-5","url":null,"abstract":"<p><strong>Background: </strong>In Alzheimer's disease (AD), MRI atrophy patterns can distinguish between amnestic (typical) and non-amnestic (atypical) clinical phenotypes and are increasingly used for diagnosis and outcome measures in clinical trials. However, understanding how protein accumulation and other key features of neurodegeneration influence these imaging measurements, are lacking. The current study aimed to assess regional MRI patterns of cortical atrophy across clinical AD phenotypes, and their association with amyloid-beta (Aβ), phosphorylated tau (pTau), neuro-axonal degeneration and microvascular deterioration.</p><p><strong>Methods: </strong>Post-mortem in-situ 3DT1 3 T-MRI data was obtained from 33 AD (17 typical, 16 atypical) and 16 control brain donors. Additionally, ante-mortem 3DT1 3 T-MRI scans of brain donors were collected if available. Regional volumes were obtained from MRI scans using an atlas based parcellation software. Eight cortical brain regions were selected from formalin-fixed right hemispheres of brain donors and then immunostained for Aβ, pTau, neurofilament light, and collagen IV. Group comparisons and volume-pathology associations were analyzed using linear mixed models corrected for age, sex, post-mortem delay, and intracranial volume.</p><p><strong>Results: </strong>Compared to controls, both typical and atypical AD showed volume loss in the temporo-occipital cortex, while typical AD showed additional volume loss in the parietal cortex. Posterior cingulate volume was lower in typical AD compared to atypical AD (- 6.9%, p = 0.043). In AD, a global positive association between MRI cortical volume and Aβ load (βs = 0.21, p = 0.010), and a global negative association with NfL load (βs = - 0.18, p = 0.018) were observed. Regionally, higher superior parietal gyrus volume was associated with higher Aβ load in typical AD (βs = 0.47, p = 0.004), lower middle frontal gyrus volume associated with higher NfL load in atypical AD (βs = - 0.50, p < 0.001), and lower hippocampal volume associated with higher COLIV load in typical AD (βs = - 1.69, p < 0.001). Comparing post-mortem with ante-mortem scans showed minimal volume differences at scan-intervals within 2 years, highlighting the translational aspect of this study.</p><p><strong>Conclusion: </strong>For both clinical phenotypes, cortical volume is affected by Aβ and neuro-axonal damage, but in opposing directions. Differences in volume-pathology relationships between clinical phenotypes are region-specific. The findings of this study could improve the interpretation of MRI datasets in heterogenous AD cohorts, both in research and clinical settings.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"93"},"PeriodicalIF":7.9,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12032798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143956352","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}