Pub Date : 2025-11-14DOI: 10.1186/s13024-025-00910-4
Jijing Wang, Julie A. Schneider, David A. Bennett, Nicholas T. Seyfried, Tracy L. Young-Pearse, Hyun-Sik Yang
<p>Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a major cause of late-onset amnestic dementia, yet no diagnostic biomarker is available [1]. The recently published clinical criteria operationally defined “probable LATE” in older individuals with negative Alzheimer’s disease (AD) biomarkers [2]. However, most LATE-NC cases are comorbid with Alzheimer’s disease neuropathologic change (ADNC), and in vivo diagnosis of LATE-NC remains challenging without a specific molecular biomarker [2]. Prior plasma biomarker investigations of other TDP-43 proteinopathies, such as frontotemporal lobar degeneration or amyotrophic lateral sclerosis (ALS), using various TDP-43 immunoassays have shown conflicting results [3]. Measuring peripheral extracellular vesicles (EV) TDP-43 has shown initial promise [4], but EV-based methods are currently limited. Recently, plasma phospho-TDP-43 (pTDP-43) measured with a highly sensitive Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) has been shown to be elevated in ALS [5], and another study showed an association between NULISA-measured plasma pTDP-43 with findings suggestive of underlying LATE-NC (hippocampal atrophy and cognitive decline) [6]. Here, we examine the biomarker potential of plasma TDP-43 measured with NULISA in detecting advanced LATE-NC.</p><p>We analyzed the data from fifty deceased participants from an extensively characterized clinical-pathologic cohort—the Religious Orders Study and the Rush Memory and Aging Project [7] (ROSMAP; <i>N</i> = 18 no/low ADNC cognitively unimpaired controls [“controls”], <i>N</i> = 32 dementia with significant ADNC [“AD”]; Table S1)—who also had plasma NULISA data [8]. LATE-NC stages were documented as follows: stage 0 = none, stage 1 = amygdala only, stage 2 = involving hippocampus/entorhinal cortex, and stage 3 = involving neocortex. We focused on detecting LATE-NC stages 2 and 3 (“advanced LATE-NC”), which are associated with clinically significant cognitive dysfunction [1]. Brain LATE-NC burden was assessed by averaging a 6-point scale TDP-43 cytoplasmic inclusion burden across six brain regions (amygdala, hippocampus CA1/subiculum, dentate gyrus, entorhinal cortex, middle temporal cortex, and midfrontal cortex) [9]. The quantitative amyloid β (Aβ) and tau burden in the brain was measured by immunohistochemistry in eight regions: hippocampus, entorhinal cortex, midfrontal cortex, inferior temporal cortex, angular gyrus, calcarine cortex, anterior cingulate cortex, and superior frontal cortex. Neocortical Lewy body (present/absent), which is associated with cognitive decline, was assessed with α-synuclein immunostaining. Hippocampal sclerosis (HS; severe neuronal loss and gliosis in the CA1/subiculum) was recorded as present/absent. Plasma samples, average 3.8 ± 1.9 years before death, were analyzed using the NULISA CNS Disease Panel (Alamar Biosciences). Data were normalized to internal control and inter-plate control values, lo
