Molecular Neurodegeneration最新文献

{"title":"Therapeutic potential of APP antisense oligonucleotides for Alzheimer’s disease and down syndrome-related Alzheimer’s disease","authors":"Srishruthi Thirumalai, Rickie Patani, Christy Hung","doi":"10.1186/s13024-024-00745-5","DOIUrl":"https://doi.org/10.1186/s13024-024-00745-5","url":null,"abstract":"<p>The amyloid cascade hypothesis of Alzheimer’s disease (AD) suggests that the accumulation of the amyloid-β (Aβ) peptide in the brain is a central event in the disease’s pathology. This hypothesis is strongly supported by both human neuropathological findings and genetic studies. As a result, Aβ-targeted monoclonal antibody (mAb) has been a central focus of efforts to develop drugs aimed at slowing or halting AD progression [1]. Importantly, following the accelerated approval of aducanumab, two further mAbs that target amyloid, lecanemab and donanemab, have received rapid FDA approval. The recent successful clinical trial of lecanemab in symptomatic AD, meeting its primary and secondary endpoints, represents a notable step forward in the battle against this prevalent disease. However, it remains controversial which Aβ species (monomers, oligomers, protofibrils or fibrils) are the most neurotoxic.</p><p>Compared to mAb-mediated immunotherapies, antisense oligonucleotides (ASOs) aimed at lowering levels of Aβ either by targeting <i>APP</i> mRNA or its enzymes involved in amyloidogenic processing offer an appealing alternative. Previous studies have showcased the potential of ASOs in reducing Aβ species in animal models of AD. For example, OL-1, an ASO targeting the <i>APP</i> mRNA region corresponding to the 17–30 amino acid fragment of Aβ [2], reduced APP expression in AD mouse models, including transgenic Tg2576 (APPswe) and SAMP8 mice. Chang et al. developed a splice-switching ASO that induces the skipping of the <i>APP</i> exon encoding proteolytic cleavage sites required for Aβ peptide production [3]. Similarly, tau plays a key role in AD pathophysiology [4]. MAPTR<sub>x</sub> is an ASO designed to reduce tau levels and has shown marked dose-dependent and sustained reductions in the concentration of CSF t-tau in a human phase 1b clinical trial [4].</p><p>In the latest issue of <i>Brain</i>, Hung et al. further demonstrated the efficiency of APP ASOs in reducing both full-length APP proteins and Aβ-containing aggregates using a human stem cell model [5]. They used a 20-mer (gapmer) APP ASO targeting Exon 5 of the <i>APP</i> mRNA and found that nearly all human iPSC-derived cortical neurons contain APP ASOs after 24 hours. Through dose optimization, they showed that APP ASOs are effective in restoring physiological APP levels from what would be expected from three copies back down to the equivalent of would be transcribed from two copies.</p><p>Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in AD [6]. Using super-resolution imaging, Hung et al. showed that APP ASOs rescue endolysosome and autophagy dysfunction in human APP duplication neurons by restoring lysosomal acidity to physiological levels. Accumulation of extracellular Aβ aggregates comprising Aβ peptide oligomers is one of the cellular hallmarks of AD. However, characterization of the aggregates secreted by human iPSC-derived neurons ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"48 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141791143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: HDGFL2 cryptic proteins report presence of TDP-43 pathology in neurodegenerative diseases","authors":"Anna Calliari, Lillian M. Daughrity, Ellen A. Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N. Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Neill R. Graff-Radford, Gregory S. Day, Bradley F. Boeve, David S. Knopman, Ronald C. Petersen, Keith A. Josephs, Björn Oskarsson, Aaron D. Gitler, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Michael E. Ward, Yong-Jie Zhang, Leonard Petrucelli","doi":"10.1186/s13024-024-00744-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00744-6","url":null,"abstract":"<p><b>Correction: Molecular Neurodegeneration (2024) 19:29</b></p><p><b>https://doi.org/10.1186/s13024-024-00718-8</b></p><p>The original article contains an error in Figure 1A.</p><figure><picture><source srcset=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00744-6/MediaObjects/13024_2024_744_Fig1_HTML.png?as=webp\" type=\"image/webp\"/><img alt=\"figure 1\" aria-describedby=\"Fig1\" height=\"719\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00744-6/MediaObjects/13024_2024_744_Fig1_HTML.png\" width=\"685\"/></picture></figure><p>The corrected figure amends the statistical significance annotation of ‘ns’ to ‘*’ and can be viewed ahead.