Molecular Neurodegeneration最新文献

{"title":"Cautions on utilizing plasma GFAP level as a biomarker for reactive astrocytes in neurodegenerative diseases","authors":"Wongu Youn, Mijin Yun, C. Justin Lee, Michael Schöll","doi":"10.1186/s13024-025-00846-9","DOIUrl":"https://doi.org/10.1186/s13024-025-00846-9","url":null,"abstract":"<p>In the recent decade, there has been a surge of efforts to develop scalable, specific and cost-effective biomarkers in blood to diagnose neurodegenerative diseases and prognose their progress even before overt symptoms manifest. Among an array of brain-associated proteins, glial fibrillary acidic protein (GFAP) has emerged as a compelling biomarker candidate, often in conjunction with other biomarkers. GFAP levels in bodily fluid, especially blood and cerebrospinal fluid (CSF), have underscored associations with disease progression by robust support in a substantial body of reports encompassing cohorts afflicted with a spectrum of brain and spinal cord disorders, including progressive neurodegenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis and Lewy body dementia. Notably, GFAP in CSF is known to reflect astrogliosis in alignment with other astrogliosis marker levels such as S100β, chitinase-3-like protein 1 (CHI3L1, also known as YKL40 in humans and BMP39 in mice), aquaporin 4, evidence in tissue by immunohistochemistry staining, and uptake of certain PET radiotracers targeting reactive astrocytes, i.e., <sup>11</sup>C-deuterium-L-deprenyl (<sup>11</sup>C-DED), <sup>11</sup>C-BU99008, <sup>11</sup>C-SMBT-1 or <sup>11</sup> C-acetate [1]. On the other hand, GFAP levels in blood seem to demonstrate more precise diagnostic performance than CSF GFAP level in an AD context. Patient case studies employing MRI and PET have underscored correlations between disease progression and GFAP levels in bodily fluids, with plasma GFAP yielding greater significance [2]. Furthermore, recent cohort studies suggest that the effect of amyloid-β (Aβ) on tau pathology may be modulated by astrocytic reactivity, which was suggested to be indicated by increased plasma GFAP levels [3]. The recent inclusion of interchangeable use of plasma and CSF GFAP as a marker of inflammation (category ‘I’) in the Alzheimer’s Association Workgroup criteria for diagnosis and staging of Alzheimer’s disease showcases its suggested diagnostic potential [4]. We argue, however, that there are several concerns regarding the use of blood GFAP as a direct biomarker for astrocyte reactivity. Research has identified discrepancies between astrocyte reactivity examined by <sup>11</sup>C-deuterium-L-deprenyl (<sup>11</sup>C-DED) PET imaging and plasma GFAP levels in AD patients [5], with more significant changes observed in blood GFAP levels than in cerebrospinal fluid (CSF) GFAP levels [6]. In this perspective, we argue that astrocytic reactivity cannot be represented solely from blood GFAP level, and more direct methods for examining astrocyte reactivity such as PET imaging must be followed. Our argument is based on two primary concerns: the ambiguous origin of plasma GFAP and inconsistencies between blood GFAP level increases and other biomarkers.</p><p>First, the origin of blood GFAP remains unclear, with uncertainty about whether plasma GFAP derives","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"49 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143926636","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":"Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration","authors":"Elise A. Kellett, Adekunle T. Bademosi, Adam K. Walker","doi":"10.1186/s13024-025-00839-8","DOIUrl":"https://doi.org/10.1186/s13024-025-00839-8","url":null,"abstract":"Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic variants, and genetic, physical, or chemical inducement in a variety of cell cultures and animal models, and via analyses of post-mortem human tissues. These studies have produced conflicting results: suggesting incongruously that TDP-43 phosphorylation may either drive disease progression or serve a neuroprotective role. In this review, we explore the roles of regulators of TDP-43 phosphorylation including the putative TDP-43 kinases c-Abl, CDC7, CK1, CK2, IKKβ, p38α/MAPK14, MEK1, TTBK1, and TTBK2, and TDP-43 phosphatases PP1, PP2A, and PP2B, in disease. Building on recent studies, we also examine the consequences of TDP-43 phosphorylation on TDP-43 pathology, especially related to TDP-43 mislocalisation, liquid–liquid phase separation, aggregation, and neurotoxicity. By comparing conflicting findings from various