Pub Date : 2025-09-26DOI: 10.1186/s13024-025-00891-4
Doris Chen, Stella Wigglesworth-Littlewood, Frank J. Gunn-Moore
The Hippo signaling pathway is well-known for its regulation of organ size, cell proliferation, apoptosis, and cell migration and differentiation. Recent studies have demonstrated that Hippo signaling also plays important roles in the nervous system, being involved in neuroinflammation, neuronal differentiation, and neuronal death and degeneration. As such, dysregulation of Hippo signaling, particularly of its core kinases MST1/2 and LATS1/2, has begun to attract attention in the Alzheimer’s disease (AD) field. Here, we discuss the therapeutic potential of targeting the Hippo pathway in AD by providing an overview of Hippo signaling with regards to its function in the nervous system, evidence for its dysregulation in AD patients and models, and recent studies involving genetic or pharmacological modulation of this pathway in AD.
{"title":"The Hippo signaling pathway as a therapeutic target in Alzheimer’s disease","authors":"Doris Chen, Stella Wigglesworth-Littlewood, Frank J. Gunn-Moore","doi":"10.1186/s13024-025-00891-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00891-4","url":null,"abstract":"The Hippo signaling pathway is well-known for its regulation of organ size, cell proliferation, apoptosis, and cell migration and differentiation. Recent studies have demonstrated that Hippo signaling also plays important roles in the nervous system, being involved in neuroinflammation, neuronal differentiation, and neuronal death and degeneration. As such, dysregulation of Hippo signaling, particularly of its core kinases MST1/2 and LATS1/2, has begun to attract attention in the Alzheimer’s disease (AD) field. Here, we discuss the therapeutic potential of targeting the Hippo pathway in AD by providing an overview of Hippo signaling with regards to its function in the nervous system, evidence for its dysregulation in AD patients and models, and recent studies involving genetic or pharmacological modulation of this pathway in AD. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"94 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141545","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 : 2025-09-26DOI: 10.1186/s13024-025-00889-y
Christof Brücke, Mohammed Al-Azzani, Nagendran Ramalingam, Maria Ramón, Rita L. Sousa, Fiamma Buratti, Michael Zech, Kevin Sicking, Leslie Amaral, Ellen Gelpi, Aswathy Chandran, Aishwarya Agarwal, Susana R. Chaves, Claudio O. Fernández, Ulf Dettmer, Janin Lautenschläger, Markus Zweckstetter, Ruben Fernandez Busnadiego, Alexander Zimprich, Tiago Fleming Outeiro
Parkinson’s disease (PD) affects millions of people worldwide, but only 5–10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation. A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing—whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine‐129 phosphorylation. The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.
帕金森病（PD）影响着全世界数百万人，但只有5-10%的患者患有孟德尔遗传的单基因形式的疾病。编码α -突触核蛋白（aSyn）的基因SNCA是第一个与家族性帕金森病相关的基因，从那时起，该基因的一些错义变异和增殖已被确定为常染色体显性帕金森病的罕见病因。在这项研究中，我们报告了一种新的SNCA突变在患者的鉴定，该患者表现为复杂的神经生成障碍，并有非常规的神经病理结果。我们还进行了深入的分子研究的影响，新的aSyn突变。本文对1例新型aSyn错义突变患者及其家庭成员进行了研究。我们提出临床特征，基因检测-全外显子组测序（WES）和神经病理结果。使用生化、生物物理和细胞分析广泛研究了这种aSyn变异的功能后果。患者表现出复杂的神经退行性疾病，包括全身性肌阵挛、运动迟缓、左臂肌张力障碍和失用症。WES鉴定出一种新的杂合SNCA变异（cDNA 40G > a; protein G14R）。神经病理检查显示广泛的非典型aSyn病理，伴有额颞叶变性（FTLD）型分布和神经变性模式，伴丰富的环状神经元包涵体和少量少突胶质包涵体。Sanger测序在患者的一位86岁的健康父母中证实了SNCA变异，表明不完全外显。核磁共振研究表明，G14R突变诱导了aSyn的局部结构改变，并在体外纤化实验中降低了硫黄素T的结合。有趣的是，G14R aSyn纤维在低温电子显微镜下显示出与路易体不同的纤维形态。G14R变异体的细胞研究显示，包涵体形成增加，膜结合增强，丝氨酸- 129磷酸化的动态可逆性受损。观察到的非典型神经病理特征与G51D aSyn变体相似，表明SNCA变体具有独特的临床和病理表型，这进一步得到了突变型aSyn的特性的支持。
