Alzheimer's Research & Therapy最新文献

{"title":"Brain age mediates gut microbiome dysbiosis-related cognition in older adults.","authors":"Sang Joon Son, Dong Yun Lee, Hyun Woong Roh, Maria Ly, Antonija Kolobaric, Howard Aizenstein, Carmen Andreescu, Eldin Jašarević, Tharick A Pascoal, Pamela C L Ferreira, Bruna Bellaver, Yong Hyuk Cho, Sunhwa Hong, You Jin Nam, Bumhee Park, Narae Kim, Jin Wook Choi, Jae Youn Cheong, Yoon-Keun Kim, Tae-Seop Shin, Chil-Sung Kang, Cheol-O Kwon, Seo-Yoon Yoon, Chang Hyung Hong, Helmet T Karim","doi":"10.1186/s13195-025-01697-8","DOIUrl":"10.1186/s13195-025-01697-8","url":null,"abstract":"<p><strong>Background: </strong>Recent studies have focused on improving our understanding of gut microbiome dysbiosis and its impact on cognitive function. However, the relationship between gut microbiome composition, accelerated brain atrophy, and cognitive function has not yet been fully explored.</p><p><strong>Methods: </strong>We recruited 292 participants from South Korean memory clinics to undergo brain magnetic resonance imaging, clinical assessments, and collected stool samples. We employed a pretrained brain age model- a measure associated with neurodegeneration. Using cluster analysis, we categorized individuals based on their microbiome profiles and examined the correlations with brain age, Mental State Examination (MMSE) scores, and the Clinical Dementia Rating Sum of Box (CDR-SB).</p><p><strong>Results: </strong>Two clusters were identified in the microbiota at the phylum level that showed significant differences on a few microbiotas phylum. Greater gut microbiome dysbiosis was associated with worse cognitive function including MMSE and CDR-SB; this effect was partially mediated by greater brain age even when accounting for chronological age, sex, and education.</p><p><strong>Conclusions: </strong>Our findings indicate that brain age mediates the link between gut microbiome dysbiosis and cognitive performance. These insights suggest potential interventions targeting the gut microbiome to alleviate age-related cognitive decline.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"52"},"PeriodicalIF":7.9,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11866832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143522356","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":"Evaluation of cerebrospinal fluid levels of VAMP-2 and SNAP-25 in a dementia with Lewy bodies clinical cohort stratified by Alzheimer's pathophysiological biomarkers.","authors":"Alba Cervantes González, Julie Goossens, Elena Vera Campuzano, Isabel Sala, M Belén Sánchez-Saudinós, Íñigo Rodríguez-Baz, Laia Lidón, Danna Perlaza, Alexandre Bejanin, Annakaisa Haapasalo, Juan Fortea, Daniel Alcolea, Alberto Lleó, Eugeen Vanmechelen, Olivia Belbin","doi":"10.1186/s13195-025-01685-y","DOIUrl":"10.1186/s13195-025-01685-y","url":null,"abstract":"<p><strong>Background: </strong>Synaptic protein levels in cerebrospinal fluid (CSF) may represent much-needed objective biomarkers of cognitive impairment, disease progression and drug efficacy in patients with dementia with Lewy bodies (DLB). Soluble N-ethylmaleimide-sensitive factor attachment proteins receptors (SNARE) proteins, such as VAMP-2 and SNAP-25, are implicated in α-synuclein pathophysiology and CSF levels of these proteins are associated with pathophysiological biomarkers and cognitive decline in Alzheimer's disease (AD). The aim of the study was to compare CSF levels of VAMP-2 and SNAP-25 in patients with DLB to cognitively unimpaired controls and AD patients and study their association with cognitive performance and AD and neurodegeneration biomarkers.</p><p><strong>Methods: </strong>VAMP-2 and SNAP-25 were quantified in CSF from cognitively normal controls (n = 62), DLB (n = 44) and AD (n = 114) patients from the Sant Pau Initiative for Neurodegeneration (SPIN) cohort using homebrew Single Molecule Array assays (Simoa). The DLB group was stratified into two groups with (\"DLB + AD\", n = 28) or without AD co-pathology (\"pure DLB\", n = 16) using our validated cut-off for the CSF phosphorylated tau (p-tau)/Aβ42 ratio. We used linear regression to test for group differences (adjusting for age) and association with AD biomarkers. We used standardized w-scores of the cognitive tests to analyze the association of the synaptic markers with cognitive performance.