Molecular Neurodegeneration最新文献

{"title":"Endothelium-specific endoglin triggers astrocyte reactivity via extracellular vesicles in a mouse model of Alzheimer’s disease","authors":"Pingao Zhang, Chenghuan Song, Jiyun Shi, Zijie Wei, Jing Wang, Wanying Huang, Rui Zhang, Jintao Wang, Xiaoli Yang, Gang Wang, Xiaoling Gao, Yongfang Zhang, Hongzhuan Chen, Hao Wang","doi":"10.1186/s13024-025-00875-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00875-4","url":null,"abstract":"Alzheimer’s disease (AD) is a multifaceted neurodegenerative disorder with a complex etiology that extends beyond the well-documented amyloid-β and tau pathologies. Growing evidence implicates cerebrovascular dysfunction, particularly brain microvascular endothelial cells (BMECs) dysfunction, as an early contributor to AD pathogenesis. However, how BMECs influence on neighboring astrocytes needs to be further explored. We employed a multi-omics approach integrating bulk RNA sequencing of human BMECs with proteomic analysis of cerebrospinal fluid (CSF) from AD patients and cerebrovascular endothelial extracellular vesicles (CEEVs). The role of identified candidate proteins was investigated in vitro and in vivo utilizing CEEVs transplantation and BMEC-astrocyte co-cultures. Endothelial cell-specific knockdown or treatment with a monoclonal antibody was used to assess the functional consequences on cognitive impairment and AD pathology via two-photon imaging and behavioral experiments on APP/PS1 mice. The elevated endothelium-specific protein Endoglin (ENG) was identified in the brain and serum of AD individuals and APP/PS1 mice, and the supernatant of injured BMECs. ENG was released and delivered to adjacent astrocytes via CEEVs, and subsequently upregulated TGFBRI/Smad3 pathway in astrocytes, leading to astrocyte reactivity and the release of pro-inflammatory cytokines. Endothelial cell-specific ENG knockdown or treating with ENG monoclonal antibody Carotuximab significantly suppressed reactive astrocytes, reduced neuroinflammation, and improved cognitive performance of APP/PS1 mice. This study reveals a novel mechanism by which BMECs-derived ENG, delivered via CEEVs, drives astrocyte reactivity. These findings redefine the role of cerebrovascular dysfunction in AD pathogenesis and identify ENG as both a potential biomarker and a promising therapeutic target for AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"112 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144684670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic landscape of Alzheimer’s disease: emerging technologies, advances and insights (2021 – 2025)","authors":"Jay M. Yarbro, Him K. Shrestha, Zhen Wang, Xue Zhang, Masihuz Zaman, Mengqi Chu, Xusheng Wang, Gang Yu, Junmin Peng","doi":"10.1186/s13024-025-00874-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00874-5","url":null,"abstract":"The advancements of proteomics technologies are shaping Alzheimer's disease (AD) research, revealing new molecular insights and improving biomarker discovery. Here, we summarize major AD proteomics studies since our 2021 review, focusing on disease mechanisms and biomarker identification. Enhanced sensitivity and throughput in proteome profiling have been driven by mass spectrometry (MS)-based approaches and affinity-based platforms (e.g., Olink and SomaScan). Emerging techniques, including single-cell, spatial, and single-molecule proteomics, provide unprecedented resolution in studying cellular heterogeneity and pathological microenvironments (e.g., amyloidome). Multi-cohort analyses of AD brain tissues have revealed consensus protein alterations (n = 866), identifying novel disease-associated proteins validated in functional studies (e.g., MDK/PTN, NTN1, SMOC1, GPNMB, NPTX2, NRN1, VGF, and U1 snRNP). Proteomic studies of AD biofluids have identified distinct disease subtypes, offering candidate proteins for early detection. Comparisons between human tissues and AD mouse models highlight shared pathways in amyloid pathology while underscoring limitations in recapitulating human disease. Combining proteomics with genomics enables protein quantitative trait locus (pQTL) analysis in AD, linking genetic risk factors to protein expression changes. Discrepancies between proteome and transcriptome suggest altered protein turnover in AD. Overall, AD proteomics continues to provide mechanistic insights into disease progression and potential biomarkers for precision medicine.