Pub Date : 2025-02-01DOI: 10.1016/j.nbd.2024.106775
Hiroto Nakano , Sadao Hikishima , Makoto Mori , Jota Minamikawa , Daiki Muramatsu , Yasuhiro Sakashita , Tokuhei Ikeda , Moeko Noguchi-Shinohara , David B. Teplow , Kenjiro Ono
The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.
225 < 250 words.
淀粉样β蛋白(a β)在细胞外空间积聚,形成不溶性斑块,是阿尔茨海默病(AD)的主要病理过程。在Aβ聚集过程中出现的各种Aβ物种中,Aβ低聚物被认为是最具神经毒性的形式。然而,它们在Aβ聚集级联中的分子功能的确切机制迄今尚未明确。本研究旨在揭示球形Aβ低聚物(gAβO)在体外条件下的结构和功能特征。我们对低分子量(LMW) Aβ42进行了硫黄素T (ThT)测定,检测了不同浓度的Aβ42成熟原纤维(MF)种子和a β o。利用高速原子力显微镜(HS-AFM)连续观察了不同样品条件下LMW a - β42的纤维形成情况。利用圆二色光谱分析了Aβ42聚集体在gAβO存在下的构象变化。ThT分析和HS-AFM观察结果表明,gAβO促进了LMW a - β42的纤维形成,而gAβO本身不形成纤维聚集体,说明gAβO对LMW a - β42的聚集具有催化作用。我们还发现,反应缓冲液中MF种子的存在和数量改变了Aβ o的分子相互作用,表明不同Aβ物种之间存在复杂的相互作用。我们目前的研究结果表明,gAβO可能在AD发病过程中具有显著的加速Aβ聚集的作用。225
{"title":"Globular-shaped Aβ oligomers have diverse mechanisms for promoting Aβ aggregations with the facilitation of fibril elongation","authors":"Hiroto Nakano , Sadao Hikishima , Makoto Mori , Jota Minamikawa , Daiki Muramatsu , Yasuhiro Sakashita , Tokuhei Ikeda , Moeko Noguchi-Shinohara , David B. Teplow , Kenjiro Ono","doi":"10.1016/j.nbd.2024.106775","DOIUrl":"10.1016/j.nbd.2024.106775","url":null,"abstract":"<div><div>The accumulation of amyloid β-proteins (Aβ) in the extracellular space, forming insoluble plaques, is a primary pathological process underlying Alzheimer's disease (AD). Among the various Aβ species that appear during Aβ aggregation, Aβ oligomers are considered the most neurotoxic form. However, the precise mechanisms of their molecular functions within the Aβ aggregation cascade have not been clarified so far. This research aimed to uncover the structural and functional characteristics of globular-shaped Aβ oligomers (gAβO) under in vitro conditions. We performed thioflavin T (ThT) assays on low-molecular-weight (LMW) Aβ42, testing different concentrations of Aβ42 mature fibril (MF) seeds and gAβO. Fibril formation was continuously observed using high-speed atomic force microscopy (HS-AFM) in LMW Aβ42 with different sample conditions. Conformational changes of Aβ42 aggregates in the presence of gAβO was also evaluated using circular dichroism spectroscopy. The results of the ThT analysis and HS-AFM observation indicated that gAβO promoted fibril formation of LMW Aβ42 while gAβO itself did not form fibrous aggregates, indicating that gAβO would have a catalytic effects on LMW Aβ42 aggregation. We also showed that the molecular interaction of gAβO was altered by the presence and amount of MF seeds in the reaction buffers, indicating that complex interactions would exist among different Aβ species. The results of our present research demonstrated that gAβO would have significant roles to accelerate Aβ aggregation in AD pathogenesis.</div><div>225 < 250 words.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106775"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142886020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.nbd.2025.106793
Valentina Naef , Devid Damiani , Rosario Licitra , Maria Marchese , Stefania Della Vecchia , Matteo Baggiani , Letizia Brogi , Daniele Galatolo , Silvia Landi , Filippo Maria Santorelli
Biallelic mutations in the SACS gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish knock-out strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.