</p><p><strong>Results: </strong>CSF VAMP-2 and SNAP-25 levels correlated across all groups (r = 0.71-0.9, p < 0.001). Both proteins were decreased in pure DLB (p < 0.001, p = 0.01) but increased in DLB + AD (p = 0.01, p = 0.02) compared to controls and showed good accuracy to discriminate pure DLB from DLB + AD (AUC = 0.84, 0.85). Both proteins were associated with CSF p-tau and total tau (t-tau) across all groups (r² = 0.49-0.88, p < 0.001), with the Aβ42/40 ratio in DLB + AD (r² = 0.29-0.36, p < 0.001) and in AD (r² = 0.12-0.23, p < 0.001) and with CSF neurofilament-light chain (NfL) in controls (r²=0.10-0.11, p < 0.001-0.01) and AD patients (r²=0.01-0.08, p = 0.01 - 0.001). SNAP-25 was associated with CSF NfL in the DLB + AD group (r²=0.15, p = 0.02). CSF VAMP-2 and SNAP-25 were associated with phonemic fluency in pure DLB (r² = 0.39 - 0.28, p = 0.01-0.03) and SNAP-25 with the Clock drawing test and the MMSE in DLB + AD (adj.r² = 0.15 - 0.14, p = 0.03-0.03) and DLB (adj.r² = 0.12 - 0.08, p = 0.02-0.04) groups.</p><p><strong>Conclusions: </strong>CSF VAMP-2 and SNAP-25 are promising surrogate markers of synapse degeneration in DLB. However, care should be taken when interpreting CSF levels of these synaptic markers in DLB in light of the confounding effect of AD pathophysiological markers.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"51"},"PeriodicalIF":7.9,"publicationDate":"2025-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11849174/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143490437","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":"γ-Secretase modulator resistance of an aggressive Alzheimer-causing presenilin mutant can be overcome in the heterozygous patient state by a set of advanced compounds.","authors":"Johannes Trambauer, Rosa Maria Rodriguez Sarmiento, Holly J Garringer, Katja Salbaum, Liliana D Pedro, Dennis Crusius, Ruben Vidal, Bernardino Ghetti, Dominik Paquet, Karlheinz Baumann, Lothar Lindemann, Harald Steiner","doi":"10.1186/s13195-025-01680-3","DOIUrl":"10.1186/s13195-025-01680-3","url":null,"abstract":"<p><strong>Background: </strong>Amyloid-β peptide (Aβ) species of 42 or 43 amino acids in length (Aβ42/43) trigger Alzheimer´s disease (AD) and are produced in abnormal amounts by mutants of the γ-secretase subunit presenilin-1 (PS1), which represent the primary cause of familial AD (FAD). Lowering these peptides by γ-secretase modulators (GSMs) is increasingly considered a safe strategy to treat AD since these compounds do not affect the overall cleavage of γ-secretase substrates. GSMs were shown to modulate not only wild-type (WT) γ-secretase but also FAD mutants, expanding their potential use also to the familial form of the disease. Unlike most other FAD mutants, the very aggressive PS1 L166P mutant is largely resistant to GSMs. However, these data were mostly obtained from overexpression models, which mimic more the less relevant homozygous state rather than the heterozygous patient situation.</p><p><strong>Methods: </strong>Mouse embryonic fibroblast and induced pluripotent stem cell-derived neuronal PS1 L166P knock-in (KI) cell models were treated with various GSMs and Aβ responses were assessed by immunoassays and/or gel-based analysis.</p><p><strong>Results: </strong>We identified GSMs that lower Aβ42 and/or Aβ43 when PS1 L166P is heterozygous, as it is the case in affected patients, and could reduce the amount of pathogenic Aβ species towards WT levels. RO7019009 was the most potent of these compounds, reducing both pathogenic species and concomitantly increasing the short Aβ37 and Aβ38, of which the latter has been associated with delayed AD progression. Another effective compound, the structurally novel indole-type GSM RO5254601 specifically acts on the Aβ42 product line leading to a selective increase of the beneficial Aβ38. Interestingly, we further found that this class of GSMs can bind not only one, but both presenilin fragments suggesting that it targets γ-secretase at an unusual binding site.</p><p><strong>Conclusion: </strong>Our data show that even highly refractory presenilin FAD mutants are in principle tractable with GSMs extending the possibilities for potential clinical studies in FAD with suitable GSM molecules.