{"title":"Plasma TDP-43 is a potential biomarker for advanced limbic-predominant age-related TDP-43 encephalopathy neuropathologic change","authors":"Jijing Wang, Julie A. Schneider, David A. Bennett, Nicholas T. Seyfried, Tracy L. Young-Pearse, Hyun-Sik Yang","doi":"10.1186/s13024-025-00910-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00910-4","url":null,"abstract":"<p>Limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is a major cause of late-onset amnestic dementia, yet no diagnostic biomarker is available [1]. The recently published clinical criteria operationally defined “probable LATE” in older individuals with negative Alzheimer’s disease (AD) biomarkers [2]. However, most LATE-NC cases are comorbid with Alzheimer’s disease neuropathologic change (ADNC), and in vivo diagnosis of LATE-NC remains challenging without a specific molecular biomarker [2]. Prior plasma biomarker investigations of other TDP-43 proteinopathies, such as frontotemporal lobar degeneration or amyotrophic lateral sclerosis (ALS), using various TDP-43 immunoassays have shown conflicting results [3]. Measuring peripheral extracellular vesicles (EV) TDP-43 has shown initial promise [4], but EV-based methods are currently limited. Recently, plasma phospho-TDP-43 (pTDP-43) measured with a highly sensitive Nucleic Acid Linked Immuno-Sandwich Assay (NULISA) has been shown to be elevated in ALS [5], and another study showed an association between NULISA-measured plasma pTDP-43 with findings suggestive of underlying LATE-NC (hippocampal atrophy and cognitive decline) [6]. Here, we examine the biomarker potential of plasma TDP-43 measured with NULISA in detecting advanced LATE-NC.</p><p>We analyzed the data from fifty deceased participants from an extensively characterized clinical-pathologic cohort—the Religious Orders Study and the Rush Memory and Aging Project [7] (ROSMAP; <i>N</i> = 18 no/low ADNC cognitively unimpaired controls [“controls”], <i>N</i> = 32 dementia with significant ADNC [“AD”]; Table S1)—who also had plasma NULISA data [8]. LATE-NC stages were documented as follows: stage 0 = none, stage 1 = amygdala only, stage 2 = involving hippocampus/entorhinal cortex, and stage 3 = involving neocortex. We focused on detecting LATE-NC stages 2 and 3 (“advanced LATE-NC”), which are associated with clinically significant cognitive dysfunction [1]. Brain LATE-NC burden was assessed by averaging a 6-point scale TDP-43 cytoplasmic inclusion burden across six brain regions (amygdala, hippocampus CA1/subiculum, dentate gyrus, entorhinal cortex, middle temporal cortex, and midfrontal cortex) [9]. The quantitative amyloid β (Aβ) and tau burden in the brain was measured by immunohistochemistry in eight regions: hippocampus, entorhinal cortex, midfrontal cortex, inferior temporal cortex, angular gyrus, calcarine cortex, anterior cingulate cortex, and superior frontal cortex. Neocortical Lewy body (present/absent), which is associated with cognitive decline, was assessed with α-synuclein immunostaining. Hippocampal sclerosis (HS; severe neuronal loss and gliosis in the CA1/subiculum) was recorded as present/absent. Plasma samples, average 3.8 ± 1.9 years before death, were analyzed using the NULISA CNS Disease Panel (Alamar Biosciences). Data were normalized to internal control and inter-plate control values, lo","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145509655","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}
Pub Date : 2025-11-04DOI: 10.1186/s13024-025-00908-y
Amy F. Keerie, Raquel Rua Martins, Chloe F. Allen, Katie Bowden, Sufana Al Mashhadi, Thomas Marlow, Monika Myszczynska, Nikitha Thakur, Selina N. Beal, Allan Shaw, Shivani Suresh, Scott N. McKinnon, Johnathan Cooper-Knock, Ryan J. H. West, Sam Bonsall, Alex Daniel, Tyler Wells, Vedanth Kumar, Brittany C. S. Ellis, Maureen Higgins, Albena T. Dinkova-Kostova, Tatyana A. Shelkovnikova, Ira N. Kalfus, Ning Shan, Pamela J. Shaw, Laura Ferraiuolo, Richard J. Mead
M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.