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144622228","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions","authors":"Min-Young Noh, Hyuk Sung  Kwon, Min-Soo Kwon, Minyeop Nahm, Hee Kyung Jin, Jae-sung Bae, Seung Hyun Kim","doi":"10.1186/s13024-025-00867-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00867-4","url":null,"abstract":"Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies—including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data—offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144594115","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Glial phagocytosis for synapse and toxic proteins in neurodegenerative diseases.","authors":"Yeseong Choi,Won-Suk Chung","doi":"10.1186/s13024-025-00870-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00870-9","url":null,"abstract":"Glia, as resident immune and supportive cells of the central nervous system, play a critical role in maintaining brain homeostasis. One of their key homeostatic functions is phagocytic capacity in pruning synapses and removing cellular debris/protein aggregates, a process vital for synaptic plasticity and brain maintenance. However, these phagocytic functions are often dysregulated with aging and in neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia. This review aims to examine the phagocytic roles of glia under both physiological and pathological conditions, with a special focus on their interactions with misfolded protein aggregates, including amyloid beta, tau, alpha synuclein, prion, huntingtin, and TAR DNA-binding protein 43. We also explore the fate of ingested molecules after being phagocytosed by glia-whether they are degraded, accumulate intracellularly, or are transferred between cells-and their implications for disease progression. Finally, we review current therapeutic strategies and the potential approaches for modulating glial phagocytosis to mitigate several NDs. We believe that understanding the exact mechanisms of glial phagocytosis and clearance will serve as key elements in developing future treatments for NDs.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":"81"},"PeriodicalIF":15.1,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144586441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methylome analysis of FTLD patients with TDP-43 pathology identifies epigenetic signatures specific to pathological subtypes","authors":"Cristina T. Vicente, Tejasvi Niranjan, Elise Coopman, Júlia Faura, Sara Alidadiani, Claudia Schrauwen, Billie J. Matchett, Bavo Heeman, Marleen Van den Broeck, Wouter De Coster, Thuy Nguyen, Julie S. Lau, Saurabh Baheti, Tim de Pooter, Peter De Rijk, Mojca Strazisar, Matt Baker, Mariely DeJesus-Hernandez, NiCole A. Finch, Cyril Pottier, Marka van Blitterswijk, Yan Asmann, Melissa E. Murray, Leonard Petrucelli, Andrew King, Claire Troakes, Safa Al-Sarraj, Robert A. Rissman, Annie Hiniker, Margaret Flanagan, Bret M. Evers, Charles L. White, Carlos Cruchaga, Rudolph Castellani, Jeroen G.J. van Rooij, Merel O. Mol, Harro Seelaar, John C. van Swieten, Björn Oskarsson, Robert Ross Reichard, Aivi T. Nguyen, Keith A. Josephs, Ronald C. Petersen, Nilüfer Ertekin-Taner, Bradley F. Boeve, Neill R. Graff-Radford, Sarah Weckhuysen, Dennis W. Dickson, Rosa Rademakers","doi":"10.1186/s13024-025-00869-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00869-2","url":null,"abstract":"In the last decade, the importance of DNA methylation in the functioning of the central nervous system has been highlighted through associations between methylation changes and differential expression of key genes involved in aging and neurodegenerative diseases. In frontotemporal lobar degeneration (FTLD), aberrant methylation has been reported in causal disease genes including GRN and C9orf72; however, the genome-wide contribution of epigenetic changes to the development of FTLD remains largely unexplored. We performed reduced representation bisulfite sequencing of matched pairs of post-mortem tissue from frontal cortex (FCX) and cerebellum (CER) from pathologically confirmed FTLD patients with TDP-43 pathology (FTLD-TDP) further divided into five subtypes and including both sporadic and genetic forms (N = 25 pairs per group), and neuropathologically normal controls (N = 42 pairs). Case-control differential methylation analyses were performed, both at the individual CpG level, and in regions of grouped CpGs (differentially methylated regions; DMRs), either including all genomic locations or only gene promoters. Gene Ontology (GO) analyses were then performed using all differentially methylated genes in each group of sporadic patients. Finally, additional datasets were queried to prioritize candidate genes for follow-up. Using the largest FTLD-TDP DNA methylation dataset generated to date, we identified thousands of differentially methylated CpGs (FCX = 6,520; CER = 7,134) and several hundred DMRs in FTLD-TDP brains (FCX = 134; CER = 219). Of these, less than 10% are shared between pathological