techniques and models, this review highlights both the discrepancies and unresolved aspects in the understanding of TDP-43 phosphorylation. We propose that the role of TDP-43 phosphorylation is site and context dependent, and includes regulation of liquid–liquid phase separation, subcellular mislocalisation, and degradation. We further suggest that greater consideration of the normal functions of the regulators of TDP-43 phosphorylation that may be perturbed in disease is warranted. This synthesis aims to build towards a comprehensive understanding of the complex role of TDP-43 phosphorylation in the pathogenesis of neurodegeneration. TDP-43 is subject to phosphorylation by kinases and dephosphorylation by phosphatases, which variably impacts protein localisation, aggregation, and neurotoxicity in neurodegenerative diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"74 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143920371","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":"Cerebrospinal fluid proteome profiling across the Alzheimer's disease continuum: a step towards solving the equation for 'X'.","authors":"Sophia Weiner,Mathias Sauer,Laia Montoliu-Gaya,Andrea L Benedet,Nicholas J Ashton,Fernando Gonzalez-Ortiz,Joel Simrén,Nesrine Rahmouni,Cecile Tissot,Joseph Therriault,Stijn Servaes,Jenna Stevenson,Ville Leinonen,Tuomas Rauramaa,Mikko Hiltunen,Pedro Rosa-Neto,Kaj Blennow,Henrik Zetterberg,Johan Gobom","doi":"10.1186/s13024-025-00841-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00841-0","url":null,"abstract":"BACKGROUNDWhile the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer's disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted 'X' in the ATX(N) framework, remain poorly understood.METHODSUsing an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF proteins across the AD continuum in three independent cohorts, finely staged by Aβ/tau positron emission tomography (PET), fluid biomarkers, or brain biopsy. Weighted protein co-expression network analysis identified clusters of proteins robustly correlating in all three cohorts which sequentially changed with AD progression. Obtained protein clusters were correlated with fluid biomarker measurements (phosphorylated tau (p-tau) species including p-tau181, p-tau217, and p-tau205, as well as Aβ), Aβ/tau PET imaging, and clinical parameters to discern disease-relevant clusters which were modelled across the AD continuum.RESULTSNeurodegeneration-related proteins (e.g., 14-3-3 proteins, PPIA), derived from different brain cell types, strongly correlated with fluid as well as imaging biomarkers and increased early in the AD continuum. Among them, the proteins SMOC1 and CNN3 were highly associated with Aβ pathology, while the 14-3-3 proteins YWHAZ and YWHAE as well as PPIA demonstrated a strong association with both Aβ and tau pathology as indexed by PET. Endo-lysosomal proteins (e.g., HEXB, TPP1, SIAE) increased early in abundance alongside neurodegeneration-related proteins, and were followed by increases in metabolic proteins such as ALDOA, MDH1, and GOT1 at the mild cognitive impairment (MCI) stage. Finally, later AD stages were characterized by decreases in synaptic/membrane proteins (e.g., NPTX2).CONCLUSIONSOur study identified proxies of Aβ and tau pathology, indexed by PET, (SMOC1, YWHAE, CNN3) and highlighted the dynamic fluctuations of the CSF proteome over the disease course, identifying candidate biomarkers for disease staging beyond Aβ and tau.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":"52"},"PeriodicalIF":15.1,"publicationDate":"2025-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143915209","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":"Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication","authors":"Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J. Moulton, Lindsey D. Goodman, Zhiping P. Pang, Alan R. Sanders, Hugo J. Bellen, Gopal Thinakaran, Jubao Duan","doi":"10.1186/s13024-025-00840-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00840-1","url":null,"abstract":"Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied. Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation. We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with the AD protective allele upregulating neuronal CLU and promoting neuron excitability. And, neuronal CLU facilitated neuron-to-glia lipid transfer and astrocytic lipid droplet formation coupled with reactive oxygen species (ROS) accumulation. These changes caused astrocytes to uptake less glutamate thereby altering neuron excitability. For a strong AD-associated locus near Clusterin (CLU), we connected an AD protective allele to a role of neuronal CLU in promoting neuron excitability through lipid-mediated neuron-glia communication. Our study provides insights into how CLU confers resilience to AD through neuron-glia interactions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"54 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-05-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143902933","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":"Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease","authors":"Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V. Heikkinen, Mitja I. Kurki, Jarkko Marttila, Petri I. Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu, Jenni Lehtisalo, Céline Bellenguez, Jean-Charles Lambert, Christian Haass, Juha Rinne, Juhana Hakumäki, Tuomas Rauramaa, Johanna Krüger, Hilkka Soininen, Annakaisa Haapasalo, Stefan F. Lichtenthaler, Ville Leinonen, Eino Solje, Mikko Hiltunen","doi":"10.1186/s13024-025-00830-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00830-3","url":null,"abstract":"Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally extremely rare and their role in neurodegenerative diseases remains unclear. The population history of Finns has favored the enrichment of deleterious founder mutations, including a 5.2 kb deletion encompassing exons 1–4 of TYROBP and causing NHD in homozygous carriers. We used here a proxy marker to identify monoallelic TYROBP deletion carriers in the Finnish biobank study FinnGen combining genome and health registry data of 520,210 Finns. We show that monoallelic TYROBP deletion associates with an increased risk and earlier onset age of AD and dementia when compared to noncarriers. In addition, we present the first reported case of a monoallelic TYROBP deletion carrier with NHD-type bone cysts. Mechanistically, monoallelic TYROBP deletion leads to decreased levels of DAP12 protein (encoded by TYROBP) in myeloid cells. Using transcriptomic and proteomic analyses of human monocyte-derived microglia-like cells, we show that upon lipopolysaccharide stimulation monoallelic TYROBP deletion leads to the upregulation of the inflammatory response and downregulation of the unfolded protein response when compared to cells with two functional copies of TYROBP. Collectively, our findings indicate TYROBP deletion as a novel risk factor for AD and suggest specific pathways for therapeutic targeting.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"8 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143884381","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":"TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis","authors":"Maria Vizziello, Ilaria Linda Dellarole, Arianna Ciullini, Riccardo Pascuzzo, Annalisa Lombardo, Floriana Bellandi, Luigi Celauro, Claudia Battipaglia, Emilio Ciusani, Ambra Rizzo, Marcella Catania, Grazia Devigili, Sara Adriana Della Seta, Valentina Margiotta, Monica Consonni, Veronica Faltracco, Pietro Tiraboschi, Nilo Riva, Sara Maria Silvia Portaleone, Gianluigi Zanusso, Giuseppe Legname, Giuseppe Lauria, Eleonora Dalla Bella, Fabio Moda","doi":"10.1186/s13024-025-00833-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00833-0","url":null,"abstract":"In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. OM samples were collected from patients with (a) sporadic motor neuron diseases (MND), including spinal ALS (n = 35), bulbar ALS (n = 18), primary lateral sclerosis (n = 10), and facial onset sensory and motor neuronopathy (n = 2); (b) genetic MND, including carriers of C9orf72exp (n = 6), TARDBP (n = 4), SQSTM1 (n = 3), C9orf72exp + SQSTM1 (n = 1), OPTN (n = 1), GLE1 (n = 1), FUS (n = 1) and SOD1 (n = 4) mutations; (c) other neurodegenerative disorders (OND), including Alzheimer’s disease (n = 3), dementia with Lewy bodies (n = 8) and multiple system atrophy (n = 6); and (d) control subjects (n = 22). All samples were subjected to SAA analysis for TDP-43 (TDP-43_SAA). Plasmatic levels of TDP-43 and neurofilament-light chain (NfL) were also assessed in a selected number of patients. TDP-43_SAA was positive in 29/65 patients with sporadic MND, 9/21 patients with genetic MND, 6/17 OND patients and 3/22 controls. Surprisingly, one presymptomatic individual also tested positive. As expected, OM of genetic non-TDP-43-related MND tested negative. Interestingly, fluorescence values from non-MND samples that tested positive were consistently and significantly lower than those obtained with sporadic and genetic MND. Furthermore, among