{"title":"A novel alpha-synuclein G14R missense variant is associated with atypical neuropathological features","authors":"Christof Brücke, Mohammed Al-Azzani, Nagendran Ramalingam, Maria Ramón, Rita L. Sousa, Fiamma Buratti, Michael Zech, Kevin Sicking, Leslie Amaral, Ellen Gelpi, Aswathy Chandran, Aishwarya Agarwal, Susana R. Chaves, Claudio O. Fernández, Ulf Dettmer, Janin Lautenschläger, Markus Zweckstetter, Ruben Fernandez Busnadiego, Alexander Zimprich, Tiago Fleming Outeiro","doi":"10.1186/s13024-025-00889-y","DOIUrl":"https://doi.org/10.1186/s13024-025-00889-y","url":null,"abstract":"Parkinson’s disease (PD) affects millions of people worldwide, but only 5–10% of patients suffer from a monogenic forms of the disease with Mendelian inheritance. SNCA, the gene encoding for the protein alpha-synuclein (aSyn), was the first to be associated with familial forms of PD and, since then, several missense variants and multiplications of the gene have been established as rare causes of autosomal dominant forms of PD. In this study, we report the identification of a novel SNCA mutation in a patient that presented with a complex neurogenerative disorder, and unconventional neuropathological findings. We also performed in depth molecular studies of the effects of the novel aSyn mutation. A patient carrying the novel aSyn missense mutation and the family members were studied. We present the clinical features, genetic testing—whole exome sequencing (WES), and neuropathological findings. The functional consequences of this aSyn variant were extensively investigated using biochemical, biophysical, and cellular assays. The patient exhibited a complex neurodegenerative disease that included generalized myocloni, bradykinesia, dystonia of the left arm and apraxia. WES identified a novel heterozygous SNCA variant (cDNA 40G > A; protein G14R). Neuropathological examination showed extensive atypical aSyn pathology with frontotemporal lobar degeneration (FTLD)-type distribution and nigral degeneration pattern with abundant ring-like neuronal inclusions, and few oligodendroglial inclusions. Sanger sequencing confirmed the SNCA variant in one healthy, 86-year-old parent of the patient suggesting incomplete penetrance. NMR studies suggest that the G14R mutation induces a local structural alteration in aSyn, and lower thioflavin T binding in in vitro fibrillization assays. Interestingly, the G14R aSyn fibers display different fibrillar morphologies than Lewy bodies as revealed by cryo-electron microscopy. Cellular studies of the G14R variant revealed increased inclusion formation, enhanced membrane association, and impaired dynamic reversibility of serine‐129 phosphorylation. The atypical neuropathological features observed, which are reminiscent of those observed for the G51D aSyn variant, suggest a causal role of the SNCA variant with a distinct clinical and pathological phenotype, which is further supported by the properties of the mutant aSyn.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"73 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145141487","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 : 2025-09-02DOI: 10.1186/s13024-025-00888-z
Kamil Borkowski, Nuanyi Liang, Na Zhao, Matthias Arnold, Kevin Huynh, Naama Karu, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Takahisa Kanekiyo, Guojun Bu, Rima Kaddurah-Daouk
Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.