subgroups. Combining additional datasets, we identified, validated and replicated hypomethylation of CAMTA1 in TDP-A potentially also impacting additional genes in the locus. GO analysis further implicated DNA methylation in myelination and developmental processes, as well as important disease-relevant mechanisms with subtype specificity such as protein phosphorylation and DNA damage repair in TDP-A, cholesterol biosynthesis in TDP-B, and protein localization in TDP-C. We identify methylation changes in all FTLD-TDP patient groups and show that most changes are unique to a specific pathological FTLD-TDP subtype, suggesting that these subtypes not only have distinct transcriptomic and genetic signatures, but are also epigenetically distinct. Our study constitutes an invaluable resource to the community and highlights the need for further studies to profile additional epigenetic layers within each FTLD-TDP pathological subtype.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"46 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144565679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Skin biopsy: an emerging tool for the diagnosis of protein misfolding diseases of the central nervous system","authors":"Wei Zhu, Hao-Lun Sun, Yan-Jiang Wang, Xia Lei, Xian-Le Bu","doi":"10.1186/s13024-025-00871-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00871-8","url":null,"abstract":"<p>Abnormal aggregation of misfolded proteins is a common characteristic of many neurodegenerative diseases [1]. Brain protein aggregates formed by phosphorylated tau, amyloid-beta (Aβ), α-synuclein, or prion proteins are toxic and can cause gradual neuronal loss and death in the central nervous system (CNS). These aggregates are linked to many neurodegenerative diseases such as Alzheimer’s disease (AD), and Parkinson’s disease (PD). Rapid advancements in brain PET imaging and body fluid biomarkers have enabled the precise diagnosis of these disorders. However, brain PET scans are expensive, cerebrospinal fluid (CSF) collection is an invasive procedure, and precise diagnostic tools remain limited. Therefore, it is imperative to develop simpler and more accessible diagnostic approaches. Skin tissue shares a common developmental origin with the CNS, as both are derived from the ectoderm during embryogenesis, and skin is rich in nerve fibers. Multiple misfolded proteins, including α-synuclein, tau, and Aβ, are deposited not only in the brain but also in skin tissue [2,3,4]. The biological classification of PD emphasizes the necessity of detecting pathological α-synuclein for diagnosis, with skin biomarkers being particularly noted as an accessible and promising detection method [5, 6]. Skin biopsy samples are more accessible than brain PET and CSF samples. Therefore, skin biopsy holds potential as a biomarker-based method for the diagnosis of protein aggregation diseases.</p><p>Synucleinopathies are defined as a group of neurodegenerative disorders characterized by the abnormal accumulation of α-synuclein in the brain. These include PD, dementia with Lewy bodies (DLB), multiple system atrophy (MSA), and pure autonomic failure (PAF). Recently, Gibbons et al. conducted a blinded, multicenter, cross-sectional study to evaluate the rate of positivity for cutaneous α-synuclein deposition among patients with synucleinopathies (PD, DLB, MSA, and PAF) [7]. The researchers enrolled 151 controls and 277 patients with synucleinopathies diagnosed on the basis of clinical consensus criteria and the findings were confirmed by an expert review panel. Among the participants, 343 participants (223 clinically diagnosed with a specific synucleinopathy and 120 who met the criteria for serving as controls without a synucleinopathy) were included in the primary analysis. Skin biopsy samples were taken from the distal leg, the distal thigh, and the posterior cervical region. Among those patients clinically diagnosed with a specific synucleinopathy, 95.5% (213 of 223) had a skin biopsy sample that was positive for phosphorylated α-synuclein. Specifically, phosphorylated α-synuclein positivity in skin biopsy samples was observed for 92.7% of PD patients, 98.2% of MSA patients, 96% of DLB patients, and 100% of PAF patients. In contrast, only 3.3% (4 of 120) of those in the control group had skin biopsy samples that were positive for phosphorylated α-synuclein. In the seconda","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"18 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Current strategies in the management of dementia with lewy bodies and future directions based on disease pathophysiology","authors":"Daniel Erskine, John-Paul Taylor","doi":"10.1186/s13024-025-00856-7","DOIUrl":"https://doi.org/10.1186/s13024-025-00856-7","url":null,"abstract":"Dementia