{"title":"M102 activates both NRF2 and HSF1 transcription factor pathways and is neuroprotective in cell and animal models of amyotrophic lateral sclerosis","authors":"Amy F. Keerie, Raquel Rua Martins, Chloe F. Allen, Katie Bowden, Sufana Al Mashhadi, Thomas Marlow, Monika Myszczynska, Nikitha Thakur, Selina N. Beal, Allan Shaw, Shivani Suresh, Scott N. McKinnon, Johnathan Cooper-Knock, Ryan J. H. West, Sam Bonsall, Alex Daniel, Tyler Wells, Vedanth Kumar, Brittany C. S. Ellis, Maureen Higgins, Albena T. Dinkova-Kostova, Tatyana A. Shelkovnikova, Ira N. Kalfus, Ning Shan, Pamela J. Shaw, Laura Ferraiuolo, Richard J. Mead","doi":"10.1186/s13024-025-00908-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00908-y","url":null,"abstract":"M102 is a central nervous system (CNS) penetrant small molecule electrophile which activates in vivo the NF-E2 p45-related factor 2-antioxidant response element (NRF2-ARE) pathway, as well as transcription of heat-shock element (HSE) associated genes. In the TDP-43Q331K transgenic mouse model of ALS dosed subcutaneously at 5 mg/kg OD or 2.5 mg/kg BD with M102, significant improvements in compound muscle action potential (CMAP) amplitude of hind limb muscles and gait parameters were observed at 6 months of age, with associated target engagement. An oral dose response study of M102 in SOD1G93A transgenic mice showed a dose-dependent improvement in CMAP of hindlimb muscles which correlated with preservation of lumbar spinal motor neurons at the same time point. These data enabled prediction of human efficacious exposures and doses, which were well within the safety margin predicted from Good Laboratory Practice (GLP) toxicology studies. A parallel program of work in vitro showed that M102 rescued motor neuron survival in co-culture with patient-derived astrocytes from sporadic, C9orf72 and SOD1 ALS cases. Markers of oxidative stress, as well as indices of TDP-43 proteinopathy were also reduced by exposure to M102 in these in vitro models. This comprehensive package of preclinical efficacy data across two mouse models as well as patient-derived astrocyte toxicity assays, provides a strong rationale for clinical evaluation of M102 in ALS patients. Combined with the development of target engagement biomarkers and the completed preclinical toxicology package, a clear translational pathway to testing in ALS patients has been developed.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"65 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145435097","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}
Pub Date : 2025-11-03DOI: 10.1186/s13024-025-00900-6
Hiroaki Sekiya, Tomoyasu Matsubara, Michael A. DeTure, Dennis W. Dickson
Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.
{"title":"Neuropathology of Lewy body dementia: Lewy-related pathology, α-synuclein oligomers, and comorbid pathologies","authors":"Hiroaki Sekiya, Tomoyasu Matsubara, Michael A. DeTure, Dennis W. Dickson","doi":"10.1186/s13024-025-00900-6","DOIUrl":"https://doi.org/10.1186/s13024-025-00900-6","url":null,"abstract":"Lewy body dementia is the second most common form of neurodegenerative dementia, following Alzheimer’s disease. This umbrella term encompasses dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). The distinction between these two conditions lies in the timing of the onset of cognitive impairment relative to motor symptoms. In DLB, cognitive impairment precedes or coincides with motor symptoms within the first year, whereas in PDD, cognitive decline occurs more than a year after the onset of motor symptoms. Clinically, in addition to cognitive decline, patients with Lewy body dementia have parkinsonism, visual hallucinations, and fluctuations of cognitive status. The pathological hallmark of this condition is the presence of Lewy bodies and Lewy neurites, collectively referred to as Lewy-related pathology. This is identical to Parkinson’s disease, where dementia is not observed. The principal component of Lewy-related pathology is α-synuclein, which classifies this disorder as an α-synucleinopathy. While Lewy-related pathology represents a later stage of α-synuclein aggregation, earlier stages involve α-synuclein oligomers. Emerging evidence suggests α-synuclein oligomers may be more toxic than Lewy-related pathology. In addition to α-synuclein pathology, previous studies frequently observed comorbid pathological conditions, including Alzheimer’s disease neuropathologic change, TAR DNA-binding protein 43 (TDP-43) pathology, and cerebral small vessel disease among others. In this review, we provide a comprehensive overview of the underlying pathologies for Lewy body dementia and their molecular mechanisms and clinical implications. We also discuss concepts including the prion-like propagation hypothesis of α-synuclein, α-synuclein strain hypothesis, and recent advances in machine learning algorithms for analyzing propagation patterns. The purpose of this manuscript is to elucidate these complex pathological conditions, advance our understanding of the disease, and improve diagnostic strategies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145427612","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}
Pub Date : 2025-10-31DOI: 10.1186/s13024-025-00884-3
Martino L. Morella, Bana Al Khayrat, Tim E. Moors, Lisanne in’t Veld, Irene Frigerio, Vinod Udayar, Bram L. van der Gaag, Wilma D. J. van de Berg
The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1–4), with a decline at later stages (5–6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.
