Molecular Neurodegeneration最新文献

{"title":"Plasma GDF15 as a potential biomarker and driver of neuroinflammation and dementia risk","authors":"José M. Izquierdo","doi":"10.1186/s13024-026-00999-1","DOIUrl":"https://doi.org/10.1186/s13024-026-00999-1","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"193 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022283","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":"Astrocyte reactivity identifies p-tau217-positive individuals at elevated risk of cognitive decline across the Alzheimer’s disease continuum","authors":"Bruna Bellaver,Guilherme Povala,Pamela C. L. Ferreira,Douglas T. Leffa,Guilherme Bauer-Negrini,João Pedro Ferrari-Souza,Firoza Z. Lussier,Livia Amaral,Raphael L. Tuma,Alvaro de Oliveira Franco,Helmet T. Karim,Chang Hyung Hong,Hyun Woong Roh,Nesrine Rahmouni,Arthur Macedo,Joseph Therriault,Stijn Servaes,Jenna Stevenson,Lydia Trudel,Cecile Tissot,Andréa L. Benedet,Nicholas J. Ashton,Henrik Zetterberg,Oscar L. Lopez,Julia Koefler,Riddhi Patira,Thomas K. Karikari,Sid O’bryant,Eduardo R. Zimmer,Joseph Masdeu,Juan Fortea,Dana L. Tudorascu,David N. Soleimani-Meigooni,Val J. Lowe,Hwamee Oh,Belen Pascual,Brian A. Gordon,Sang Joon Son,Suzanne Baker,Pedro Rosa-Neto,Tharick A. Pascoal,the HEAD study,Cristiano S. Aguzzoli,Livia Amaral,Guilherme Bauer-Negrini,Bruna Bellaver,Ann D. Cohen,Alvaro de Oliveira Franco,Douglas T. Leffa,Pamela C. L. Ferreira,Firoza Z. Lussier,Marina S. Medeiros,Rayan Mroué,Markley S. Oliveira,Tharick A. Pascoal,Guilherme Povala,Andréia Rocha,Matheus S. Rodrigues,Emma Ruppert,Pampa Saha,Juli Singer,Carolina Soares,Dana L. Tudorascu,Raphael L. Tuma,Suzanne L. Baker,Cecile Tissot,Hsin-Yeh Tsai,Pedro Rosa-Neto,Tevy Chan,Vladimir Fonov,Yasser Iturria-Medina,WanLu Jia,Jesse Klostranec,Maxime Montembault,Nesrine Rahmouni,Jenna Stevenson,Paolo Vitali,Selma Avdagic,Emerine Cummings,Brian A. Gordon,Danielle Gray,Victoria Tate,Joseph C. Masdeu,Belen Pascual,Hwamee Oh,Xiaoyang Hu,Val Lowe,David N. Soleimani-Meigooni,Juan Fortea,Arthur Toga,Tatiana Foroud","doi":"10.1186/s13024-026-00995-5","DOIUrl":"https://doi.org/10.1186/s13024-026-00995-5","url":null,"abstract":"Abstract Background Plasma phosphorylated tau at threonine 217 (p-tau217) is a robust marker of Alzheimer’s disease (AD) pathology and progression. However, individuals positive for p-tau217 show substantial clinical heterogeneity, suggesting the influence of modifying biological processes. Here, we investigated whether plasma glial fibrillary acidic protein (GFAP) modifies the association between p-tau217 and clinical progression. Methods We analyzed 3,505 individuals across the aging and AD spectrum from six independent cohorts. All participants had baseline Aβ PET, plasma GFAP, plasma p-tau217, and CDR-SB. Participants were classified into four biomarker groups based on GFAP and p-tau217 positivity. Cross-sectional associations with cognitive severity were examined using linear regression and ANCOVA. Longitudinal cognitive trajectories over five years were modeled using linear mixed-effects models. Variance partitioning decomposed biomarker-attributable variance in individual-level annual CDR-SB change rates. Time to clinical worsening (CDR-SB increase ≥ 0.5 points) was assessed using Kaplan–Meier survival analysis and Cox proportional hazards regression. Results We show that elevated plasma GFAP significantly modulates the association between p-tau217 and both cross-sectional cognitive severity and longitudinal clinical decline. Compared to individuals p-tau217-positive-only, individuals with co-elevated GFAP and p-tau217 exhibited worse baseline cognitive performance, faster annual CDR-SB progression (62% higher rate; p  = 0.008), and an increased hazard of cognitive worsening (HR 1.28; 95% CI 1.01–1.61). The interaction between GFAP and p-tau217 accounted for a large proportion of biomarker-related variance in longitudinal cognitive decline (68.6%), far exceeding the independent contributions