</p><span>Author notes</span><ol><li><p> Anna Calliari and Lillian M. Daughrity contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA</p><p>Anna Calliari, Lillian M. Daughrity, Ellen A. Albagli, Paula Castellanos Otero, Mei Yue, Karen Jansen-West, Naeyma N. Islam, Thomas Caulfield, Bailey Rawlinson, Michael DeTure, Casey Cook, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Yong-Jie Zhang & Leonard Petrucelli</p></li><li><p>Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA</p><p>Michael DeTure, Casey Cook, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Yong-Jie Zhang & Leonard Petrucelli</p></li><li><p>Department of Neurology, Mayo Clinic, Jacksonville, FL, USA</p><p>Neill R. Graff-Radford, Gregory S. Day & Björn Oskarsson</p></li><li><p>Department of Neurology, Mayo Clinic, Rochester, MN, USA</p><p>Bradley F. Boeve, David S. Knopman, Ronald C. Petersen & Keith A. Josephs</p></li><li><p>Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA</p><p>Aaron D. Gitler</p></li><li><p>National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA</p><p>Michael E. Ward</p></li><li><p>Center for Alzheimer’s and Related Dementias, National Institute on Aging and National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA</p><p>Michael E. Ward</p></li></ol><span>Authors</span><ol><li><span>Anna Calliari</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Lillian M. Daughrity</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Ellen A. Albagli</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Paula Castellanos Otero</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Mei Yue</span>View author publ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"34 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-07-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141769151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Astrocytic autophagy plasticity modulates Aβ clearance and cognitive function in Alzheimer’s disease","authors":"Suhyun Kim, Heejung Chun, Yunha Kim, Yeyun Kim, Uiyeol Park, Jiyeon Chu, Mridula Bhalla, Seung-Hye Choi, Ali Yousefian-Jazi, Sojung Kim, Seung Jae Hyeon, Seungchan Kim, Yeonseo Kim, Yeon Ha Ju, Seung Eun Lee, Hyunbeom Lee, Kyungeun Lee, Soo-Jin Oh, Eun Mi Hwang, Junghee Lee, C. Justin Lee, Hoon Ryu","doi":"10.1186/s13024-024-00740-w","DOIUrl":"https://doi.org/10.1186/s13024-024-00740-w","url":null,"abstract":"Astrocytes, one of the most resilient cells in the brain, transform into reactive astrocytes in response to toxic proteins such as amyloid beta (Aβ) in Alzheimer’s disease (AD). However, reactive astrocyte-mediated non-cell autonomous neuropathological mechanism is not fully understood yet. We aimed our study to find out whether Aβ-induced proteotoxic stress affects the expression of autophagy genes and the modulation of autophagic flux in astrocytes, and if yes, how Aβ-induced autophagy-associated genes are involved Aβ clearance in astrocytes of animal model of AD. Whole RNA sequencing (RNA-seq) was performed to detect gene expression patterns in Aβ-treated human astrocytes in a time-dependent manner. To verify the role of astrocytic autophagy in an AD mouse model, we developed AAVs expressing shRNAs for MAP1LC3B/LC3B (LC3B) and Sequestosome1 (SQSTM1) based on AAV-R-CREon vector, which is a Cre recombinase-dependent gene-silencing system. Also, the effect of astrocyte-specific overexpression of LC3B on the neuropathology in AD (APP/PS1) mice was determined. Neuropathological alterations of AD mice with astrocytic autophagy dysfunction were observed by confocal microscopy and transmission electron microscope (TEM). Behavioral changes of mice were examined through novel object recognition test (NOR) and novel object place recognition test (NOPR). Here, we show that astrocytes, unlike neurons, undergo plastic changes in autophagic processes to remove Aβ. Aβ transiently induces expression of LC3B gene and turns on a prolonged transcription of SQSTM1 gene. The Aβ-induced astrocytic autophagy accelerates urea cycle and putrescine degradation pathway. Pharmacological inhibition of autophagy exacerbates mitochondrial dysfunction and oxidative stress in astrocytes. Astrocyte-specific knockdown of LC3B and SQSTM1 significantly increases Aβ plaque formation and GFAP-positive astrocytes in APP/PS1 mice, along with a significant reduction of neuronal marker and cognitive function. In contrast, astrocyte-specific overexpression of LC3B reduced Aβ aggregates in the brain of APP/PS1 mice. An increase of LC3B and SQSTM1 protein is found in astrocytes of the hippocampus in AD patients. Taken together, our data indicates that Aβ-induced astrocytic autophagic plasticity is an important cellular event to modulate Aβ clearance and maintain cognitive function in AD mice.