{"title":"C-terminus-dependent detection of lysosomal alpha-synuclein in nigral Parkinson’s disease human brain neurons","authors":"Martino L. Morella, Bana Al Khayrat, Tim E. Moors, Lisanne in’t Veld, Irene Frigerio, Vinod Udayar, Bram L. van der Gaag, Wilma D. J. van de Berg","doi":"10.1186/s13024-025-00884-3","DOIUrl":"https://doi.org/10.1186/s13024-025-00884-3","url":null,"abstract":"The abnormal accumulation of alpha-Synuclein (αSyn) within neurons is a hallmark of synucleinopathies, such as Parkinson's disease (PD), and could stem from impaired protein degradation. Genetic, in vitro, and post-mortem studies have suggested that lysosomal dysfunction and impaired proteolytic activity play important roles in the pathogenesis of PD. Lysosomes have been proposed as key sites for αSyn degradation, but direct evidence of the lysosomal localization of endogenous αSyn in the human brain is limited. This study aimed to investigate the localization of αSyn proteoforms, including different post-translational modifications (PTMs), within lysosomes of post-mortem human nigral neurons. We analyzed formalin-fixed, paraffin-embedded brain tissue from donors diagnosed with PD, PD with Dementia (PDD) or incidental Lewy body disease (iLBD). Substantia nigra sections were assessed using an extensive panel of αSyn-specific antibodies, including PTM-specific antibodies, and selected lysosomal markers via multiplex immunofluorescence, confocal and stimulated emission depletion (STED) microscopy. Here, we demonstrate widespread accumulation of αSyn within lysosomes in nigral dopaminergic neuron somas of donors with PD/PDD and iLBD. This lysosomal αSyn appeared morphologically distinct from cytosolic inclusions such as Lewy bodies (LBs) and related macro-aggregates, and was present both in cells with and without these larger αSyn deposits. When present, macro-aggregates were consistently accompanied by ring-shaped lysosomal structures. Compared to other neuronal morphologies, lysosomal αSyn was the most frequent morphology at early Braak stages (1–4), with a decline at later stages (5–6). Interestingly, lysosomal αSyn was detected solely by targeting the N-terminus or the NAC domain of αSyn, and not with antibodies targeting Serine 129-phosphorylated αSyn or other epitopes at the C-terminus (CT), suggesting that lysosome-associated αSyn lacks the CT. Our findings reveal two co-existing pools of neuronal somatic αSyn: a CT-negative lysosome-associated form, and a primarily non-lysosomal CT-positive form. Overall, we provide direct evidence of lysosomal involvement in cellular αSyn metabolism in post-mortem human PD brain.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"68 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145405150","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}
Pub Date : 2025-10-29DOI: 10.1186/s13024-025-00906-0
Xiaoxie Mao, Yan Wang, Ying Luan, Ying Wang, Jie Wang, Wenlin Dai, Yihui Guan, Qi Huang, Roger N. Gunn, Rik Ossenkoppele, Binyin Li, Zijing Li, Qihao Guo, Fang Xie
Various plasma phosphorylated tau species have been shown to be associated with amyloid-β (Aβ) PET and Tau PET in Alzheimer’s disease (AD), but whether APOE ε4 affects the interaction between glial fibrillary acidic protein (GFAP) and phosphorylated tau (pTau), and whether a three-way interaction exists among APOE ε4, GFAP, and pTau that influences AD progression remain unclear. The study included 563 participants from the Chinese Preclinical Alzheimer’s Disease Study (CPAS) and 243 from Alzheimer’s Disease Neuroimaging Initiative (ADNI), all of whom underwent Aβ PET, magnetic resonance imaging (MRI), neuropsychological assessments, and plasma biomarker analyses (GFAP, pTau181, pTau231, pTau217), with subsets undergoing Tau PET. The longitudinal data of 101 participants from ADNI were additionally included. We employed linear regression models with interaction terms to examine how APOE ε4 status and plasma GFAP levels modulate the relationships between plasma pTau biomarkers and AD pathology cross-sectionally and longitudinally. Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p = 0.003 for pTau231; ADNI: β = 0.45, p < 0.001 for pTau181). Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET. Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort. In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV). We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele. These findings underscore the role of reactive astrogliosis in tau propagation and support the utility of plasma biomarkers for AD diagnosis and prognosis.