TDP-43-positive samples, the lag phase observed in MND patients was significantly longer than that in non-MND patients. Plasma TDP-43 levels were significantly higher in sporadic MND patients compared to controls and decreased as the disease progressed. Similarly, plasma NfL levels were higher in both sporadic and genetic MND patients and positively correlated with disease progression rate (ΔFS). No significant correlations were detected between TDP-43_SAA findings and the biological, clinical, or neuropsychological parameters considered. The OM of a subset of patients with sporadic MND can trigger seeding activity for TDP-43, as previously observed in genetic MND. Thus, TDP-43_SAA analysis of OM can improve the clinical characterization of ALS across different phenotypes and enhance our understanding of these diseases. Finally, plasma TDP-43 could serve as a potential biomarker for monitoring disease progression. However, further research is needed to confirm and expand these findings.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"14 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878120","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":"Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes","authors":"Sara Gutiérrez Fernández, Cristina Gan Oria, Dieter Petit, Wim Annaert, John M. Ringman, Nick C. Fox, Natalie S. Ryan, Lucía Chávez-Gutiérrez","doi":"10.1186/s13024-025-00832-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00832-1","url":null,"abstract":"Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests with early onset (< 65 years). Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding this clinical variability is crucial for understanding disease mechanisms, developing predictive models and tailored interventions in ADAD, with potential implications for sporadic AD. We performed biochemical assessment of γ-secretase dysfunction on 28 PSEN2 and 19 APP mutations, including disease-associated, unclear and benign variants. This analysis has been valuable in the assessment of PSEN1 variant pathogenicity, disease onset and progression. Our analysis reveals linear correlations between the molecular composition of Aβ profiles and AAO for both PSEN2 (R2 = 0.52) and APP (R2 = 0.69) mutations. The integration of PSEN1, PSEN2 and APP correlation data shows parallel but shifted lines, suggesting a common pathogenic mechanism with gene-specific shifts in onset. We found overall “delays” in AAOs of 27 years for PSEN2 and 8 years for APP variants, compared to PSEN1. Notably, extremely inactivating PSEN1 variants delayed onset, suggesting that reduced contribution to brain APP processing underlies the later onset of PSEN2 variants. This study supports a unified model of ADAD pathogenesis wherein γ-secretase dysfunction and the resulting shifts in Aβ profiles are central to disease onset across all causal genes. While similar shifts in Aβ occur across causal genes, their impact on AAO varies in the function of their contribution to APP processing in the brain. This biochemical analysis establishes quantitative relationships that enable predictive AAO modelling with implications for clinical practice and genetic research. Our findings also support the development of therapeutic strategies modulating γ-secretase across different genetic ADAD forms and potentially more broadly in AD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"9 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875992","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":"Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement","authors":"Natalie Grima, Andrew N. Smith, Claire E. Shepherd, Lyndal Henden, Thiri Zaw, Luke Carroll, Dominic B. Rowe, Matthew C. Kiernan, Ian P. Blair, Kelly L. Williams","doi":"10.1186/s13024-025-00820-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00820-5","url":null,"abstract":"Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165 sample-matched post-mortem brain transcriptomes from 22 sporadic ALS patients with pTDP-43 pathological staging and 11 non-neurological controls. For each individual, five brain regions underwent mRNA sequencing: motor cortex (pTDP-43 inclusions always present), prefrontal cortex and hippocampus (pTDP-43 inclusions sometimes present), and occipital cortex and cerebellum (pTDP-43 inclusions rarely present). We examined gene expression, cell-type composition, transcript usage (% contribution of a transcript to total gene expression) and alternative splicing, comparing ALS-specific changes between brain regions. We also considered whether post-mortem pTDP-43 