of p-tau217 (25.3%) and GFAP (1.1%). Conclusion These findings support that astrocyte reactivity is associated with greater cognitive impairment and faster clinical decline among individuals with elevated p-tau217, providing additional prognostic stratification within the p-tau217-positive population. Combining plasma GFAP and p-tau217 may therefore have value for identifying individuals at higher risk of progression, with potential implications for risk stratification and clinical trial enrichment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"40 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020368","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":"Human cellular models of the brain to study lipid homeostasis in Alzheimer’s disease and related dementias","authors":"Sarah E. Heuer,Fasih M. Ahsan,Tracy L. Young-Pearse","doi":"10.1186/s13024-026-00992-8","DOIUrl":"https://doi.org/10.1186/s13024-026-00992-8","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020394","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":"CSF proteomics and machine learning reveal distinct stages across the Alzheimer’s disease continuum","authors":"Saima Rathore,Eric B. Dammer,Anantharaman Shantaraman,Fang Wu,Duc M. Duong,Edward J. Fox,Erik C. B. Johnson,James J. Lah,Alzheimer’s Disease Neuroimaging Initiative,Allan I. Levey,James J. Lah,Janet S. Cellar,Paul Aisen,Anthony Gamst,Ronald G. Thomas,Michael Donohue,Sarah Walter,Anders Dale,James Brewer,Helen Vanderswag,Arthur W. Toga,Paul Thompson,Karen Crawford,Scott Neu,George Bartzokis,Daniel H. S. Silverman,Po H. Lu,Norbert Schuff,Laurel Beckett,Charles DeCarli,Danielle Harvey,John Kornak,Steven G. Potkin,Ruth A. Mulnard,Gaby Thai,Catherine Mc-Adams-Ortiz,Adrian Preda,Dana Nguyen,Lon Schneider,Sonia Pawluczyk,Bryan M. Spann,Evan Fletcher,Owen Carmichael,Matthew Bernstein,Joel Felmlee,Ronald Petersen,Kris Johnson,Clifford R. Jack Jr,Andrew J. Saykin,Tatiana M. Foroud,Li Shen,Martin Farlow,Scott Herring,Ann M. Hake,Neil Buckholtz,Jeffrey Kaye,Sara Dolen,Joseph Quinn,Judith L. Heidebrink,Joanne L. Lord,Rachelle S. Doody,Javier Villanueva-Meyer,Munir Chowdhury,Yaakov Stern,Lawrence S. Honig,Karen L. Bell,John C. Morris,Mark A. Mintun,Stacy Schneider,Daniel Marson,Randall Griffith,David Clark,Hillel Grossman,Cheuk Tang,George Marzloff,Leyla deToledo-Morrell,Raj C. Shah,Ranjan Duara,Daniel Varon,Peggy Roberts,Marilyn S. Albert,Julia Pedroso,Jaimie Toroney,Henry Rusinek,Mony J. de Leon,Susan M. De Santi,P. Murali Doraiswamy,Jeffrey R. Petrella,Marilyn Aiello,Charles D. Smith,Curtis A. Given II,Peter Hardy,Oscar L. Lopez,MaryAnn Oakley,Donna M. Simpson,M. Saleem Ismail,Connie Brand,Jennifer Richard,Jeffrey M. Burns,Heather S. Anderson,Mary M. Laubinger,Neill R. Graff-Radford,Francine Parfitt,Heather Johnson,Christopher H. van Dyck,Martha G. MacAvoy,Amanda L. Benincasa,Howard Chertkow,Howard Bergman,Chris Hosein,Sandra Black,Simon Graham,Curtis Caldwell,Ging-Yuek Robin Hsiung,Howard Feldman,Michele Assaly,Andrew Kertesz,John Rogers,Dick Trost,Charles Bernick,Donna Munic,Chuang-Kuo Wu,Nancy Johnson,Marsel Mesulam,Carl Sadowsky,Walter Martinez,Teresa Villena,Scott Turner,Kathleen B. Johnson,Kelly E. Behan,Reisa A. Sperling,Dorene M. Rentz,Keith A. Johnson,Allyson Rosen,Jared Tinklenberg,Wes Ashford,Marwan Sabbagh,Donald Connor,Sandra Jacobson,Ronald Killiany,Alexander Norbash,Anil Nair,Robert C. Green,Thomas O. Obisesan,Annapurni Jayam-Trouth,Paul Wang,Alan Lerner,Leon Hudson,Paula Ogrocki,Smita Kittur,Seema Mirje,Michael Borrie,T. Y. Lee,Rob Bartha,Sterling Johnson,Sanjay Asthana,Cynthia M. Carlsson,Pierre Tariot,Adam Fleisher,Stephanie Reeder,Gene Alexander,Dan Bandy,Kewei Chen,Vernice Bates,Horacio Capote,Michelle Rainka,Barry A. Hendin,Douglas W. Scharre,Maria Kataki,Earl A. Zimmerman,Dzintra Celmins,Alice D. Brown,Sam Gandy,Marjorie E. Marenberg,Barry W. Rovner,Godfrey Pearlson,Karen Blank,Karen Anderson,Robert B. Santulli,Jessica Englert,Jeff D. Williamson,Kaycee M. Sink,Franklin