{"title":"Interplay between astrocyte reactivity and APOE ε4 status is associated with accelerated pTau-related tau pathology in Alzheimer’s disease","authors":"Xiaoxie Mao, Yan Wang, Ying Luan, Ying Wang, Jie Wang, Wenlin Dai, Yihui Guan, Qi Huang, Roger N. Gunn, Rik Ossenkoppele, Binyin Li, Zijing Li, Qihao Guo, Fang Xie","doi":"10.1186/s13024-025-00906-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00906-0","url":null,"abstract":"Various plasma phosphorylated tau species have been shown to be associated with amyloid-β (Aβ) PET and Tau PET in Alzheimer’s disease (AD), but whether APOE ε4 affects the interaction between glial fibrillary acidic protein (GFAP) and phosphorylated tau (pTau), and whether a three-way interaction exists among APOE ε4, GFAP, and pTau that influences AD progression remain unclear. The study included 563 participants from the Chinese Preclinical Alzheimer’s Disease Study (CPAS) and 243 from Alzheimer’s Disease Neuroimaging Initiative (ADNI), all of whom underwent Aβ PET, magnetic resonance imaging (MRI), neuropsychological assessments, and plasma biomarker analyses (GFAP, pTau181, pTau231, pTau217), with subsets undergoing Tau PET. The longitudinal data of 101 participants from ADNI were additionally included. We employed linear regression models with interaction terms to examine how APOE ε4 status and plasma GFAP levels modulate the relationships between plasma pTau biomarkers and AD pathology cross-sectionally and longitudinally. Plasma GFAP and pTau biomarkers (pTau181, pTau231, pTau217) are significantly elevated in Aβ-positive individuals, with stronger Aβ–pTau associations observed in APOE ε4 carriers (CPAS: β = 0.26, p = 0.003 for pTau231; ADNI: β = 0.45, p < 0.001 for pTau181). Across two cohorts, plasma GFAP levels significantly strengthened the associations between pTau biomarkers and Tau PET. Furthermore, subsequent analyses revealed that this modulatory effect of GFAP on the links between pTau and PET-derived pathological changes was more pronounced in APOE ε4 non-carriers, whereas in APOE ε4 carriers, a significant interaction between GFAP and pTau was only observed in specific Braak stage-specific regions within the CPAS cohort. In longitudinal analyses, we also observed stronger pTau181-associated longitudinal tau accumulation in individuals with high GFAP levels (Braak III-IV). We demonstrate that APOE ε4 status critically modulates the relationship between pTau and Aβ pathology, whereas plasma GFAP primarily influences pTau–tau pathology associations, particularly in individuals without APOE ε4 allele. These findings underscore the role of reactive astrogliosis in tau propagation and support the utility of plasma biomarkers for AD diagnosis and prognosis.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"85 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397986","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}
Pub Date : 2025-10-29DOI: 10.1186/s13024-025-00905-1
Claire E. Young, Melanie A. Samuel
Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could serve as a central hub of detection and regulation of body state changes. In addition, improving understanding of how microglia respond to peripheral cues will allow for improved preclinical experimental design. As peripheral cues have the potential to be more readily manipulated than central cues, these interactions also have implications for the treatment of many diseases and neurodegenerative disorders.