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"49"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456729","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":"Social frailty and its association with cognitive trajectories in older adults: a prospective cohort study.","authors":"Hui Zhang, Meng Hao, Zixin Hu, Shuai Jiang, Yi Li, Xiaofeng Wang, Xiangwei Li","doi":"10.1186/s13195-025-01687-w","DOIUrl":"10.1186/s13195-025-01687-w","url":null,"abstract":"<p><strong>Background: </strong>Social frailty, a multidimensional construct encompassing various social behaviors, resources, and needs, significantly impacts cognitive health in older adults. Despite existing studies linking specific social factors to cognitive function, the association between social frailty and long-term cognitive trajectories remains underexplored. This study aims to evaluate the longitudinal association between social frailty and trajectory of cognitive function in dementia-free older adults.</p><p><strong>Methods: </strong>This prospective cohort study used data from the National Health and Aging Trends Study (NHATS). Social frailty was assessed using the Makizako Social Frailty Index. According to the presence of social components, individuals were categorized into social frailty (≥ 2), pre-social frailty (1), and robust (0), respectively. Cognitive function was annually evaluated through memory, orientation, and executive function tests from 2011 to 2018. Mixed-effects linear models were employed to assess the associations between social frailty and changes in global and domain-specific cognitive function, adjusting for relevant covariates.</p><p><strong>Results: </strong>In this study, 4956 dementia-free older adults (mean age 76.57 [7.41]) with complete at least 2 times of cognitive tests were included. Compared with the robust, social frailty was associated with significantly faster decline in global cognitive function (β = -0.041, 95% CI [-0.047, -0.036] z score per year) and domain-specific cognitive function (β_memory = -0.045, 95% CI [-0.055, -0.036] z score per year; β_orientation = -0.027, 95% CI [-0.034, -0.020] z score per year; β_executive = -0.042, 95% CI [-0.053, -0.032] z score per year) over the follow-up. Additionally, pre social frailty was associated with significantly faster decline in global cognitive function (β = -0.016, 95% CI [-0.021, -0.012] z score per year), memory function (β= -0.045, 95% CI [-0.055, -0.036] z score per year), and orientation function (β= -0.027, 95% CI [-0.034, -0.020] z score per year) over the follow-up.</p><p><strong>Conclusions: </strong>Social frailty is associated with faster decline in cognition in older adults, underscoring the necessity for enhanced social support and engagement to mitigate cognitive deterioration in vulnerable populations.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"50"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837587/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456712","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":"Cornuside alleviates cognitive impairments induced by Aβ_1-42 through attenuating NLRP3-mediated neurotoxicity by promoting mitophagy.","authors":"Fulin Zhou, Wenwen Lian, Xiaotang Yuan, Zexing Wang, Congyuan Xia, Yu Yan, Wenping Wang, Zhuohang Tong, Yungchi Cheng, Jiekun Xu, Jun He, Weiku Zhang","doi":"10.1186/s13195-025-01695-w","DOIUrl":"10.1186/s13195-025-01695-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a progressive neurodegenerative disorder in which mitochondrial dysfunction and neuroinflammation play crucial roles in its progression. Our previous studies found that cornuside from Cornus officinalis Sieb.Et Zucc is an anti-AD candidate, however, its underlying mechanism remains unknown. In the present study, AD mice were established by intracerebroventricular injection of Aβ_1-42 and treated with cornuside (3, 10, 30 mg/kg) for 2 weeks. Cornuside significantly ameliorated behavioral deficits, protected synaptic plasticity and relieved neuronal damage in Aβ_1-42 induced mice. Importantly, cornuside decreased NLRP3 inflammasome activation, characterized by decreased levels of NLRP3, ASC, Caspase-1, GSDMD, and IL-1β. Furthermore, cornuside promoted mitophagy accompanied by decreasing SQSTM1/p62 and promoting LC3B-I transforming into LC3B-II, via Pink1/Parkin signaling instead of FUNDC1 or BNIP3 pathways. In order to investigate the relationship between NLRP3 inflammasome and mitophagy in the neuroprotective mechanism of cornuside, we established an in-vitro model in BV2 cells exposed to LPS