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141750301","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tau protein profiling in tauopathies: a human brain study.","authors":"Juan Lantero-Rodriguez, Elena Camporesi, Laia Montoliu-Gaya, Johan Gobom, Diana Piotrowska, Maria Olsson, Irena Matečko Burmann, Bruno Becker, Ann Brinkmalm, Björn M Burmann, Michael Perkinton, Nicholas J Ashton, Nick C Fox, Tammaryn Lashley, Henrik Zetterberg, Kaj Blennow, Gunnar Brinkmalm","doi":"10.1186/s13024-024-00741-9","DOIUrl":"10.1186/s13024-024-00741-9","url":null,"abstract":"<p><p>Abnormal accumulation of misfolded and hyperphosphorylated tau protein in brain is the defining feature of several neurodegenerative diseases called tauopathies, including Alzheimer's disease (AD). In AD, this pathological change is reflected by highly specific cerebrospinal fluid (CSF) tau biomarkers, including both phosphorylated and non-phosphorylated variants. Interestingly, despite tau pathology being at the core of all tauopathies, CSF tau biomarkers remain unchanged in certain tauopathies, e.g., progressive supranuclear palsy (PSP), Pick's disease (PiD), and corticobasal neurodegeneration (CBD). To better understand commonalities and differences between tauopathies, we report a multiplex assay combining immunoprecipitation and high-resolution mass spectrometry capable of detecting and quantifying peptides from different tau protein isoforms as well as non-phosphorylated and phosphorylated peptides, including those carrying multiple phosphorylations. We investigated the tau proteoforms in soluble and insoluble fractions of brain tissue from subjects with autopsy-confirmed tauopathies, including sporadic AD (n = 10), PSP (n = 11), PiD (n = 10), and CBD (n = 10), and controls (n = 10). Our results demonstrate that non-phosphorylated tau profiles differ across tauopathies, generally showing high abundance of microtubule-binding region (MTBR)-containing peptides in insoluble protein fractions compared with controls; the AD group showed 12-72 times higher levels of MTBR-containing aggregates. Quantification of tau isoforms showed the 3R being more abundant in PiD and the 4R isoform being more abundant in CBD and PSP in the insoluble fraction. Twenty-three different phosphorylated peptides were quantified. Most phosphorylated peptides were measurable in all investigated tauopathies. All phosphorylated peptides were significantly increased in AD insoluble fraction. However, doubly and triply phosphorylated peptides were significantly increased in AD even in the soluble fraction. Results were replicated using a validation cohort comprising AD (n = 10), CBD (n = 10), and controls (n = 10). Our study demonstrates that abnormal levels of phosphorylation and aggregation do indeed occur in non-AD tauopathies, however, both appear pronouncedly increased in AD, becoming a distinctive characteristic of AD pathology.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"54"},"PeriodicalIF":14.9,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11264707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141723980","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress.","authors":"Ken Uekawa, Yorito Hattori, Sung Ji Ahn, James Seo, Nicole Casey, Antoine Anfray, Ping Zhou, Wenjie Luo, Josef Anrather, Laibaik Park, Costantino Iadecola","doi":"10.1186/s13024-024-00743-7","DOIUrl":"10.1186/s13024-024-00743-7","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"52"},"PeriodicalIF":14.9,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11241705/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141590797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The interplay of inflammation and remyelination: rethinking MS treatment with a focus on oligodendrocyte progenitor cells","authors":"Omri Zveik, Ariel Rechtman, Tal Ganz, Adi Vaknin-Dembinsky","doi":"10.1186/s13024-024-00742-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00742-8","url":null,"abstract":"Multiple sclerosis (MS) therapeutic goals have traditionally been dichotomized into two distinct avenues: immune-modulatory-centric interventions and pro-regenerative strategies. Oligodendrocyte progenitor cells (OPCs) were regarded for many years solely in concern to their potential to generate oligodendrocytes and myelin in the central nervous system (CNS). However, accumulating data elucidate the multifaceted roles of OPCs, including their immunomodulatory functions, positioning them as cardinal constituents