{"title":"Microglia sensing of peripheral signals that bridge the brain and body","authors":"Claire E. Young, Melanie A. Samuel","doi":"10.1186/s13024-025-00905-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00905-1","url":null,"abstract":"Microglia are the resident immune cell of the brain, and alterations in microglia signaling have been implicated in many neurodegenerative disorders. While microglia responses to central cues and other brain cell types are well documented, studies are increasingly investigating the impact of peripherally derived signals on microglia function. A diverse array of peripheral cues, including dietary components, hormones, and bacteria metabolites and components from the microbiome cross the blood brain barrier and directly influence microglia state through ligand-receptor interactions. This review highlights the complexity of brain-body interactions from the perspective of microglia function and proposes the idea that microglia could serve as a central hub of detection and regulation of body state changes. In addition, improving understanding of how microglia respond to peripheral cues will allow for improved preclinical experimental design. As peripheral cues have the potential to be more readily manipulated than central cues, these interactions also have implications for the treatment of many diseases and neurodegenerative disorders. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"36 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145397987","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}
The potential neuroprotective effects of antidiabetic treatments have been largely assessed in Alzheimer's disease (AD) and AD-like dementia models, with or without metabolic disorders. In this Line, these effects Have also been addressed in wide population-based studies or in patients with mild cognitive impairment, AD, diabetes or combined pathologies. Most common treatments include glucagon-like peptide 1 receptor agonists; thiazolidinediones; biguanides; sulphonylureas; dipeptidyl peptidase-4 inhibitors, insulin, amylin and others. To assess their impact, we have conducted a systematic search in PubMed to Identify studies addressing the effect of Antidiabetic treatments on AD or AD-like dementia preclinical models And clinical studies, yielding 3560 research items. After screening titles And abstracts, 380 papers met eligibility criteria (original full-text articles, written in English, focused on AD or AD-like dementia, involving antidiabetic treatments, containing data on neuropathological AD markers and/or cognitive function, and conducted in vivo or ex vivo), And 25 additional papers were added through citations, resulting in a Total of 405 primary research articles published between 1996 And 2024. We have reviewed the effects of antidiabetic treatments on tau pathology, neuronal health, oxidative stress and neuroinflammation, vascular alterations, implicated signaling pathways and cognitive function in AD and AD-like dementia preclinical models and patients. Overall, antidiabetic medications represent a promising therapeutic strategy to tackle neurodegeneration and cognitive decline in AD preclinical models. Nevertheless, further research is needed to optimize their clinical effectiveness.
{"title":"Effect of antidiabetic drugs in Alzheimer´s disease: a systematic review of preclinical and clinical studies.","authors":"Miriam Corraliza-Gomez,Maria Vargas-Soria,Monica Garcia-Alloza","doi":"10.1186/s13024-025-00894-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00894-1","url":null,"abstract":"The potential neuroprotective effects of antidiabetic treatments have been largely assessed in Alzheimer's disease (AD) and AD-like dementia models, with or without metabolic disorders. In this Line, these effects Have also been addressed in wide population-based studies or in patients with mild cognitive impairment, AD, diabetes or combined pathologies. Most common treatments include glucagon-like peptide 1 receptor agonists; thiazolidinediones; biguanides; sulphonylureas; dipeptidyl peptidase-4 inhibitors, insulin, amylin and others. To assess their impact, we have conducted a systematic search in PubMed to Identify studies addressing the effect of Antidiabetic treatments on AD or AD-like dementia preclinical models And clinical studies, yielding 3560 research items. After screening titles And abstracts, 380 papers met eligibility criteria (original full-text articles, written in English, focused on AD or AD-like dementia, involving antidiabetic treatments, containing data on neuropathological AD markers and/or cognitive function, and conducted in vivo or ex vivo), And 25 additional papers were added through citations, resulting in a Total of 405 primary research articles published between 1996 And 2024. We have reviewed the effects of antidiabetic treatments on tau pathology, neuronal health, oxidative stress and neuroinflammation, vascular alterations, implicated signaling pathways and cognitive function in AD and AD-like dementia preclinical models and patients. Overall, antidiabetic medications represent a promising therapeutic strategy to tackle neurodegeneration and cognitive decline in AD preclinical models. Nevertheless, further research is needed to optimize their clinical effectiveness.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":"112"},"PeriodicalIF":15.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374048","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}
BACKGROUNDThe accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.METHODSTo this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.RESULTSWe found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.CONCLUSIONSThese findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.