{"title":"APOE genotype influences on the brain metabolome of aging mice – role for mitochondrial energetics in mechanisms of resilience in APOE2 genotype","authors":"Kamil Borkowski, Nuanyi Liang, Na Zhao, Matthias Arnold, Kevin Huynh, Naama Karu, Siamak Mahmoudiandehkordi, Alexandra Kueider-Paisley, Takahisa Kanekiyo, Guojun Bu, Rima Kaddurah-Daouk","doi":"10.1186/s13024-025-00888-z","DOIUrl":"https://doi.org/10.1186/s13024-025-00888-z","url":null,"abstract":"Alzheimer’s disease (AD) risk and progression are significantly influenced by APOE genotype with APOE4 increasing and APOE2 decreasing susceptibility compared to APOE3. While the effect of those genotypes was extensively studied on blood metabolome, less is known about their impact in the brain. Here we investigated the impacts of APOE genotypes and aging on brain metabolic profiles across the lifespan, using human APOE-targeted replacement mice. Biocrates P180 targeted metabolomics platform was used to measure a broad range of metabolites probing various metabolic processes. In all genotypes investigated we report changes in acylcarnitines, biogenic amines, amino acids, phospholipids and sphingomyelins during aging. The decreased ratio of medium to long-chain acylcarnitine suggests a reduced level of fatty acid β-oxidation and thus the possibility of mitochondrial dysfunction as these animals age. Additionally, aging APOE2/2 mice had altered branch-chain amino acids (BCAA) profile and increased their downstream metabolite C5 acylcarnitine, indicating increased branched-chain amino acid utilization in TCA cycle and better energetic profile endowed by this protective genotype. We compared these results with human dorsolateral prefrontal cortex metabolomic data from the Religious Orders Study/Memory and Aging Project, and we found that the carriers of APOE2/3 genotype had lower markers of impaired BCAA katabolism, including tiglyl carnitine, methylmalonate and 3-methylglutaconate. In summary, these results suggest a potential involvement of the APOE2 genotype in BCAA utilization in the TCA cycle and nominate these humanized APOE mouse models for further study of APOE in AD, brain aging, and brain BCAA utilization for energy. We have previously shown lower plasma BCAA to be associated with incident dementia, and their higher levels in brain with AD pathology and cognitive impairment. Those findings together with our current results could potentially explain the AD-protective effect of APOE2 genotype by enabling higher utilization of BCAA for energy during the decline of fatty acid β-oxidation.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"60 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144928257","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 : 2025-08-29DOI: 10.1186/s13024-025-00883-4
Brandon B. Holmes, Thaddeus K. Weigel, Jesseca M. Chung, Sarah K. Kaufman, Brandon I. Apresa, James R. Byrnes, Kaan S. Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V. L. Rose, Yun Zhang, Alissa L. Nana, Dina Alter, Lea T. Grinberg, Salvatore Spina, Kevin K. Leung, Bruce L. Miller, Carlo Condello, Martin Kampmann, William W. Seeley, Jaeda C. Coutinho-Budd, James A. Wells
To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.
{"title":"β-Amyloid induces microglial expression of GPC4 and APOE leading to increased neuronal tau pathology and toxicity","authors":"Brandon B. Holmes, Thaddeus K. Weigel, Jesseca M. Chung, Sarah K. Kaufman, Brandon I. Apresa, James R. Byrnes, Kaan S. Kumru, Jaime Vaquer-Alicea, Ankit Gupta, Indigo V. L. Rose, Yun Zhang, Alissa L. Nana, Dina Alter, Lea T. Grinberg, Salvatore Spina, Kevin K. Leung, Bruce L. Miller, Carlo Condello, Martin Kampmann, William W. Seeley, Jaeda C. Coutinho-Budd, James A. Wells","doi":"10.1186/s13024-025-00883-4","DOIUrl":"https://doi.org/10.1186/s13024-025-00883-4","url":null,"abstract":"To define how Aβ pathology alters microglia function in Alzheimer’s disease, we profiled the microglia surfaceome following treatment with Aβ fibrils. Our findings reveal that Aβ-associated human microglia upregulate Glypican 4 (GPC4), a GPI-anchored heparan sulfate proteoglycan (HSPG). Glial GPC4 expression exacerbates motor deficits and reduces lifespan in a Drosophila amyloidosis model, implicating GPC4 in a toxic neurodegenerative program. In cell culture, GPC4 enhances microglia phagocytosis of tau aggregates, and shed GPC4 can act in trans to facilitate tau aggregate uptake and seeding in neurons. Additionally, our data demonstrate that GPC4-mediated effects are amplified in the presence of APOE. In human Alzheimer’s disease brain, microglial GPC4 expression surrounding Aβ plaques correlates with neuritic tau pathology, supporting a pathological link between amyloid, GPC4, and tau. These studies define a mechanistic pathway by which Aβ primes microglia to promote tau pathology via HSPGs and APOE.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"82 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915357","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 : 2025-08-29DOI: 10.1186/s13024-025-00886-1