Watkins,Brian R. Ott,Ronald Cohen,Stephen Salloway,Paul Malloy,Stephen Correia,Howard J. Rosen,Bruce L. Miller,Jacobo Mintzer,Nick Fox,Ramon Diaz-Arrastia,Kristen Martin-Cook,Michael DeVous,Holly Soares,Christopher M. Clark,Cassie Pham,Jessica Nunez,Nicholas T. Seyfried,Allan I. Levey","doi":"10.1186/s13024-026-00983-9","DOIUrl":"https://doi.org/10.1186/s13024-026-00983-9","url":null,"abstract":"Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by heterogeneous pathophysiological changes that begin years before symptoms emerge. Existing biomarkers like Aβ and pTau capture only fragments of this complexity, limiting diagnosis and therapeutic development. Leveraging high-resolution cerebrospinal fluid (CSF) proteomics, quantifying 2,492 proteins using tandem-mass-tag mass spectrometry (TMT-MS), in 1,104 ADNI participants, we identified pathways reflecting AD pathogenesis and stage-specific molecular events in-vivo. In biomarker-positive MCI (due-to-AD) and AD Dementia, beyond well-established metabolic and mitochondrial dysfunction, we observed upregulated neuropeptide signaling, G-protein-coupled receptors activity, and synaptic remodeling, highlighting underrecognized synaptic and signaling alterations. Asymptomatic AD showed significant alterations in mitochondrial metabolism, RNA processing, and extracellular matrix pathways. Across the continuum from asymptomatic AD to MCI (due-to-AD) and AD Dementia, 92 proteins were differentially abundant, revealing a stage-specific progression, with early disruptions in neurodevelopmental and extracellular vesicle-related pathways in asymptomatic and MCI (due-to-AD) participants, transitioning to impairments in intracellular signaling, synaptic architecture, and cytoskeletal integrity in AD Dementia. This progressive dysregulation supports a continuum model where early compensatory mechanisms gradually give way to widespread neuronal degeneration. Using machine learning, we derived CSF proteomic panels capable of accurately distinguishing disease stages (asymptomatic AD vs. MCI (due-to-AD): AUC = 0.92; MCI (due-to-AD) vs. AD Dementia: AUC = 0.87). In parallel, we developed machine learning models to estimate pathological burden (Aβ-PET, tau-PET), which substantially outperformed conventional biomarkers. These findings uncover protein signatures that reflect underlying AD biology and provide a foundation for stage-specific biomarkers and therapeutic targeting, with important implications for patient stratification and personalized intervention strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149022456","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":"Intranasal drug delivery for neurodegenerative diseases: therapeutic opportunities across molecules, organelles, and cells","authors":"Tu Chen Guan,William H. Frey II,Mei Liu,Yan Liu,Qing Wang,Yun Cheng Wu,Eng King Tan,Zhi Dong Zhou","doi":"10.1186/s13024-026-00994-6","DOIUrl":"https://doi.org/10.1186/s13024-026-00994-6","url":null,"abstract":"Abstract Neurodegenerative diseases (NDDs) are a heterogeneous group of disorders characterized by progressive neuronal loss that leads to cognitive, motor, and behavioral impairment. With population aging, NDDs impose an expanding medical and socioeconomic burden, yet most available treatments remain symptomatic rather than disease modifying. Disease mechanisms are increasingly understood as multicellular processes involving neurons, astrocytes, microglia, and other cell types, which complicates target selection and limits translation from conventional models. Intranasal administration offers a noninvasive route for delivering therapeutics to the central nervous system by leveraging olfactory and trigeminal pathways and reducing dependence on blood-brain barrier penetration. This review summarizes recent advances in intranasal strategies for NDDs across diverse therapeutic classes, including peptides and proteins, small molecules and metabolic modulators, nucleic acid-based