{"title":"Modeling sacsin depletion in Danio Rerio offers new insight on retinal defects in ARSACS","authors":"Valentina Naef , Devid Damiani , Rosario Licitra , Maria Marchese , Stefania Della Vecchia , Matteo Baggiani , Letizia Brogi , Daniele Galatolo , Silvia Landi , Filippo Maria Santorelli","doi":"10.1016/j.nbd.2025.106793","DOIUrl":"10.1016/j.nbd.2025.106793","url":null,"abstract":"<div><div>Biallelic mutations in the <em>SACS</em> gene, encoding sacsin, cause early-onset autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS), a neurodegenerative disease also characterized by unique and poorly understood retinal abnormalities. While two murine models replicate the phenotypic and neuronal features observed in patients, no retinal phenotype has been described so far. In a zebrafish <em>knock-out</em> strain that faithfully mirrors the main aspects of ARSACS, we observed impaired visual function due to photoreceptor degeneration, likely caused by cell cycle defects in progenitor cells. RNA-seq analysis in embryos revealed dysfunction in proteins related to fat-soluble vitamins (e.g., TTPA, RDH5, VKORC) and suggested a key role of neuroinflammation in driving the retinal defects. Our findings indicate that studying retinal pathology in ARSACS could be crucial for understanding the impact of sacsin depletion and may offer insights into halting disease progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106793"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11757156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142952067","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-02-01DOI: 10.1016/j.nbd.2025.106798
Wenxuan Wang, Sarah J. Myers, Nikita Ollen-Bittle, Shawn N. Whitehead
Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with Hexa gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.
{"title":"Elevation of ganglioside degradation pathway drives GM2 and GM3 within amyloid plaques in a transgenic mouse model of Alzheimer's disease","authors":"Wenxuan Wang, Sarah J. Myers, Nikita Ollen-Bittle, Shawn N. Whitehead","doi":"10.1016/j.nbd.2025.106798","DOIUrl":"10.1016/j.nbd.2025.106798","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a progressive neurodegenerative disease that accounts for two-thirds of all dementia cases, and age is the strongest risk factor. In addition to the amyloid hypothesis, lipid dysregulation is now recognized as a core component of AD pathology. Gangliosides are a class of membrane lipids of the glycosphingolipid family and are enriched in the central nervous system (CNS). Ganglioside dysregulation has been implicated in various neurodegenerative diseases, including AD, but the spatial distribution of ganglioside dysregulation with respect to amyloid-beta (Aβ) deposition is not well understood. To address this gap, matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI) was employed to investigate the age-dependent expression profiles of the A-series ganglioside species GD1a, GM1, GM2, and GM3 in the APP/PS1 transgenic mouse model of AD in which age-dependent amyloid-beta (Aβ) plaques develop. This study utilized a dual-resolution approach in combination with whole-brain imaging for comprehensive detection of ganglioside expression across neuroanatomical regions via high-resolution imaging of the cerebral cortex and hippocampus to investigate plaque-associated ganglioside alterations. The results revealed age-dependent changes in the complex gangliosides GM1 and GD1a across white and gray matter regions in both wildtype and APP/PS1 mice. Significantly greater levels of simple gangliosides GM2 and GM3 were observed in the cortex and dentate gyrus of the hippocampus in transgenic mice at 12 and 18 m than in age-matched controls. The accumulation of GM3 colocalized with Aβ plaques in aged APP/PS1 mice and correlated with <em>Hexa</em> gene expression, suggesting that ganglioside degradation is a mechanism for the accumulation of GM3. This work is the first to demonstrate that age-related ganglioside dysregulation is spatiotemporally associated with Aβ plaques using sophisticated MSI and reveals novel mechanistic insights into lipid regulation in AD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"205 ","pages":"Article 106798"},"PeriodicalIF":5.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142966034","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.nbd.2025.106822
Sonja Heiduschka , Alessandro Prigione
Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.