Denise Balta, Anish Varghese, Susy Prieto Huarcaya, Alessandro Di Spiezio, André R. A. Marques, Enes Yağız Akdaş, Doğa Tabakacilar, Alice Drobny, Christian Werner, Wei Xiang, Rebecca Mächtel, Jan Philipp Dobert, Anna Fejtova, Franziska Richter, Melanie Küspert, Philipp Arnold, Paul Saftig, Friederike Zunke
The autophagy-lysosomal pathway is crucial for maintaining homeostasis and survival of neurons, hence defects in this system have been associated with neurodegeneration, including Parkinson's disease (PD). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related proteins such as amyloid- $$:{upbeta:}$$ , huntingtin and the prion protein. While there are studies implicating CTSB and CTSL as mediators of α-synuclein/SNCA clearance, their exact roles remain unclear. We previously demonstrated that recombinant procathepsin D can enhance the clearance of pathological-aggregates of SNCA both in vitro and in vivo, as well as restoring autophagy function. These results prompted us to investigate the role of the two cysteine proteases CTSB and CTSL regarding SNCA degradation by dosing recombinant human procathepsin B (rHsCTSB) and procathepsin L (rHsCTSL) alone or in combination. We here demonstrate that both proteases are efficiently endocytosed by neuronal cells and transported to lysosomes, where they undergo maturation into active enzymes. Treatment with either rHsCTSB or rHsCTSL resulted in a reduction of different SNCA species, present in Triton-insoluble protein fractions as well as sensitive for various pathology- and structure-specific antibodies analyzed via Western blot, immunofluorescence and ELISA. These effects were found to be similar in all models used here: dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the SNCA A53T mutation, ex vivo organotypic brain slices and primary neuronal cultures of human SNCA overexpressing Thy1 mice. Interestingly, our data so far do not indicate a synergistic effect of both cysteine cathepsins when applied together. As proof-of-concept for future therapeutic studies, intracranial injections of both recombinant enzymes reduced SNCA in brains of a transgenic mouse model (Ctsd knockout) harboring SNCA pathology. Moreover, treatment with recombinant CTSB and CTSL improved lysosomal/autophagy functions indicated by recovery of β-glucocerebrosidase (GCase) activity and SQSTM1 (p62) level. Further, SNCA-dependent synaptic defects as well as toxicity was reduced after treatment of neuronal cells. These findings suggest that enhancing lysosomal CTSB or CTSL effectively degrades pathology-associated SNCA, suggesting a potential therapeutic protease-based strategy for PD and other synucleinopathies.
{"title":"Recombinant cathepsins B and L promote α-synuclein clearance and restore lysosomal function in human and murine models with α-synuclein pathology","authors":"Denise Balta, Anish Varghese, Susy Prieto Huarcaya, Alessandro Di Spiezio, André R. A. Marques, Enes Yağız Akdaş, Doğa Tabakacilar, Alice Drobny, Christian Werner, Wei Xiang, Rebecca Mächtel, Jan Philipp Dobert, Anna Fejtova, Franziska Richter, Melanie Küspert, Philipp Arnold, Paul Saftig, Friederike Zunke","doi":"10.1186/s13024-025-00886-1","DOIUrl":"https://doi.org/10.1186/s13024-025-00886-1","url":null,"abstract":"The autophagy-lysosomal pathway is crucial for maintaining homeostasis and survival of neurons, hence defects in this system have been associated with neurodegeneration, including Parkinson's disease (PD). The cysteine proteases cathepsin B (CTSB) and cathepsin L (CTSL) are involved in the clearance of various neurodegenerative disease-related proteins such as amyloid- $$:{upbeta:}$$ , huntingtin and the prion protein. While there are studies implicating CTSB and CTSL as mediators of α-synuclein/SNCA clearance, their exact roles remain unclear. We previously demonstrated that recombinant procathepsin D can enhance the clearance of pathological-aggregates of SNCA both in vitro and in vivo, as well as restoring autophagy function. These results prompted us to investigate the role of the two cysteine proteases CTSB and CTSL regarding SNCA degradation by dosing recombinant human procathepsin B (rHsCTSB) and procathepsin L (rHsCTSL) alone or in combination. We here demonstrate that both proteases are efficiently endocytosed by neuronal cells and transported to lysosomes, where they undergo maturation into active enzymes. Treatment with either rHsCTSB or rHsCTSL resulted in a reduction of different SNCA species, present in Triton-insoluble protein fractions as well as sensitive for various pathology- and structure-specific antibodies analyzed via Western blot, immunofluorescence and ELISA. These effects were found