of the CNS’s immune landscape. In this review, we will discuss how the two therapeutic approaches converge. We present a model by which (1) an inflammation is required for the appropriate pro-myelinating immune function of OPCs in the chronically inflamed CNS, and (2) the immune function of OPCs is crucial for their ability to differentiate and promote remyelination. This model highlights the reciprocal interactions between OPCs’ pro-myelinating and immune-modulating functions. Additionally, we review the specific effects of anti- and pro-inflammatory interventions on OPCs, suggesting that immunosuppression adversely affects OPCs’ differentiation and immune functions. We suggest a multi-systemic therapeutic approach, which necessitates not a unidimensional focus but a harmonious balance between OPCs’ pro-myelinating and immune-modulatory functions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"23 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141597270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-acetylated-tau immunotherapy is neuroprotective in tauopathy and brain injury","authors":"Celeste Parra Bravo, Karen Krukowski, Sarah Barker, Chao Wang, Yaqiao Li, Li Fan, Edwin Vázquez-Rosa, Min-Kyoo Shin, Man Ying Wong, Louise D. McCullough, Ryan S. Kitagawa, H. Alex Choi, Angela Cacace, Subhash C. Sinha, Andrew A. Pieper, Susanna Rosi, Xu Chen, Li Gan","doi":"10.1186/s13024-024-00733-9","DOIUrl":"https://doi.org/10.1186/s13024-024-00733-9","url":null,"abstract":"Tau is aberrantly acetylated in various neurodegenerative conditions, including Alzheimer’s disease, frontotemporal lobar degeneration (FTLD), and traumatic brain injury (TBI). Previously, we reported that reducing acetylated tau by pharmacologically inhibiting p300-mediated tau acetylation at lysine 174 reduces tau pathology and improves cognitive function in animal models. We investigated the therapeutic efficacy of two different antibodies that specifically target acetylated lysine 174 on tau (ac-tauK174). We treated PS19 mice, which harbor the P301S tauopathy mutation that causes FTLD, with anti-ac-tauK174 and measured effects on tau pathology, neurodegeneration, and neurobehavioral outcomes. Furthermore, PS19 mice received treatment post-TBI to evaluate the ability of the immunotherapy to prevent TBI-induced exacerbation of tauopathy phenotypes. Ac-tauK174 measurements in human plasma following TBI were also collected to establish a link between trauma and acetylated tau levels, and single nuclei RNA-sequencing of post-TBI brain tissues from treated mice provided insights into the molecular mechanisms underlying the observed treatment effects. Anti-ac-tauK174 treatment mitigates neurobehavioral impairment and reduces tau pathology in PS19 mice. Ac-tauK174 increases significantly in human plasma 24 h after TBI, and anti-ac-tauK174 treatment of PS19 mice blocked TBI-induced neurodegeneration and preserved memory functions. Anti-ac-tauK174 treatment rescues alterations of microglial and oligodendrocyte transcriptomic states following TBI in PS19 mice. The ability of anti-ac-tauK174 treatment to rescue neurobehavioral impairment, reduce tau pathology, and rescue glial responses demonstrates that targeting tau acetylation at K174 is a promising neuroprotective therapeutic approach to human tauopathies resulting from TBI or genetic disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141444929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mis-localization of endogenous TDP-43 leads to ALS-like early-stage metabolic dysfunction and progressive motor deficits","authors":"Yiying Hu, Alexander Hruscha, Chenchen Pan, Martina Schifferer, Michael K. Schmidt, Brigitte Nuscher, Martin Giera, Sarantos Kostidis, Özge Burhan, Frauke van Bebber, Dieter Edbauer, Thomas Arzberger, Christian Haass, Bettina Schmid","doi":"10.1186/s13024-024-00735-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00735-7","url":null,"abstract":"The key pathological signature of ALS/ FTLD is the mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm. However, TDP-43 gain of function in the cytoplasm is still poorly understood since TDP-43 animal models recapitulating mis-localization of endogenous TDP-43 from the nucleus to the cytoplasm are missing. CRISPR/Cas9 technology was used to generate a zebrafish line (called CytoTDP), that mis-locates endogenous TDP-43 from the nucleus to the cytoplasm. Phenotypic characterization of motor neurons and the neuromuscular junction was performed by immunostaining, microglia were immunohistochemically localized by whole-mount tissue clearing and muscle ultrastructure was analyzed by scanning electron microscopy. Behavior