{"title":"iPSC models of mitochondrial diseases","authors":"Sonja Heiduschka , Alessandro Prigione","doi":"10.1016/j.nbd.2025.106822","DOIUrl":"10.1016/j.nbd.2025.106822","url":null,"abstract":"<div><div>Mitochondrial diseases are historically difficult to study. They cause multi-systemic defects with prevalent impairment of hard-to-access tissues such as the brain and the heart. Furthermore, they suffer from a paucity of conventional model systems, especially because of the challenges associated with mitochondrial DNA (mtDNA) engineering. Consequently, most mitochondrial diseases are currently untreatable. Human induced pluripotent stem cells (iPSCs) represent a promising approach for developing human model systems and assessing therapeutic avenues in a patient- and tissue-specific context. iPSCs are being increasingly used to investigate mitochondrial diseases, either for dissecting mutation-specific defects within two-dimensional (2D) or three-dimensional (3D) progenies or for unveiling the impact of potential treatment options. Here, we review how iPSC-derived 2D cells and 3D organoid models have been applied to the study of mitochondrial diseases caused by either nuclear or mtDNA defects. We anticipate that the field of iPSC-driven modeling of mitochondrial diseases will continue to grow, likely leading to the development of innovative platforms for treatment discovery and toxicity that could benefit the patient community suffering from these debilitating disorders with highly unmet medical needs.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"207 ","pages":"Article 106822"},"PeriodicalIF":5.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075138","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.nbd.2025.106821
Tao Guo , Cheng Zhou , Jiaqi Wen , Jingjing Wu , Yaping Yan , Jianmei Qin , Min Xuan , Haoting Wu , Chenqing Wu , Jingwen Chen , Sijia Tan , Xiaojie Duanmu , Baorong Zhang , Xiaojun Xu , Minming Zhang , Xiaojun Guan
Patients with Parkinson's disease (PD) exhibit heterogenous clinical deficits not only in motor function, other deficits in both sensory and higher-order cognitive processing are also involved. Connectome studies have suggested a primary-to-transmodal gradient and a primary-to-primary gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether these gradients are altered in PD patients and how these alterations associate with neurotransmitter profiles remain unknown. By constructing functional network and calculating its gradient in 134 PD patients and 172 normal controls, we compared functional connectivity gradients between groups and performed spearman correlation to explore the association between neurotransmitter expression and functional network gradient-based alternations in PD. Decreased first gradients were detected mainly in association cortex, including frontal cortex, insula, cingulate, and parietal cortex, corresponding to the decrement of frontoparietal/ventral attention network observed in network-level analyses. Decreased second gradients were observed in primary motor and somatosensory cortex, meeting the decrement of somatomotor network at the network level. Besides, network-level comparisons revealed the increment of visual network in the first gradient and increment of ventral attention network in the second gradient. Transcription-neuroimaging association analyses showed that changes of the first gradient were mainly negatively correlated with nondopaminergic system, while alterations of the second gradient were positively correlated with both dopaminergic and nondopaminergic systems. These results highlight the connectome gradient dysfunction in PD and its linkage with neurotransmitter expression profiles, providing insight into the molecular mechanisms for functional alterations underlying PD.
{"title":"Aberrant functional connectome gradient and its neurotransmitter basis in Parkinson's disease","authors":"Tao Guo , Cheng Zhou , Jiaqi Wen , Jingjing Wu , Yaping Yan , Jianmei Qin , Min Xuan , Haoting Wu , Chenqing Wu , Jingwen Chen , Sijia Tan , Xiaojie Duanmu , Baorong Zhang , Xiaojun Xu , Minming Zhang , Xiaojun Guan","doi":"10.1016/j.nbd.2025.106821","DOIUrl":"10.1016/j.nbd.2025.106821","url":null,"abstract":"<div><div> <!