to be similar in all models used here: dopaminergic neurons derived from induced pluripotent stem cells (iPSC) of PD patients harboring the SNCA A53T mutation, ex vivo organotypic brain slices and primary neuronal cultures of human SNCA overexpressing Thy1 mice. Interestingly, our data so far do not indicate a synergistic effect of both cysteine cathepsins when applied together. As proof-of-concept for future therapeutic studies, intracranial injections of both recombinant enzymes reduced SNCA in brains of a transgenic mouse model (Ctsd knockout) harboring SNCA pathology. Moreover, treatment with recombinant CTSB and CTSL improved lysosomal/autophagy functions indicated by recovery of β-glucocerebrosidase (GCase) activity and SQSTM1 (p62) level. Further, SNCA-dependent synaptic defects as well as toxicity was reduced after treatment of neuronal cells. These findings suggest that enhancing lysosomal CTSB or CTSL effectively degrades pathology-associated SNCA, suggesting a potential therapeutic protease-based strategy for PD and other synucleinopathies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"23 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915751","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}
Alzheimer’s disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.
{"title":"MS4A6A/Ms4a6d deficiency disrupts neuroprotective microglia functions and promotes inflammation in Alzheimer’s disease model","authors":"Hai-Shan Jiao, Yi-Jun Ge, Liang-Yu Huang, Ying Liu, Bang-Sheng Wu, Piao-Piao Lian, Yi-Ning Hao, Shan-Shan Han, Yi-Ting Li, Kai-Min Wu, Chen-Yun Wu, Tian-Lin Cheng, Peng Yuan, Jin-Tai Yu","doi":"10.1186/s13024-025-00887-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00887-0","url":null,"abstract":"Alzheimer’s disease (AD) is the most common type of dementia. Genetic polymorphisms are associated with altered risks of AD onset, pointing to biological processes and potential targets for interventions. Consistent with the important roles of microglia in AD development, genetic mutations of several genes expressed on microglia have been identified as risks for AD. Emerging evidences indicate that the expression of a microglia-specific gene MS4A6A is thought to be associated with AD, since AD patients show upregulation of MS4A6A, and its levels correlate with the severity of clinical neuropathology. However, the mechanism linking MS4A6A and AD has not been experimentally studied. We performed a meta genome-wide association analysis with 734,121 subjects to examine the associations between polymorphisms of MS4A6A with AD risks. In addition, we analyzed the correlation between MS4A6A and AD-related cerebrospinal fluid biomarkers from our own cohort. Furthermore, we for the first time generated a Ms4a6d deficient APP/PS1 model, and systematically examined pathological changes using high-resolution microscopy, biochemistry, and behavioral analysis. We identified several new mutations of MS4A6A with altered AD risks, and discovered specific correlation for some of them with the amount of β-amyloid in cerebrospinal fluid. Protective variant of MS4A6A is associated with elevated expression of the gene. Deficient Ms4a6d led to reduced amyloid clearance in the brain. Immunostaining from postmortem AD patients brain revealed selective expression of MS4A6A in microglia. In APP/PS1 mice lacking Ms4a6d, microglia showed markedly diminished envelopment and phagocytosis of amyloid, leading to increased plaque burden, less compact structure, and more severe synaptic damage. Importantly, Ms4a6d deficiency markedly exacerbated inflammatory responses in both microglia and astrocytes by disinhibiting NF-κB signaling. Overexpressing MS4A6A in human microglia cell line promoted gene expression related to plaque-associated responses and diminished inflammation signatures. Our findings reveal that Ms4a6d deficiency suppresses neuroprotection and worsens neuroinflammation. Sufficient Ms4a6d maybe beneficial for boosting amyloid-related responses and suppressing inflammation in microglia, making it superior than previously reported candidates for microglia modulation. Thus, the elevated MS4A6A levels in AD are likely compensatory and boosting MS4A6A could be an effective treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"11 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144915356","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 : 2025-08-27DOI: 10.1186/s13024-025-00882-5
Yanaika S. Hok-A-Hin, Lisa Vermunt, Carel F.W. Peeters, Emma L. van der Ende, Sterre C.M. de Boer, Lieke H. Meeter, Julie de Houwer, Harro Seelaar, John C. van Swieten, William T. Hu, Alberto Lleó, Daniel Alcolea, Sebastiaan Engelborghs, Anne Sieben, Alice Chen-Plotkin, David J. Irwin, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Charlotte E. Teunissen, Marta del Campo
Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.