and Aβ_1-42. And cornuside inhibited NLRP3 inflammasome activation and subsequent cytokine release, also protected neurons from damaging factors in microenvironment of conditional culture. Cornuside improved mitochondrial function by promoting oxidative phosphorylation and glycolysis, decreasing the production of ROS and mitochondrial membrane potential depolarization. Besides, mitophagy was also facilitated with increased colocalization of MitoTracker with LC3B and Parkin, and Pink1/Parkin, FUNDC1 and BNIP3 pathways were all involved in the mechanism of cornuside. By blocking the formation of autophagosomes by 3-MA, the protective effects on mitochondria, the inhibition on NLRP3 inflammasome as well as neuronal protection in conditional culture were eliminated. There is reason to believe that the promotion of mitophagy plays a key role in the NLRP3 inhibition of cornuside. In conclusion, cornuside re-establishes the mitophagy flux which eliminates damaged mitochondria and recovers mitochondrial function, both of them are in favor of inhibiting NLRP3 inflammasome activation, then alleviating neuronal and synaptic damage, and finally improving cognitive function.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"47"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837312/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456708","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 impact of kidney function on Alzheimer's disease blood biomarkers: implications for predicting amyloid-β positivity.","authors":"Burak Arslan, Wagner S Brum, Ilaria Pola, Joseph Therriault, Nesrine Rahmouni, Jenna Stevenson, Stijn Servaes, Kübra Tan, Paolo Vitali, Maxime Montembeault, Jesse Klostranec, Arthur C Macedo, Cecile Tissot, Serge Gauthier, Juan Lantero-Rodriguez, Eduardo R Zimmer, Kaj Blennow, Henrik Zetterberg, Pedro Rosa-Neto, Andrea L Benedet, Nicholas J Ashton","doi":"10.1186/s13195-025-01692-z","DOIUrl":"10.1186/s13195-025-01692-z","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Impaired kidney function has a potential confounding effect on blood biomarker levels, including biomarkers for Alzheimer's disease (AD). Given the imminent use of certain blood biomarkers in the routine diagnostic work-up of patients with suspected AD, knowledge on the potential impact of comorbidities on the utility of blood biomarkers is important. We aimed to evaluate the association between kidney function, assessed through estimated glomerular filtration rate (eGFR) calculated from plasma creatinine and AD blood biomarkers, as well as their influence over predicting Aβ-positivity.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We included 242 participants from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort, comprising cognitively unimpaired individuals (CU; n = 124), mild cognitive impairment (MCI; n = 58), AD dementia (n = 34), and non-AD dementia (n = 26) patients all characterized by [&lt;sup&gt;18&lt;/sup&gt;F] AZD-4694. Plasma samples were analyzed for Aβ42, Aβ40, glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), tau phosphorylated at threonine 181 (p-tau181), 217 (p-tau217), 231 (p-tau231) and N-terminal containing tau fragments (NTA-tau) using Simoa technology. Kidney function was assessed by eGFR in mL/min/1.73 m&lt;sup&gt;2&lt;/sup&gt;, based on plasma creatinine levels, age, and sex. Participants were also stratified according to their eGFR-indexed stages of chronic kidney disease (CKD). We evaluated the association between eGFR and blood biomarker levels with linear models and assessed whether eGFR provided added predictive value to determine Aβ-positivity with logistic regression models.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Biomarker concentrations were highest in individuals with CKD stage 3, followed by stages 2 and 1, but differences were only significant for NfL, Aβ42, and Aβ40 (not Aβ42/Aβ40). All investigated biomarkers showed significant associations with eGFR except plasma NTA-tau, with stronger relationships observed for Aβ40 and NfL. However, after adjusting for either age, sex or Aβ-PET SUVr, the association with eGFR was no longer significant for all biomarkers except Aβ40, Aβ42, NfL, and GFAP. When evaluating whether accounting for kidney function could lead to improved prediction of Aβ-positivity, we observed no improvements in model fit (Akaike Information Criterion, AIC) or in discriminative performance (AUC) by adding eGFR to a base model including each plasma biomarker, age, and sex. While covariates like age and sex improved model fit, eGFR contributed minimally, and there were no significant differences in clinical discrimination based on AUC values.