-->Patients with Parkinson's disease (PD) exhibit heterogenous clinical deficits not only in motor function, other deficits in both sensory and higher-order cognitive processing are also involved. Connectome studies have suggested a primary-to-transmodal gradient and a primary-to-primary gradient in functional brain networks, supporting the spectrum from sensation to cognition. However, whether these gradients are altered in PD patients and how these alterations associate with neurotransmitter profiles remain unknown. By constructing functional network and calculating its gradient in 134 PD patients and 172 normal controls, we compared functional connectivity gradients between groups and performed spearman correlation to explore the association between neurotransmitter expression and functional network gradient-based alternations in PD. Decreased first gradients were detected mainly in association cortex, including frontal cortex, insula, cingulate, and parietal cortex, corresponding to the decrement of frontoparietal/ventral attention network observed in network-level analyses. Decreased second gradients were observed in primary motor and somatosensory cortex, meeting the decrement of somatomotor network at the network level. Besides, network-level comparisons revealed the increment of visual network in the first gradient and increment of ventral attention network in the second gradient. Transcription-neuroimaging association analyses showed that changes of the first gradient were mainly negatively correlated with nondopaminergic system, while alterations of the second gradient were positively correlated with both dopaminergic and nondopaminergic systems. These results highlight the connectome gradient dysfunction in PD and its linkage with neurotransmitter expression profiles, providing insight into the molecular mechanisms for functional alterations underlying PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106821"},"PeriodicalIF":5.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-30DOI: 10.1016/j.nbd.2025.106820
Lauren Fielding , Marissa A. Menard , Justin Roth , Maria Iuliano , Benjamin Dehay , Patricia Aguilar-Calvo , Laura A. Volpicelli-Daley
α-Synuclein (α-syn) can form amyloid fibrils. Lewy bodies and Lewy neurites containing aggregated α-syn are pathological markers of Parkinson's Disease and Dementia with Lewy Bodies. To better understand the role of pathological α-syn in disease, many labs use α-syn preformed fibrils (PFFs). Neurons take up the PFFs, which act as seeds to corrupt endogenously expressed α-syn, inducing it to form aggregates very similar to those found in diseased brains. The PFFs are typically generated using recombinant mouse or human α-syn. α-Syn fibrils can also be extracted or amplified from brain tissue extracts, cerebrospinal fluid, or skin biopsies from patients with known synucleinopathy. The PFFs are then added to cell culture, or injected into rodents or primates to induce pathology. Because PFFs can corrupt endogenous α-syn, researchers should adhere to strict safety protocols when handling PFFs to minimize potential exposures. Our group consulted with biosafety professionals at the University of Alabama at Birmingham (UAB) to identify potential risks related to working with α-syn PFFs and offer containment controls to mitigate those risks. Potential exposures include pipetting, opening tubes, and sonication of the PFFs to generate fragments, all of which could potentially generate aerosols. Here, we outline best practices for the safe conduct of research with α-syn fibrils, including personal protective equipment and decontamination procedures. We highlight steps in which extra precautions should be taken and how to minimize exposure and potential risk associated with use of PFFs in scientific research.
{"title":"Current safety recommendations for handling mouse and human αsynuclein pre-formed fibrils","authors":"Lauren Fielding , Marissa A. Menard , Justin Roth , Maria Iuliano , Benjamin Dehay , Patricia Aguilar-Calvo , Laura A. Volpicelli-Daley","doi":"10.1016/j.nbd.2025.106820","DOIUrl":"10.1016/j.nbd.2025.106820","url":null,"abstract":"<div><div>α-Synuclein (α-syn) can form amyloid fibrils. Lewy bodies and Lewy neurites containing aggregated α-syn are pathological markers of Parkinson's Disease and Dementia with Lewy Bodies. To better understand the role of pathological α-syn in disease, many labs use α-syn preformed fibrils (PFFs). Neurons take up the PFFs, which act as seeds to corrupt endogenously expressed α-syn, inducing it to form aggregates very similar to those found in diseased brains. The PFFs are typically generated using recombinant mouse or human α-syn. α-Syn fibrils can also be extracted or amplified from brain tissue extracts, cerebrospinal fluid, or skin biopsies from patients with known synucleinopathy. The PFFs are then added to cell culture, or injected into rodents or primates to induce pathology. Because PFFs can corrupt endogenous α-syn, researchers should adhere to strict safety protocols when handling PFFs to minimize potential exposures. Our group consulted with biosafety professionals at the University of Alabama at Birmingham (UAB) to identify potential risks related to working with α-syn PFFs and offer containment controls to mitigate those risks. Potential exposures include pipetting, opening tubes, and sonication of the PFFs to generate fragments, all of which could potentially generate aerosols. Here, we outline best practices for the safe conduct of research with α-syn fibrils, including personal protective equipment and decontamination procedures. We highlight steps in which extra precautions should be taken and how to minimize exposure and potential risk associated with use of PFFs in scientific research.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106820"},"PeriodicalIF":5.1,"publicationDate":"2025-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.nbd.2025.106818