with Lewy bodies (DLB) is thought to be the second most common form of dementia after Alzheimer’s disease, and is characterised by a combination of cognitive, neuropsychiatric and motor symptoms. The present review seeks to discuss current strategies for the management of DLB, and future directions for novel disease-modifying therapies. Current best practice for the clinical management of DLB is based upon therapies that target specific symptom domains due to the lack of disease-modifying therapies. Cholinesterase inhibitors are the frontline treatment for treating cognitive decline in DLB, whereas the treatment of motor symptoms remains challenging due to poor response to dopaminergic therapies and the potential for exacerbation of neuropsychiatric features. There is emerging evidence suggesting a range of further pharmacological and non-pharmacological therapies may be effective in treating specific symptom domains of DLB, but further evidence is warranted to demonstrate their efficacy. A key challenge in the treatment of DLB is incomplete understanding of disease pathophysiology, which has limited attempts to develop disease-modifying therapies. In the present article, we discuss the multi-faceted nature of DLB neuropathology, from Lewy body pathology to mitochondrial dysfunction, and discuss therapies in development that target particular aspects of DLB neuropathology. In particular, we highlight antibody-based therapies to attenuate protein aggregation, compounds that enhance the generation of cellular energy and autophagy-enhancing agents as particular areas of promise. Furthermore, we discuss how optimal strategies for disease modification will be centred on agents that treat DLB neuropathology more holistically, and will be underpinned by a more complete understanding of the pathogenic events that underlie the full spectrum of pathological changes observed in the DLB brain.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"9 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alpha-synuclein seeding amplification assays in Lewy body dementia: a brief review","authors":"Maria Bregendahl, Zeynep Bengisu Kaya, Wolfgang Singer, Pamela J. McLean","doi":"10.1186/s13024-025-00868-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00868-3","url":null,"abstract":"Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD), is characterized by cognitive decline, sleep disturbances, motor dysfunction, and other debilitating clinical symptoms. Neuropathologically, LBD is characterized by the progressive accumulation of alpha-synuclein (aSYN) in vulnerable cellular populations in the brain. Diagnosing LBD is challenging due to the overlap of clinical symptoms with Alzheimer’s disease (AD) and other neurodegenerative disorders with current diagnostic tools, including clinical examinations by specialized neurologists and brain imaging, limited by accessibility. Taken together, LBD is often misdiagnosed, especially at early disease stages. Seed amplification assays to detect pathogenic aSYN (aSYN SAAs) are emerging as promising tools to detect aSYN pathology in biological specimens. These assays amplify trace amounts of misfolded aSYN, enabling their potential detection in brain, CSF, saliva, skin, and blood. This review compares the sensitivity and specificity of aSYN SAAs across different biological samples and explores the potential of the assay as a diagnostic in LBD. We also highlight challenges that will need to be addressed going forward if the aSYN SAA is to be widely adopted as a diagnostic test. Despite current limitations, aSYN SAAs hold promise for early and precise diagnosis, paving the way for targeted treatments that could significantly improve patient care and outcomes.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"48 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144520953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of interventions targeting modifiable factors for dementia risk reduction.","authors":"Anna Matton,Ruth Stephen,Makrina Daniilidou,Mariagnese Barbera,Vilma Alanko,Marcel Ballin,Jamie Ford,Katri Hemiö,Jenni Lehtisalo,Sabsil López Rocha,Francesca Mangialasche,Tiia Ngandu,Anna Rosenberg,Gazi Saadmaan,Chinedu Udeh-Momoh,Kerttu Uusimäki,Alina Solomon,Miia Kivipelto","doi":"10.1186/s13024-025-00845-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00845-w","url":null,"abstract":"The global prevalence of dementia is increasing. With no widely available and accessible treatments to halt or reverse the progression of dementia, exploring preventative strategies is critical. Lifestyle-based interventions show promise in preventing or delaying dementia onset. However, understanding the