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusions: &lt;/strong&gt;We found that kidney function seems to be associated with AD blood biomarker concentrations. However, these associations did not remain significant after adjusting for age and sex, except for Aβ40, Aβ42, NfL, and GFAP. While covariates such as age and sex improved prediction of Aβ-positivity, inclu","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"48"},"PeriodicalIF":7.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837363/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143456719","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":"Sex differences in the association of Alzheimer's disease biomarkers and cognition in a multicenter memory clinic study.","authors":"Cecilia Boccalini, Debora Elisa Peretti, Max Scheffler, Linjing Mu, Alessandra Griffa, Nathalie Testart, Gilles Allali, John O Prior, Nicholas J Ashton, Henrik Zetterberg, Kaj Blennow, Giovanni B Frisoni, Valentina Garibotto","doi":"10.1186/s13195-025-01684-z","DOIUrl":"10.1186/s13195-025-01684-z","url":null,"abstract":"<p><strong>Background: </strong>This study investigated sex differences in the associations between Alzheimer's disease (AD) biomarkers, cognitive performance, and decline in memory clinic settings.</p><p><strong>Methods: </strong>249 participants (females/males:123/126), who underwent tau-PET, amyloid-PET, structural MRI, and plasma glial fibrillary acidic protein (GFAP) measurement were included from Geneva and Lausanne Memory Clinics. Mann-Whitney U tests investigated sex differences in clinical and biomarker data. Linear regression models estimated the moderating effect of sex on the relationship between biomarkers and cognitive performance and decline. Sex differences in cognitive decline were further evaluated using longitudinal linear mixed-effect models with three-way interaction effects.</p><p><strong>Results: </strong>Women and men present similar clinical features, amyloid, and neurodegeneration. Women had higher tau load and plasma levels of GFAP than men (p < 0.05). Tau associations with amyloid (standardized β = 0.54,p < 0.001), neurodegeneration (standardized β=-0.44,p < 0.001), and cognition (standardized β=-0.48,p < 0.001) were moderated by a significant interaction with sex. Specifically, the association between amyloid and tau was stronger among women than men (standardized β=-0.19,p = 0.047), whereas the associations between tau and cognition and between tau and neurodegeneration were stronger among men than in women (standardized β=-0.76,p = 0.001 and standardized β=-0.56,p = 0.044). Women exhibited faster cognitive decline than men in the presence of severe cortical thinning (p < 0.001).</p><p><strong>Conclusion: </strong>Women showed higher tau load and stronger association between amyloid and tau than men. In individuals with high tau burden, men exhibited greater neurodegeneration and cognitive impairment than women. These findings support that sex differences may impact tau deposition through an upstream interplay with amyloid, leading to downstream effects on neurodegeneration and cognitive outcomes.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"46"},"PeriodicalIF":7.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11837373/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143447992","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":"Investigating the Aβ and tau pathology in autosomal dominant Alzheimer's disease: insights from hybrid PET/MRI and network mapping.","authors":"Zhi Zhou, Qigeng Wang, Linwen Liu, Qi Wang, Xiaojun Zhang, Can Li, Jiajin Liu, Yidan Wei, Jin Gao, Liping Fu, Ruimin Wang","doi":"10.1186/s13195-025-01690-1","DOIUrl":"10.1186/s13195-025-01690-1","url":null,"abstract":"<p><strong>Background: </strong>Autosomal dominant Alzheimer's disease (ADAD) offers a distinct framework to study the preclinical phase of Alzheimer's disease (AD), due to its predictable symptom onset and high penetrance of causative mutations. The study aims to examine the spatial distribution and temporal progression of amyloid-beta (Aβ) and tau pathologies, along with mapping the pathology-functional connectivity network, in asymptomatic ADAD mutation carriers using hybrid positron emission tomography/magnetic resonance imaging (PET/MRI).