cargos, and nanocarrier enabled formulations designed to improve retention, stability, and brain deposition. We further highlight emerging organelle centered and bioengineered approaches, such as mitochondrial delivery and other cell organelle or organelle derived systems, alongside cell-based and cell-free biologics including stem cells, secretomes, and extracellular vesicles that provide multi target neuroprotective and immunomodulatory effects. Finally, we discuss key translational challenges, including limited delivery efficiency due to mucociliary clearance, uncertainty in dosing regimens, manufacturing and quality control for complex biologics and organelles, and the need for robust biomarkers and imaging readouts to confirm central target engagement. Collectively, these advances position intranasal delivery as a versatile but evolving platform for next generation interventions in NDDs.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"5 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149020071","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":"Retromer-targeted therapy for neurodegenerative diseases","authors":"Michele Persico,Sophronea Tuithung,Alejandra Lorenzo,Darynaisha Crawford,Simona Eleuteri,David K. Simon","doi":"10.1186/s13024-026-00971-z","DOIUrl":"https://doi.org/10.1186/s13024-026-00971-z","url":null,"abstract":"Abstract Alzheimer’s disease (AD), Parkinson’s disease (PD), and Amyotrophic Lateral Sclerosis (ALS) are neurodegenerative diseases characterized by dysfunction of the endosomal-lysosomal system (ELS). Four shared neurodegenerative mechanisms across ALS, PD and AD are regulated by the ELS, namely proteostasis and related protein misfolding, mitochondrial function, neurotransmission and neuroinflammation. These mechanisms are interconnected, contributing to neurodegeneration in a “snowball” manner. The retromer, a multimeric, evolutionarily conserved protein complex involved in intracellular protein trafficking, is at the crossroad of these neurodegenerative processes. This narrative review focuses on exploring the retromer structure, function as a master regulator of the ELS, and how this impacts proteostasis, mitochondrial biogenesis and homeostasis, neurotransmission and neuroinflammation across neurodegenerative diseases. We explore how alterations in retromer function can play an important role in neurodegeneration and discuss the impact of genetic and pharmacological manipulations of VPS35, one of the main retromer subunits. In vitro and in vivo studies have identified that the retromer enhances the activity of protein degradation pathways via the ELS, namely macroautophagy, chaperone-mediated autophagy, and the ELS itself, with concomitant reduction in misfolded protein levels. Also, in some model systems, when the retromer role is enhanced or restored, mitochondrial function is rescued, dysfunctional neurotransmission is restored, and the damaging effects of neuroinflammation are dampened. Lastly, we highlight the role of a novel pharmacological class of agents that enhance retromer function as a strategy for potentially slowing the progression of these neurodegenerative diseases in in vivo models of PD and ALS. We discuss the challenges in targeting the retromer, current limitations and potential off-target effects of retromer enhancement. Overall, the retromer regulates shared mechanisms across neurodegenerative diseases and retromer enhancers could represent a novel disease-modifying strategy in AD, PD and ALS.