{"title":"Modulation of O-GlcNAc cycling influences α-synuclein amplification, degradation, and associated neuroinflammatory pathology.","authors":"Yongzhen Miao,Ting Zhang,Zhuoya Ma,Huanhuan Du,Qipei Gu,Mengni Jiang,Kangping Xiong,Chun-Feng Liu,Hongrui Meng","doi":"10.1186/s13024-025-00904-2","DOIUrl":"https://doi.org/10.1186/s13024-025-00904-2","url":null,"abstract":"BACKGROUNDThe accumulation and propagation of α-synuclein (α-syn) are hallmark features of Parkinson's disease (PD) and related neurodegenerative disorders. O-GlcNAcylation, an abundant post-translational modification throughout the brain, is regulated by the enzymatic activity of the cycling enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) and has been implicated in altering α-syn toxicity. Nevertheless, the interplay between modulating O-GlcNAc cycling and α-syn aggregation and the propagation of amyloid pathology is not well elucidated.METHODSTo this end, we delivered conformational strains of α-syn in the striatum of mice or neuronal and microglial co-cultured cells following pharmacologically or genetically inhibited OGT and OGA. The substantia nigra was injected with an adeno-associated viral vector coding for α-syn combined with α-syn preformed fibrils to examine α-syn-induced dopaminergic cytotoxicity. The α-syn pathology and spreading, protein O-GlcNAcylation, OGT and OGA levels, microglial inflammation, and behavioral impairments were evaluated. Furthermore, the O-GlcNAc modification and proteolysis status of α-syn under O-GlcNAc cycling modification were also assessed using a combination of approaches, including Click-iT™ O-GlcNAc enzyme labeling, sWGA pulldown, HPLC-MS/MS, and immunohistochemical analysis following proteasome and autophagy-lysosome inhibition.RESULTSWe found that modulation of O-GlcNAc cycling, governed by the two enzymes OGT and OGA, significantly affected α-syn aggregation, propagation, dopaminergic neuronal degeneration, and microglial inflammation. Pathological α-syn transmission to adjacent cells and anatomically connected brain regions was found to suppress recipient cellular O-GlcNAc levels, concomitant with reduced OGT expression. Pharmacological inhibition or genetic knockdown of OGT exacerbated α-syn aggregation, enhanced its intercellular transmission, and intensified NOD-, LRR-, and pyrin domain-containing 3 (NLRP3)-mediated microglial inflammation. Conversely, increasing O-GlcNAcylation via OGA inhibition ameliorated these pathological processes. Furthermore, we demonstrate that enzymatic O-GlcNAcylation significantly regulates the aggregation of fibril-induced initial dimer formation and facilitates the clearance of α-syn aggregates through autophagosome-lysosome flux.CONCLUSIONSThese findings highlight the critical regulatory role of O-GlcNAc modification in α-syn pathology and conformational strain formation, and provide mechanical evidence that enhancing O-GlcNAc modifications alleviates pathological α-syn proteolysis by restoring autophagosome-lysosome flux.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"13 1","pages":"113"},"PeriodicalIF":15.1,"publicationDate":"2025-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145374047","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}
Pub Date : 2025-10-23DOI: 10.1186/s13024-025-00890-5
Frances Theunissen,Loren Flynn,Alfredo Iacoangeli,Ahmad Al Khleifat,Ammar Al-Chalabi,James J Giordano,Masha Strømme,P Anthony Akkari
With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.