{"title":"Large-scale CSF proteome profiling identifies biomarkers for accurate diagnosis of frontotemporal dementia","authors":"Yanaika S. Hok-A-Hin, Lisa Vermunt, Carel F.W. Peeters, Emma L. van der Ende, Sterre C.M. de Boer, Lieke H. Meeter, Julie de Houwer, Harro Seelaar, John C. van Swieten, William T. Hu, Alberto Lleó, Daniel Alcolea, Sebastiaan Engelborghs, Anne Sieben, Alice Chen-Plotkin, David J. Irwin, Wiesje M. van der Flier, Yolande A.L. Pijnenburg, Charlotte E. Teunissen, Marta del Campo","doi":"10.1186/s13024-025-00882-5","DOIUrl":"https://doi.org/10.1186/s13024-025-00882-5","url":null,"abstract":"Diagnosis of Frontotemporal dementia (FTD) and its specific underlying neuropathologies (frontotemporal lobar degeneration; FTLD-Tau and FTLD-TDP) are challenging, and thus, fluid biomarkers are needed to improve diagnostic accuracy. We used proximity extension assays to analyze 665 proteins in cerebrospinal fluid (CSF) samples from a multicenter cohort, which included patients with FTD (n = 189), Alzheimer’s Disease dementia (AD; n = 232), and cognitively unimpaired individuals (n = 196). In a subset, FTLD neuropathology was determined based on phenotype or genotype (FTLD-Tau = 87 and FTLD-TDP = 67). Differences in protein expression profiles were analyzed using nested linear models. Penalized generalized linear modeling was used to identify classification protein panels, which were translated to custom multiplex assays and validated in two clinical cohorts (cohort 1: n = 161; cohort 2: n = 162), one autopsy-confirmed cohort (n = 100), and one genetic cohort (n = 55). Forty-three proteins were differentially regulated in FTD compared to controls and AD, reflecting axon development, regulation of synapse assembly, and cell-cell adhesion mediator activity pathways. Classification analysis identified a 14- and 13-CSF protein panel that discriminated FTD from controls (FTD diagnostic panel, AUC: 0.96) or AD (FTD differential diagnostic panel, AUC: 0.91). Custom multiplex panels confirmed the strong discriminative performancen between FTD and controls (AUCs > 0.96) and between FTD and AD (AUCs > 0.88) across three validation cohorts, including one with autopsy confirmation (AUCs > 0.90). Validation in genetic FTD (including C9orf72, GRN, and MAPT mutation carriers) revealed high accuracy of the FTD diagnostic panel in identifying both the presymptomatic (AUCs > 0.95) and symptomatic (AUC: 1) stages. Six proteins were differentially regulated between FTLD-TDP and FTLD-Tau. However, a reproducible classification model could not be generated (AUC: 0.80). Overall, this study introduces novel FTD-specific biomarker panels with potential use in diagnostic settings.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"24 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144906471","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 : 2025-08-20DOI: 10.1186/s13024-025-00878-1
Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass
Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.