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"56 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148923241","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 YTHDF proteins modulate Alzheimer’s disease-associated brain gene signatures","authors":"Shinya Tasaki,Denis R. Avey,Nicola A. Kearns,Chunjiang Yu,Sashini De Tissera,Himanshu Vyas,Lin Cheng,Jishu Xu,Artemis Iatrou,Daniel J. Flood,Wenlong Li,Lisa L. Barnes,Katherine Rothamel,Aliza P. Wingo,Thomas S. Wingo,Nicholas T. Seyfried,Chuan He,Philip L. De Jager,Gene W. Yeo,Chris Gaiteri,David A. Bennett,Yanling Wang","doi":"10.1186/s13024-026-00986-6","DOIUrl":"https://doi.org/10.1186/s13024-026-00986-6","url":null,"abstract":"Abstract Gene signatures of Alzheimer’s disease (AD) brains reflect the output of a complex interplay of genetic, epigenetic, epi-transcriptomic, and post-transcriptional regulations. To nominate candidate factors modulating these signatures, we developed a machine learning model to integrate cellular and molecular features explaining differential gene expression in AD. Among the features tested, YTHDF proteins, the canonical readers of N6-methyladenosine (m6A) RNA modification, are among the most influential predictors of AD gene signatures. Protein modules containing YTHDFs were downregulated in human AD brains, and knockdown or pharmacological inhibition of YTHDFs in iPSC-derived 2D and 3D neuronal models recapitulated key AD-associated gene signatures. Furthermore, eCLIP-seq revealed altered YTHDF binding to transcripts in AD brains, at both m6A-dependent and m6A-independent sites. Together, these results support an important role for YTHDF proteins in modulating AD-associated gene signatures in the human brain.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"1 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148895773","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":"Inflammasomes: central mediators of neuroinflammatory neurodegeneration in Alzheimer’s and Parkinson’s disease","authors":"Clémence Tropis,Janna Jernigan Posey,Malú Gámez Tansey,Michael T. Heneka","doi":"10.1186/s13024-026-00991-9","DOIUrl":"https://doi.org/10.1186/s13024-026-00991-9","url":null,"abstract":"Abstract As life expectancy increases worldwide, the proportion of people aged 65 and older is expected to double by 2050 and these global demographic shifts will be accompanied by an increase in age-related neurodegenerative diseases such as Alzheimer’s (AD) and Parkinson’s disease (PD). AD is the leading cause of dementia worldwide, characterized by progressive cognitive decline linked to amyloid beta accumulation, tau pathology, neuronal cell death and chronic neuroinflammation. PD is the most common movement disorder worldwide, characterized by progressive motor decline linked to alpha-synuclein accumulation, formation of Lewy bodies and neurites, dopaminergic neuron death, as well as chronic neuroinflammation. Increasing evidence implicates inflammasomes, intracellular multiprotein complexes that orchestrate innate immune responses, as key drivers of the neuroinflammatory milieu in AD and PD. The NLRP3 inflammasome, mostly expressed by microglia, has been shown to activate caspase-1, resulting in the cleavage and release of pro-inflammatory cytokines IL-1β and IL-18 and promoting pyroptotic cell death within the central nervous system. This review synthesizes current knowledge on the molecular mechanisms of inflammasome activation, their pathological involvement in AD and PD, and the genetic underpinnings supporting their role. It further highlights emerging therapeutic strategies aimed at modulating inflammasome activity, evaluating preclinical outcomes and clinical trial progress. Understanding inflammasome dynamics provides critical insight into AD and PD pathophysiology and presents promising targets for future disease-modifying treatments.