pathological stage classification defined ALS subgroups with distinct gene expression profiles. Significant gene expression changes were observed in ALS cases for all five brain regions, with the cerebellum demonstrating the largest number of total (> 3,000) and unique (60%) differentially expressed genes. Pathway enrichment and predicted activity were largely concordant across brain regions, suggesting that ALS-linked mechanisms, including inflammation, mitochondrial dysfunction and oxidative stress, are also dysregulated in non-motor brain regions. Switches in transcript usage were identified for a small set of genes including increased usage of a POLDIP3 transcript, associated with TDP-43 loss-of-function, in the cerebellum and a XBP1 transcript, indicative of unfolded protein response activity, in the motor cortex. Extensive variation in RNA splicing was identified in the ALS brain, with 26–41% of alternatively spliced genes unique to a given brain region. This included detection of TDP-43-associated cryptic splicing events such as the STMN2 cryptic exon which was shown to have a pTDP-43 pathology-specific expression pattern. Finally, ALS patients with stage 4 pTDP-43 pathology demonstrated distinct gene and protein expression changes in the cerebellum. Together our findings highlighted widespread transcriptome alterations in ALS post-mortem brain and showed that, despite the absence of pTDP-43 pathology in the cerebellum, extensive and pTDP-43 pathological stage-specific RNA changes are evident in this brain region.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"69 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143872975","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":"Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities","authors":"Abdel Ali Belaidi, Ashley I. Bush, Scott Ayton","doi":"10.1186/s13024-025-00843-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00843-y","url":null,"abstract":"Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years, the role of apoE has been shown to extend beyond its primary function in lipid transport, influencing multiple biological processes, including amyloid-β (Aβ) aggregation, tau pathology, neuroinflammation, autophagy, cerebrovascular integrity and protection from lipid peroxidation and the resulting ferroptotic cell death. While the detrimental influence of apoE ε4 on these and other processes has been well described, the molecular mechanisms underpinning this disadvantage require further enunciation, particularly to realize therapeutic opportunities related to apoE. This review explores the multifaceted roles of apoE in AD pathogenesis, emphasizing recent discoveries and translational approaches to target apoE-mediated pathways. These findings underscore the potential for apoE-based therapeutic strategies to prevent or mitigate AD in genetically at-risk populations.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143873000","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":"Research models to study lewy body dementia","authors":"Suelen Lucio Boschen, Aarushi A. Mukerjee, Ayman H. Faroqi, Ben E. Rabichow, John Fryer","doi":"10.1186/s13024-025-00837-w","DOIUrl":"https://doi.org/10.1186/s13024-025-00837-w","url":null,"abstract":"Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer’s disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and amyloid plaques. These pathological features position LBD as a comorbid condition of both Parkinson’s disease (PD) and AD, with over 50% of LBD cases exhibiting co-pathologies. LBD’s mixed pathology complicates the development of comprehensive models that reflect the full spectrum of LBD’s etiological, clinical, and pathological features. While existing animal and cellular models have facilitated significant discoveries in PD and AD research, they lack specificity in capturing LBD’s unique pathogenic mechanisms, limiting the exploration of therapeutic avenues for LBD specifically. This review assesses widely used PD and AD models in terms of their relevance to LBD, particularly focusing on their ability to replicate human disease pathology and assess treatment efficacy. Furthermore, we discuss potential modifications to these models to advance the understanding of LBD mechanisms and propose innovative research directions aimed at developing models with enhanced etiological, face, predictive, and construct validity.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"70 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143866695","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}