Stephanie N. Fox , Cody H. Savage , Narcy R. Amireddy , Laura J. McMeekin , David K. Crossman , Peter J. Detloff , Michelle Gray , Rita M. Cowell
Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are hallmarks of multiple neurodegenerative disorders, including Huntington's disease (HD). Strategies are needed to counteract these processes to restore neuronal health and function in HD. Recent evidence indicates that the transcription factor estrogen-related receptor gamma (ERRγ/Esrrg) is required for normal expression of mitochondrial, synaptic, and autophagy genes in neurons. Further, overexpression of Esrrg in dopaminergic neurons reduces synuclein load in the pre-formed fibril model of synucleinopathy. For these reasons, we sought to understand ERRγ's role in transcriptional regulation in spiny projection neurons (SPNs), one of the neuronal populations vulnerable to transcriptional dysregulation, mitochondrial dysfunction, and protein aggregation in HD. Here, we demonstrate that developmental deletion of Esrrg selectively in SPNs causes a transcriptional pattern consistent with a reduction of Drd1 and Drd2–positive neurons in the mouse dorsolateral striatum. To avoid effects of developmental deletion and explore Esrrg's role within adult SPN populations, we deleted or overexpressed Esrrg in adult SPNs. While overexpression was sufficient to increase the expression of mitochondrial and lysosome-related transcripts, Esrrg deletion surprisingly caused increased expression of immediate-early genes and genes with enrichment of binding sites for transcriptional repressors. In contrast, these genes were downregulated by Esrrg overexpression. Concordantly, Esrrg-deficient mice exhibited lack of amphetamine-induced hyperactivity and further upregulation of immediate-early genes. To determine whether the alterations observed with ERRγ modulation have any relevance for understanding transcriptional changes in SPNs in neurodegeneration, we measured Esrrg and its responsive genes in two mouse models of HD. We found an increase in Esrrg expression in HD models, accompanied by a transcriptional profile with similarities to that observed with Esrrg overexpression, suggesting the existence of an ERRγ-dependent, stress-related response. Altogether, these studies suggest that ERRγ is a key activator of mitochondrial and lysosomal transcripts in SPNs with a potential bi-functional role as a mediator of immediate-early gene repression. Ongoing studies are investigating mechanisms underlying ERRγ's roles in transcriptional activation and repression in SPNs to inform strategies to promote neuroprotective actions of ERRγ in SPNs in HD.
{"title":"Estrogen-related receptor gamma is a regulator of mitochondrial, autophagy, and immediate-early gene programs in spiny projection neurons: Relevance for transcriptional changes in Huntington disease","authors":"Stephanie N. Fox , Cody H. Savage , Narcy R. Amireddy , Laura J. McMeekin , David K. Crossman , Peter J. Detloff , Michelle Gray , Rita M. Cowell","doi":"10.1016/j.nbd.2025.106818","DOIUrl":"10.1016/j.nbd.2025.106818","url":null,"abstract":"<div><div>Mitochondrial dysfunction, transcriptional dysregulation, and protein aggregation are hallmarks of multiple neurodegenerative disorders, including Huntington's disease (HD). Strategies are needed to counteract these processes to restore neuronal health and function in HD. Recent evidence indicates that the transcription factor estrogen-related receptor gamma (ERRγ/<em>Esrrg</em>) is required for normal expression of mitochondrial, synaptic, and autophagy genes in neurons. Further, overexpression of <em>Esrrg</em> in dopaminergic neurons reduces synuclein load in the pre-formed fibril model of synucleinopathy. For these reasons, we sought to understand ERRγ's role in transcriptional regulation in spiny projection neurons (SPNs), one of the neuronal populations vulnerable to transcriptional dysregulation, mitochondrial dysfunction, and protein aggregation in HD. Here, we demonstrate that developmental deletion of <em>Esrrg</em> selectively in SPNs causes a transcriptional pattern consistent with a reduction of <em>Drd1</em> and <em>Drd2</em>–positive neurons in the mouse dorsolateral striatum. To avoid effects of developmental deletion and explore <em>Esrrg</em>'s role within adult SPN populations, we deleted or overexpressed <em>Esrrg</em> in adult SPNs. While overexpression was sufficient to increase the expression of mitochondrial and lysosome-related transcripts, <em>Esrrg</em> deletion surprisingly caused increased expression of immediate-early genes and genes with enrichment of binding sites for transcriptional repressors. In contrast, these genes were downregulated by <em>Esrrg</em> overexpression. Concordantly, <em>Esrrg</em>-deficient mice exhibited lack of amphetamine-induced hyperactivity and further upregulation of immediate-early genes. To determine whether the alterations observed with ERRγ modulation have any relevance for understanding transcriptional changes in SPNs in neurodegeneration, we measured <em>Esrrg</em> and its responsive genes in two mouse models of HD. We found an increase in <em>Esrrg</em> expression in HD models, accompanied by a transcriptional profile with similarities to that observed with <em>Esrrg</em> overexpression, suggesting the existence of an ERRγ-dependent, stress-related response. Altogether, these studies suggest that ERRγ is a key activator of mitochondrial and lysosomal transcripts in SPNs with a potential bi-functional role as a mediator of immediate-early gene repression. Ongoing studies are investigating mechanisms underlying ERRγ's roles in transcriptional activation and repression in SPNs to inform strategies to promote neuroprotective actions of ERRγ in SPNs in HD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106818"},"PeriodicalIF":5.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.nbd.2025.106815
Lisha Ye , Katarina Stoklund Dittlau , Adria Sicart , Rekin'’s Janky , Philip Van Damme , Ludo Van Den Bosch
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.
{"title":"Sporadic ALS hiPSC-derived motor neurons show axonal defects linked to altered axon guidance pathways","authors":"Lisha Ye , Katarina Stoklund Dittlau , Adria Sicart , Rekin'’s Janky , Philip Van Damme , Ludo Van Den Bosch","doi":"10.1016/j.nbd.2025.106815","DOIUrl":"10.1016/j.nbd.2025.106815","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by the selective and progressive loss of motor neurons, leading to gradual paralysis and death within 2 to 5 years after diagnosis. The exact underlying pathogenic mechanism(s) remain elusive. This is particularly the case for sporadic ALS (sALS), representing 90 % of cases, as modelling a sporadic disease is extremely difficult. We used human induced pluripotent stem cell (hiPSC)-derived motor neurons from sALS patients to investigate early disease mechanisms. The earliest phenotype that we observed were profound axonal defects including impaired axonal transport, defective axonal outgrowth and a reduced formation of neuromuscular junctions. Transcriptomic profiling revealed significant dysregulation in axon guidance pathways, with upregulation of specific axonal regeneration-inhibiting genes, such as EphA4 and DCC in sALS motor neurons. Our findings suggest that dysregulation of axon guidance pathways contributes to axonal defects and that this could play a crucial role in the pathogenesis of sALS.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106815"},"PeriodicalIF":5.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.nbd.2025.106817
Katryna Pampuscenko , Silvija Jankeviciute , Ramune Morkuniene , Darius Sulskis , Vytautas Smirnovas , Guy C. Brown , Vilmante Borutaite
S100 calcium-binding protein A9 (S100A9, also known as calgranulin B) is expressed and secreted by myeloid cells under inflammatory conditions, and S100A9 can amplify inflammation. There is a large increase in S100A9 expression in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease, and S100A9 has been suggested to contribute to neurodegeneration, but the mechanisms are unclear. Here we investigated the effects of extracellular recombinant S100A9 protein on microglia, neurons and synapses in primary rat brain neuronal-glial cell cultures. Incubation of cell cultures with 250–500 nM S100A9 caused neuronal loss without signs of apoptosis or necrosis, but accompanied by exposure of the “eat-me” signal - phosphatidylserine on neurons. S100A9 caused activation of microglial inflammation as evidenced by an increase in the microglial number, morphological changes, release of pro-inflammatory cytokines, and increased phagocytic activity. At lower concentrations, 10–100 nM S100A9 induced synaptic loss in the cultures. Depletion of microglia from the cultures prevented S100A9-induced neuronal and synaptic loss, indicating that neuronal and synaptic loss was mediated by microglia. These results suggest that extracellular S100A9 may contribute to neurodegeneration by activating microglial inflammation and phagocytosis, resulting in loss of synapses and neurons. This further suggests the possibility that neurodegeneration may be reduced by targeting S100A9 or microglia.