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"10 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148893714","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":"Lipid-driven membrane remodeling engages a lysosome-dependent adaptive repair program during retinal aging.","authors":"Emily Tom, Fangyuan Gao, Carolina N Franco, Adrian Wong, Nathan Kemmerer, Zichen Wang, Amit Jairaman, Qianlan Xu, Yinyin Zhuang, Samuel W Du, Grazyna Palczewska, Krzysztof Palczewski, Itay Budin, Shivashankar Othy, Xiaoyu Shi, Vera L Bonilha, Johannes Schoeneberg, Karl J Wahlin, Lauren V Albrecht, Dorota Skowronska-Krawczyk","doi":"10.1186/s13024-026-00990-w","DOIUrl":"10.1186/s13024-026-00990-w","url":null,"abstract":"<p><p>Age-associated remodeling of membrane lipid composition has been implicated in cellular dysfunction, yet the mechanisms linking lipid changes to membrane integrity and disease remain poorly defined. In the retinal pigment epithelium (RPE), lipid dysregulation is strongly associated with aging and age-related macular degeneration (AMD), a neurodegenerative disease of the central nervous system, but the causal pathways remain unclear. Here, we identify reduced activity of the lipid elongase ELOVL2 as a central driver of age-dependent membrane remodeling. Loss of ELOVL2-dependent polyunsaturated fatty acid (PUFA) elongation shifts plasma membrane lipid composition, leading to altered membrane biophysical properties and compromised membrane integrity. In response to this stress, RPE cells do not undergo apoptosis but instead activate a lysosome-dependent plasma membrane repair program that preserves barrier function under metabolic challenge. However, this adaptive response drives spatially polarized lysosomal exocytosis, promoting extracellular remodeling and accumulation of sub-RPE deposits associated with aging and AMD. Restoration of ELOVL2-derived lipid products reverses membrane abnormalities and suppresses lysosome-mediated remodeling phenotypes, demonstrating direct metabolic control of membrane homeostasis. Together, these findings define an ELOVL2-dependent lipid-lysosome axis that links PUFA elongation to plasma membrane integrity and reveals how compensatory repair mechanisms can contribute to tissue remodeling and disease progression in aging epithelia.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13563809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148930625","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":"Advancing a systems-level understanding of neurodegeneration: the BrightFocus Alzheimer's disease research portfolio.","authors":"Sharyn L Rossi, Diane E Bovenkamp","doi":"10.1186/s13024-026-00984-8","DOIUrl":"10.1186/s13024-026-00984-8","url":null,"abstract":"<p><p>Alzheimer's disease research is entering a period of rapid acceleration. After decades focused on identifying individual disease-associated proteins and pathways, the field is moving toward a deeper understanding of how these mechanisms interact to influence cellular function, biological systems, and ultimately behavior and cognition. The emphasis is moving from isolated molecular targets to coordinated biological systems. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and, ultimately, to cognition and behavior. Moving beyond single-target approaches will depend on understanding these upstream drivers, how they interact, and how sex, genetic background, and accumulated stressors shape when and how these systems fail. Underlying pathological mechanisms point toward the breakdown of core cellular maintenance systems, including proteostasis, metabolism, and immune regulation. This dysfunction propagates from organelles to cells, from cells to neural circuits, and ultimately to cognition and behavior. The BrightFocus Alzheimer's Disease Research (ADR) program [1] has long operated within this broad framework. Rather than focusing narrowly on single disease targets, the portfolio takes a 360° approach and prioritizes innovative research that reveals how fundamental cellular processes interact across cell types and biological systems to drive neurodegeneration and resilience. This includes supporting early-career investigators and researchers entering the field from other disciplines to advance current hypotheses and define where the field is going next.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"21 1","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13495267/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148795808","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}