complex and multifactorial mechanisms underlying dementia, and how interventions target these pathways, is essential for developing personalized and effective strategies. In this review, we examined the current evidence of the mediating pathways in dementia risk reduction. We focused on mechanisms investigated in single-domain interventions on physical exercise, cognitive training, diet, metabolic/cardiovascular or psycho-social risk factors in line with those combined in the landmark FINGER trial. Additionally, we synthesized existing literature on mechanisms of action in multimodal interventions combining multiple lifestyle changes. Most evidence was identified in relation to neuroimaging biomarkers with positive effects for all intervention components. The evidence among fluid biomarkers of Alzheimer's disease and related disorders (ADRD) (amyloid-beta peptide (Aβ), tau and neurofilament light chain (Nfl)) vascular markers, inflammatory markers, and neurotrophins were less conclusive, though physical exercise consistently appeared to impact several of these pathways. The findings of this review underscore the potential of lifestyle-based interventions in modulating several different types of pathophysiological pathways associated with dementia. As the number of dementia cases reach epidemic proportions, a multifaceted approach is needed. We propose that the next critical step in dementia prevention/risk reduction is to refine existing intervention tools and develop an adaptive platform that integrates different lifestyle interventions tailored to individual risk profiles and needs. Understanding the underlying mechanisms and biomarkers related to modifiable risk factors will be instrumental to optimising these interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"640 1","pages":"75"},"PeriodicalIF":15.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370269","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The PKCι-β-arrestin2 axis disrupts SORLA retrograde trafficking, driving its degradation and amyloid pathology in Alzheimer's disease.","authors":"Hasibur Rehman,Shun Yan,Shalini Saggu,Mae Aida,Fang Zhang,Yang Shu,Alexis Jones,Amy Trang,Emily Dew,Wenbo Zhi,Emily T Claeboe,Anthony J Baucum,Guangyu Wu,Kai Jiao,Qin Wang","doi":"10.1186/s13024-025-00865-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00865-6","url":null,"abstract":"BACKGROUNDVariants of SORL1 have been associated with both late and early onset of Alzheimer's disease (AD). SORL1 encodes the sorting-related receptor with A repeat (SORLA) protein, which belongs to the VPS10 receptor family. SORLA protects against AD pathogenesis through its sorting function, and reduced SORLA levels have been consistently observed in sporadic AD. Although the importance of SORLA in AD pathogenesis is well recognized, how it can be targeted for AD treatment remains to be established, owing to the inadequate understanding of its regulation by intracellular signaling.METHODSWe employed combined biochemical, cell biological, and pharmacological approaches to investigate how SORLA trafficking and stability are regulated. Additionally, we used an AD mouse model, postmortem tissue samples, and iPSC-derived neurons to examine the functional outcomes of this regulation.RESULTSWe identified a novel direct interaction between SORLA and β-arrestin2 (βARR2), which impedes the interaction of SORLA with the retromer complex, thus reducing the retrograde trafficking of SORLA. βARR2 promotes the interaction between SORLA and the ESCRT0 complex, leading to the lysosomal localization and degradation of SORLA. We also found that PKCι/λ induces SORLA phosphorylation and enhances its interaction with βARR2, promoting SORLA degradation. Importantly, blocking PKCι/λ with auranofin disrupts the SORLA-βARR2 interaction, elevates SORLA levels, decreases amyloidogenic processing of APP, and improves cognition in the AppNL-G-F/NL-G-F AD mouse model. Furthermore, PKCι is hyperactive in human AD brains, and auranofin reduces Aβ production in AD iPSC-derived neurons through increasing SORLA levels.CONCLUSIONOur study reveals the PKCι/λ-βARR2 axis as a key molecular mechanism that disrupts SORLA retrograde trafficking and drives its degradation. Our findings represent the first evidence that SORLA levels can be pharmacologically manipulated through blocking PKCι/λ to reduce Aβ production and alleviate AD-related phenotypes. Notably, repurposing auranofin, an FDA-approved drug for rheumatoid arthritis, may offer the potential for AD treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"48 1","pages":"76"},"PeriodicalIF":15.1,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144370270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}