</p><p><strong>Methods: </strong>Participants were recruited from the Chinese Familial Alzheimer's Disease Network, comprising 14 asymptomatic ADAD mutation carriers and 20 cognitively normal healthy controls (CN). Aβ deposition was evaluated using ¹¹C-PIB PET, while tau aggregation was assessed via ¹⁸F-MK6240 PET imaging. Resting-state functional connectivity (rsFC) was analyzed to investigate relationships between pathological burden and neural network changes. Through qualitative analysis, ADAD carriers with marked ¹⁸F-MK6240 uptake in intracranial regions were categorized into Group 2, while others were designated as Group 1.</p><p><strong>Results: </strong>Asymptomatic ADAD carriers demonstrated a significantly greater Aβ burden across the cortex and striatum compared to CN, although tau PET binding did not differ significantly between the groups. Group 2 participants exhibited elevated ¹¹C-PIB uptake in the neocortex and striatum, and increased ¹⁸F-MK6240-PET uptake in the medial temporal and other cortical regions. Compared with Group 1, network mapping of rsFC in Group 2 indicated increased connectivity associated with tau deposition in limbic, posterior cortical, and bilateral temporal regions, overlapping with the default mode network, suggesting potential compensatory mechanisms. Additionally, reduced connectivity in the left medial inferior temporal cortex and fusiform gyrus aligned with findings in sporadic AD cases.</p><p><strong>Conclusions: </strong>This study shows the spatiotemporal progression of Aβ and tau pathologies in preclinical ADAD, supporting the hypothesis that Aβ deposition precedes tau pathology. The rsFC alterations observed associate with tau deposition in asymptomatic carriers indicate early network disruptions. Tau network mapping presents a valuable approach for assessing individualized brain connectivity changes in preclinical AD, mitigating single-subject variability and advancing precision assessment in early-stage AD diagnosis.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"45"},"PeriodicalIF":7.9,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143439526","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":"Circular RNA APP contributes to Alzheimer's disease pathogenesis by modulating microglial polarization via miR-1906/CLIC1 axis.","authors":"Deng-Pan Wu, Yan-Su Wei, Li-Xiang Hou, Yu-Xuan Du, Qiu-Qing Yan, Ling-Ling Liu, Yuan-Dan Zhao, Ru-Yu Yan, Chao Yu, Zhen-Guo Zhong, Jin-Lan Huang","doi":"10.1186/s13195-025-01698-7","DOIUrl":"10.1186/s13195-025-01698-7","url":null,"abstract":"<p><strong>Background: </strong>Abnormal microglial polarization phenotypes contribute to the pathogenesis of Alzheimer's disease (AD). Circular RNAs (circRNAs) have garnered increasing attention due to their significant roles in human diseases. Although research has demonstrated differential expression of circRNAs in AD, their specific functions in AD pathogenesis remain largely unexplored.</p><p><strong>Methods: </strong>CircRNA microarray was performed to identify differentially expressed circRNAs in the hippocampus of APP/PS1 and WT mice. The stability of circAPP was assessed via RNase R treatment assay. CircAPP downstream targets miR-1906 and chloride intracellular channel 1 (CLIC1) were identified using bioinformatics and proteomics, respectively. RT-PCR assay was conducted to detect the expression of circAPP, miR-1906 and CLIC1. Morris water maze (MWM) test, passive avoidance test and novel object recognition task were used to detect cognitive function of APP/PS1 mice. Microglial M1/M2 polarization and AD pathology were assessed using Western blot, flow cytometry and Golgi staining assays. CLIC1 expression and channel activity were evaluated using Western blot and functional chloride channel assays, respectively. The subcellular location of circAPP was assessed via FISH and RT-PCR assays. RNA pull-down assay was performed to detect the interaction of miR-1906 with circAPP and 3' untranslated region (3'UTR) of CLIC1 mRNA.