{"title":"S100A9 protein activates microglia and stimulates phagocytosis, resulting in synaptic and neuronal loss","authors":"Katryna Pampuscenko , Silvija Jankeviciute , Ramune Morkuniene , Darius Sulskis , Vytautas Smirnovas , Guy C. Brown , Vilmante Borutaite","doi":"10.1016/j.nbd.2025.106817","DOIUrl":"10.1016/j.nbd.2025.106817","url":null,"abstract":"<div><div>S100 calcium-binding protein A9 (S100A9, also known as calgranulin B) is expressed and secreted by myeloid cells under inflammatory conditions, and S100A9 can amplify inflammation. There is a large increase in S100A9 expression in the brains of patients with neurodegenerative diseases, such as Alzheimer's disease, and S100A9 has been suggested to contribute to neurodegeneration, but the mechanisms are unclear. Here we investigated the effects of extracellular recombinant S100A9 protein on microglia, neurons and synapses in primary rat brain neuronal-glial cell cultures. Incubation of cell cultures with 250–500 nM S100A9 caused neuronal loss without signs of apoptosis or necrosis, but accompanied by exposure of the “eat-me” signal - phosphatidylserine on neurons. S100A9 caused activation of microglial inflammation as evidenced by an increase in the microglial number, morphological changes, release of pro-inflammatory cytokines, and increased phagocytic activity. At lower concentrations, 10–100 nM S100A9 induced synaptic loss in the cultures. Depletion of microglia from the cultures prevented S100A9-induced neuronal and synaptic loss, indicating that neuronal and synaptic loss was mediated by microglia. These results suggest that extracellular S100A9 may contribute to neurodegeneration by activating microglial inflammation and phagocytosis, resulting in loss of synapses and neurons. This further suggests the possibility that neurodegeneration may be reduced by targeting S100A9 or microglia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106817"},"PeriodicalIF":5.1,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066583","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.nbd.2025.106813
Xiaoye Ma , Dmitry Prokopenko , Ni Wang , Tomonori Aikawa , Younjung Choi , Can Zhang , Dan Lei , Yingxue Ren , Keiji Kawatani , Skylar C. Starling , Ralph B. Perkerson , Bhaskar Roy , Astrid C. Quintero , Tammee M. Parsons , Yining Pan , Zonghua Li , Minghui Wang , Hanmei Bao , Xianlin Han , Guojun Bu , Takahisa Kanekiyo
The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.
One sentence summary
A rare Alzheimer's disease risk ABCA7 p.A696S variant compromises microglial response to amyloid pathology.
{"title":"Alzheimer's disease risk ABCA7 p.A696S variant disturbs the microglial response to amyloid pathology in mice","authors":"Xiaoye Ma , Dmitry Prokopenko , Ni Wang , Tomonori Aikawa , Younjung Choi , Can Zhang , Dan Lei , Yingxue Ren , Keiji Kawatani , Skylar C. Starling , Ralph B. Perkerson , Bhaskar Roy , Astrid C. Quintero , Tammee M. Parsons , Yining Pan , Zonghua Li , Minghui Wang , Hanmei Bao , Xianlin Han , Guojun Bu , Takahisa Kanekiyo","doi":"10.1016/j.nbd.2025.106813","DOIUrl":"10.1016/j.nbd.2025.106813","url":null,"abstract":"<div><div>The adenosine triphosphate–binding cassette transporter A7 (<em>ABCA7</em>) gene is ranked as one of the top susceptibility loci for Alzheimer's disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare <em>ABCA7</em> p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including <em>Trem2</em> and <em>Tyrobp,</em> are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.</div></div><div><h3>One sentence summary</h3><div>A rare Alzheimer's disease risk <em>ABCA7</em> p.A696S variant compromises microglial response to amyloid pathology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"206 ","pages":"Article 106813"},"PeriodicalIF":5.1,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066579","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}