{"title":"Entering the era of precision medicine to treat amyotrophic lateral sclerosis.","authors":"Frances Theunissen,Loren Flynn,Alfredo Iacoangeli,Ahmad Al Khleifat,Ammar Al-Chalabi,James J Giordano,Masha Strømme,P Anthony Akkari","doi":"10.1186/s13024-025-00890-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00890-5","url":null,"abstract":"With the disease modifying therapy Qalsody (tofersen) which targets the RNA product of the SOD1 gene, having been shown effective in amyotrophic lateral sclerosis (ALS), the present perspective seeks to explore progress towards the implementation of precision medicine principles in ALS drug development. We address the advances in our understanding of the complex genetic architecture of ALS, including the varying models of genetic contribution to disease, and the importance of understanding population genetics and genetic testing when considering patient selection for clinical studies. Additionally, we discuss the advances in long-read whole-genome sequencing technology and how this method can improve streamlined genetic testing and our understanding of the genetic heterogeneity in ALS. We highlight the recent advances in omics-data for understanding ALS patient sub-groups and how this knowledge should be applied to pre-clinical drug development in a proposed patient profiling workflow, particularly for gene targeted therapies. Finally, we summarise key ethical considerations that are pertinent to equitable care for patients, as we enter the era of precision medicine to treat ALS.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"39 1","pages":"111"},"PeriodicalIF":15.1,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145351490","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}
Pub Date : 2025-10-17DOI: 10.1186/s13024-025-00896-z
Heeyoung An, Sora Kang, Jaejin Shin, Purum Kim, Sunpil Kim, Suyeol Im, Ji Hwan Kim, Keun Woo Lee, Dong Hwan Kim, Jung Hee Park, Min-Ho Park, Jaemin Lee, Sun Kyung Park, Kwang Pyo Kim, Hyeong Min Lee, Jae Ho Lee, Leo S. Choi, Hyun Ju Jeon, Suyeon Yellena Kim, In Young Hwang, Mridula Bhalla, Woojin Won, Hyung Soon Park, Sang-Ku Yoo, Byoung Dae Lee, C. Justin Lee, Youngmi Kim Pak
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes. In this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP+ treatment and overexpression of the A53T mutated α-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin. Vutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in α-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin’s reliance on PON2 for its neuroprotective effects. These findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson’s diseases.
{"title":"Neurotherapeutic effects of Vutiglabridin as a Paraoxonase-2 modulator in preclinical models of Parkinson’s disease","authors":"Heeyoung An, Sora Kang, Jaejin Shin, Purum Kim, Sunpil Kim, Suyeol Im, Ji Hwan Kim, Keun Woo Lee, Dong Hwan Kim, Jung Hee Park, Min-Ho Park, Jaemin Lee, Sun Kyung Park, Kwang Pyo Kim, Hyeong Min Lee, Jae Ho Lee, Leo S. Choi, Hyun Ju Jeon, Suyeon Yellena Kim, In Young Hwang, Mridula Bhalla, Woojin Won, Hyung Soon Park, Sang-Ku Yoo, Byoung Dae Lee, C. Justin Lee, Youngmi Kim Pak","doi":"10.1186/s13024-025-00896-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00896-z","url":null,"abstract":"Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease characterized by motor impairment resulting from the degeneration of dopaminergic neurons in the substantia nigra, alongside α -synuclein (α-syn) accumulation, mitochondrial dysfunction, and oxidative stress. Recent studies on PD treatment have focused primarily on exploring oxidative stress and mitochondrial function as ways to restore dopamine release. Notably, previous studies have demonstrated that Paraoxonase 2 (PON2) plays a critical role in neuroprotection and neuroinflammation by reducing oxidative stress in striatal neurons and astrocytes. In this study, we investigated the potential therapeutic effect of a newly developed drug, Vutiglabridin, which is demonstrated to augment the activity of PON2 in the mouse model of PD. We assessed the impact of Vutiglabridin in a PD model induced by MPP+ treatment and overexpression of the A53T mutated α-syn. Furthermore, we administered Vutiglabridin subsequent to PON2 gene knockdown through PON2-shRNA overexpression to elucidate the interplay between PON2 and Vutiglabridin. Vutiglabridin effectively crosses the blood-brain barrier (BBB) and maintains a presence in the brain for over 24 h, achieving concentrations up to 2.5 times higher than in the bloodstream. It successfully binds to PON2 in both its (R) and (S) forms. Vutiglabridin reversed mitochondrial dysfunction, reduced oxidative stress, improved motor functions, and protected dopaminergic neurons against MPP+-induced damage. Similarly, in α-syn A53T overexpressed PD models, it not only reduced astrocytic reactivity and microglia activation but also doubled the tyrosine hydroxylase positive neurons /dopa decarboxylase positive neurons (TH+/DDC+) ratio, signifying enhanced neuronal health. However, these positive outcomes were absent in PON2-knockdown mice, underscoring Vutiglabridin’s reliance on PON2 for its neuroprotective effects. These findings indicate that Vutiglabridin may serve as a promising therapeutic approach for reducing reactive oxygen species (ROS) levels by modulating PON2 activity in Parkinson’s diseases.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145311257","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}
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