</p><p><strong>Results: </strong>In this study, we identified a novel circRNA, named circAPP, that is encoded by amyloid precursor protein (APP) and is implicated in AD. CircAPP is a stable circRNA that was upregulated in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice. Downregulation of circAPP or CLIC1, or overexpression of miR-1906 in microglia modulated microglial M1/M2 polarization in Aβ-treated microglial cells and the hippocampus of APP/PS1 mice, and improved AD pathology and the cognitive function of APP/PS1 mice. Further results revealed that circAPP was mainly distributed in the cytoplasm, and circAPP could regulate CLIC1 expression and channel activity by interacting with miR-1906 and affecting miR-1906 expression, thereby regulating microglial polarization in AD.</p><p><strong>Conclusions: </strong>Taken together, our study elucidates the regulatory role of circAPP in AD microglial polarization via miR-1906/CLIC1 axis, and suggests that circAPP may act as a critical player in AD pathogenesis and represent a promising therapeutic target for AD.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"44"},"PeriodicalIF":7.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424672","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":"Pathway-based network medicine identifies novel natural products for Alzheimer's disease.","authors":"Yumei Liang, Siqi Xie, Jianping Jia","doi":"10.1186/s13195-025-01694-x","DOIUrl":"10.1186/s13195-025-01694-x","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the leading cause of dementia, characterized by a complex pathogenesis that complicates the development of effective treatments. Natural products are promising multitarget agents because of their ability to interact with multiple molecular targets. Network-based medicine presents a robust strategy for discovering such agents, which can address the intricate mechanisms underlying AD.</p><p><strong>Methods: </strong>In this study, we constructed an AD-related pathway-gene network via text mining and pathway database construction. This network facilitated the identification of natural products that target multiple pathways and genes associated with AD. We evaluated the safety profiles of two selected natural products in C57BL/6J mice through assessments of general behavior, body weight changes, vital organ weight and morphology, and hematological and biochemical parameters. APP/PS1 transgenic mice were subsequently treated with these natural products-either individually or in combination-to assess their therapeutic effects. Cognitive function was evaluated via behavioral tests, such as novel object recognition, Y-maze, and Morris water maze tests. Additionally, immunohistochemical staining and enzyme-linked immunosorbent assays were performed to examine Aβ-associated pathological changes. Transcriptomic analysis and quantitative real-time polymerase chain reaction (qRT-PCR) were employed to elucidate the mechanisms underlying the effects of the natural products.</p><p><strong>Results: </strong>The constructed AD-related pathway-gene network encompassed three perspectives: (i) Most Studied Pathways (21 pathways with 5325 genes), (ii) Gene-Associated Pathways (26 pathways with 2557 genes), and (iii) Popular Pathways (24 pathways with 3435 genes). Two natural products, (-)-Vestitol and Salviolone, were selected for further validation. Their safety was confirmed in C57BL/6J mice. Notably, the combination of (-)-Vestitol and Salviolone synergistically affected cognitive function in APP/PS1 transgenic mice by reducing Aβ deposition and lowering toxic soluble Aβ levels in the brain. Transcriptomic analysis and qRT-PCR experiments revealed that their combination regulated AD-related pathways and genes more comprehensively, particularly affecting the Neuroactive ligand-receptor interaction and Calcium signaling pathway.</p><p><strong>Conclusions: </strong>Our findings demonstrate that screening potential natural products through an AD-related pathway-gene network is a promising strategy for discovering novel therapeutics for AD. The therapeutic potential of (-)-Vestitol and Salviolone as novel candidates for AD treatment is underscored by their synergistic effects, attributed to their comprehensive regulation of AD-associated pathways and genes.</p>","PeriodicalId":7516,"journal":{"name":"Alzheimer's Research & Therapy","volume":"17 1","pages":"43"},"PeriodicalIF":7.9,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829514/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143424689","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}