was investigated by video tracking and quantitative analysis of swimming parameters. RNA sequencing was used to identify mis-regulated pathways with validation by molecular analysis. CytoTDP fish have early larval phenotypes resembling clinical features of ALS such as progressive motor defects, neurodegeneration and muscle atrophy. Taking advantage of zebrafish’s embryonic development that solely relys on yolk usage until 5 days post fertilization, we demonstrated that microglia proliferation and activation in the hypothalamus is independent from food intake. By comparing CytoTDP to a previously generated TDP-43 knockout line, transcriptomic analyses revealed that mis-localization of endogenous TDP-43, rather than TDP-43 nuclear loss of function, leads to early onset metabolic dysfunction. The new TDP-43 model mimics the ALS/FTLD hallmark of progressive motor dysfunction. Our results suggest that functional deficits of the hypothalamus, the metabolic regulatory center, might be the primary cause of weight loss in ALS patients. Cytoplasmic gain of function of endogenous TDP-43 leads to metabolic dysfunction in vivo that are reminiscent of early ALS clinical non-motor metabolic alterations. Thus, the CytoTDP zebrafish model offers a unique opportunity to identify mis-regulated targets for therapeutic intervention early in disease progression.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141430481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fate-mapping and functional dissection reveal perilous influence of type I interferon signaling in mouse brain aging","authors":"Ethan R. Roy, Sanming Li, Sepideh Saroukhani, Yanyu Wang, Wei Cao","doi":"10.1186/s13024-024-00736-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00736-6","url":null,"abstract":"Aging significantly elevates the risk of developing neurodegenerative diseases. Neuroinflammation is a universal hallmark of neurodegeneration as well as normal brain aging. Which branches of age-related neuroinflammation, and how they precondition the brain toward pathological progression, remain ill-understood. The presence of elevated type I interferon (IFN-I) has been documented in the aged brain, but its role in promoting degenerative processes, such as the loss of neurons in vulnerable regions, has not been studied in depth. To comprehend the scope of IFN-I activity in the aging brain, we surveyed IFN-I-responsive reporter mice at multiple ages. We also examined 5- and 24-month-old mice harboring selective ablation of Ifnar1 in microglia to observe the effects of manipulating this pathway during the aging process using bulk RNA sequencing and histological parameters. We detected age-dependent IFN-I signal escalation in multiple brain cell types from various regions, especially in microglia. Selective ablation of Ifnar1 from microglia in aged mice significantly reduced overall brain IFN-I signature, dampened microglial reactivity, lessened neuronal loss, restored expression of key neuronal genes and pathways, and diminished the accumulation of lipofuscin, a core hallmark of cellular aging in the brain. Overall, our study demonstrates pervasive IFN-I activity during normal mouse brain aging and reveals a pathogenic, pro-degenerative role played by microglial IFN-I signaling in perpetuating neuroinflammation, neuronal dysfunction, and molecular aggregation. These findings extend the understanding of a principal axis of age-related inflammation in the brain, one likely shared with multiple neurological disorders, and provide a rationale to modulate aberrant immune activation to mitigate neurodegenerative process at all stages.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"31 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141334423","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Urolithin A promotes p62-dependent lysophagy to prevent acute retinal neurodegeneration.","authors":"Juan Ignacio Jiménez-Loygorri, Álvaro Viedma-Poyatos, Raquel Gómez-Sintes, Patricia Boya","doi":"10.1186/s13024-024-00739-3","DOIUrl":"10.1186/s13024-024-00739-3","url":null,"abstract":"<p><strong>Background: </strong>Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death.</p><p><strong>Methods: </strong>A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question.</p><p><strong>Results: </strong>UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy.</p><p><strong>Conclusions: </strong>Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"49"},"PeriodicalIF":14.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11186080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141419902","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}