{"title":"Early intervention anti-Aβ immunotherapy attenuates microglial activation without inducing exhaustion at residual plaques.","authors":"Lis de Weerd, Selina Hummel, Stephan A Müller, Iñaki Paris, Thomas Sandmann, Marie Eichholtz, Robin Gröger, Amelie L Englert, Stephan Wagner, Connie Ha, Sonnet S Davis, Valerie Warkins, Dan Xia, Brigitte Nuscher, Anna Berghofer, Marvin Reich, Astrid F Feiten, Kai Schlepckow, Michael Willem, Stefan F Lichtenthaler, Joseph W Lewcock, Kathryn M Monroe, Matthias Brendel, Christian Haass","doi":"10.1186/s13024-025-00878-1","DOIUrl":"10.1186/s13024-025-00878-1","url":null,"abstract":"<p><p>Anti-amyloid β-peptide (Aβ) immunotherapy was developed to reduce amyloid plaque pathology and slow cognitive decline during progression of Alzheimer's disease. Efficient amyloid clearance has been proven in clinical trials testing anti-Aβ antibodies, by their impact on cognitive endpoints correlating with the extent of amyloid removal. However, treatment is associated with adverse side effects, such as oedema and haemorrhages, which are potentially linked to the induced immune response. To improve the safety profile of these molecules, it is imperative to understand the consequences of anti-Aβ antibody treatment on immune cell function. Here, we investigated the effects of long-term chronic anti-Aβ treatment on amyloid plaque pathology and microglial response in the APP-SAA triple knock-in mouse model with an intervention paradigm early during amyloidogenesis. Long-term treatment with anti-Aβ results in a robust and dose-dependent lowering of amyloid plaque pathology, with a higher efficiency for reducing diffuse over dense-core plaque deposition. Analysis of the CSF proteome indicates a reduction of markers for neurodegeneration including Tau and α-Synuclein, as well as immune-cell-related proteins. Bulk RNA-seq revealed a dose-dependent attenuation of disease-associated microglial (DAM) and glycolytic gene expression, which is supported by a parallel decrease of glucose uptake and protein levels of Triggering Receptor Expressed on Myeloid cells 2 (Trem2) protein, a major immune receptor involved in DAM activation of microglia. In contrast, DAM activation around residual plaques remains high, regardless of treatment dose. In addition, microglia surrounding residual plaques display a dose-dependent increase in microglial clustering and a selective increase in antigen-presenting and immune signalling proteins. These findings demonstrate that chronic early intervention by an anti-amyloid immunotherapy leads to a dose-dependent decrease in plaque formation, which is associated with lower brain-wide microglial DAM activation and neurodegeneration. Microglia at residual plaques still display a combined DAM and antigen-presenting phenotype that suggests a continued treatment response.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"20 1","pages":"92"},"PeriodicalIF":17.5,"publicationDate":"2025-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12366171/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144883201","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}
Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.
{"title":"Lewy body dementia: exploring biomarkers and pathogenic interactions of amyloid β, tau, and α-synuclein","authors":"Jingfeng Liang, Rongzhen Li, Garry Wong, Xiaobing Huang","doi":"10.1186/s13024-025-00879-0","DOIUrl":"https://doi.org/10.1186/s13024-025-00879-0","url":null,"abstract":"Lewy body dementia (LBD) is a neurodegenerative disorder characterized by a combination of progressive dementia and spontaneous parkinsonian symptoms. As the second most prevalent form of neurodegenerative dementia after Alzheimer’s disease (AD), LBD necessitates a deeper understanding of its pathogenesis to enable the development of targeted therapeutic interventions. While numerous reviews focus on documenting the clinical manifestations and therapeutic modalities for LBD, animal models provide valuable insights into the underlying mechanisms and potential therapeutic strategies. In this review, we systematically analyze the hallmarks of LBD pathogenesis, genetic risk factors, clinical features, and treatment strategies. Importantly, we emphasize and critically evaluate the pivotal role of animal models in LBD research in advancing our understanding of this disorder, offering a comprehensive framework to elucidate the interactions among misfolded proteins and their role in LBD pathogenesis. Our review proposes new directions for LBD therapeutic management and facilitates the development of innovative pharmacological interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"37 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2025-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144819215","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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