Molecular Neurodegeneration最新文献

{"title":"Unraveling the complex role of MAPT-containing H1 and H2 haplotypes in neurodegenerative diseases","authors":"Chiara Pedicone, Sarah A. Weitzman, Alan E. Renton, Alison M. Goate","doi":"10.1186/s13024-024-00731-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00731-x","url":null,"abstract":"A ~ 1 Mb inversion polymorphism exists within the 17q21.31 locus of the human genome as direct (H1) and inverted (H2) haplotype clades. This inversion region demonstrates high linkage disequilibrium, but the frequency of each haplotype differs across ancestries. While the H1 haplotype exists in all populations and shows a normal pattern of genetic variability and recombination, the H2 haplotype is enriched in European ancestry populations, is less frequent in African ancestry populations, and nearly absent in East Asian ancestry populations. H1 is a known risk factor for several neurodegenerative diseases, and has been associated with many other traits, suggesting its importance in cellular phenotypes of the brain and entire body. Conversely, H2 is protective for these diseases, but is associated with predisposition to recurrent microdeletion syndromes and neurodevelopmental disorders such as autism. Many single nucleotide variants and copy number variants define H1/H2 haplotypes and sub-haplotypes, but identifying the causal variant(s) for specific diseases and phenotypes is complex due to the extended linkage equilibrium. In this review, we assess the current knowledge of this inversion region regarding genomic structure, gene expression, cellular phenotypes, and disease association. We discuss recent discoveries and challenges, evaluate gaps in knowledge, and highlight the importance of understanding the effect of the 17q21.31 haplotypes to promote advances in precision medicine and drug discovery for several diseases. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141165177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer’s disease associated isoforms of human CD33 distinctively modulate microglial cell responses in 5XFAD mice","authors":"Ghazaleh Eskandari-Sedighi, Madeline Crichton, Sameera Zia, Erik Gomez-Cardona, Leonardo M. Cortez, Zain H. Patel, Kei Takahashi-Yamashiro, Chris D. St. Laurent, Gaurav Sidhu, Susmita Sarkar, Vivian Aghanya, Valerie L. Sim, Qiumin Tan, Olivier Julien, Jason R. Plemel, Matthew S. Macauley","doi":"10.1186/s13024-024-00734-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00734-8","url":null,"abstract":"Microglia play diverse pathophysiological roles in Alzheimer’s disease (AD), with genetic susceptibility factors skewing microglial cell function to influence AD risk. CD33 is an immunomodulatory receptor associated with AD susceptibility through a single nucleotide polymorphism that modulates mRNA splicing, skewing protein expression from a long protein isoform (CD33M) to a short isoform (CD33m). Understanding how human CD33 isoforms differentially impact microglial cell function in vivo has been challenging due to functional divergence of CD33 between mice and humans. We address this challenge by studying transgenic mice expressing either of the human CD33 isoforms crossed with the 5XFAD mouse model of amyloidosis and find that human CD33 isoforms have opposing effects on the response of microglia to amyloid-β (Aβ) deposition. Mice expressing CD33M have increased Aβ levels, more diffuse plaques, fewer disease-associated microglia, and more dystrophic neurites compared to 5XFAD control mice. Conversely, CD33m promotes plaque compaction and microglia-plaque contacts, and minimizes neuritic plaque pathology, highlighting an AD protective role for this isoform. Protective phenotypes driven by CD33m are detected at an earlier timepoint compared to the more aggressive pathology in CD33M mice that appears at a later timepoint, suggesting that CD33m has a more prominent impact on microglia cell function at earlier stages of disease progression. In addition to divergent roles in modulating phagocytosis, scRNAseq and proteomics analyses demonstrate that CD33m+ microglia upregulate nestin, an intermediate filament involved in cell migration, at plaque contact sites. Overall, our work provides new functional insights into how CD33, as a top genetic susceptibility factor for AD, modulates microglial cell function. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"78 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141156656","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":"Variants in the MS4A cluster interact with soluble TREM2 expression on biomarkers of neuropathology","authors":"Rebecca L. Winfree, Emma Nolan, Logan Dumitrescu, Kaj Blennow, Henrik Zetterberg, Katherine A. Gifford, Kimberly R. Pechman, Mabel Seto, Vladislav A. Petyuk, Yanling Wang, Julie Schneider, David A. Bennett, Angela L. Jefferson, Timothy J. Hohman","doi":"10.1186/s13024-024-00727-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00727-7","url":null,"abstract":"Recent evidence suggests that Alzheimer’s disease (AD) genetic risk variants (rs1582763 and rs6591561) of the MS4A locus are genome-wide significant regulators of soluble TREM2 levels such that the minor allele of the protective variant (rs1582763) is associated with higher sTREM2 and lower AD risk while the minor allele of (rs6591561) relates to lower sTREM2 and higher AD risk. Our group previously found that higher sTREM2 relates to higher Aβ40, worse blood–brain barrier (BBB) integrity (measured with the CSF/plasma albumin ratio), and higher CSF tau, suggesting strong associations with amyloid abundance and both BBB and neurodegeneration complicate interpretation. We expand on this work by leveraging these common variants as genetic tools to tune the interpretation of high CSF sTREM2, and by exploring the potential modifying role of these variants on the well-established associations between CSF sTREM2 as well as TREM2 transcript levels in the brain with AD neuropathology. Biomarker analyses leveraged data from the Vanderbilt Memory & Aging Project (n = 127, age = 72 ± 6.43) and were replicated in the Alzheimer’s Disease Neuroimaging Initiative (n = 399, age = 73 ± 7.39). Autopsy analyses were performed leveraging data from the Religious Orders Study and Rush Memory and Aging Project (n = 577, age = 89 ± 6.46). We found that the protective variant rs1582763 attenuated the association between CSF sTREM2 and Aβ40 (β = -0.44, p-value = 0.017) and replicated this interaction in ADNI (β = -0.27, p = 0.017). We did not observe this same interaction effect between TREM2 mRNA levels and Aβ peptides in brain (Aβ total β = -0.14, p = 0.629; Aβ1-38, β = 0.11, p = 0.200). In contrast to the effects on Aβ, the minor allele of this same variant seemed to enhance the association with blood–brain barrier dysfunction (β = 7.0e-4, p = 0.009), suggesting that elevated sTREM2 may carry a much different interpretation in carriers vs. non-carriers of this allele. When evaluating the risk variant (rs6591561) across datasets, we did not observe a statistically significant interaction against any outcome in VMAP and observed opposing directions of associations in ADNI and ROS/MAP on Aβ levels. Together, our results suggest that the protective effect of rs1582763 may act by decoupling the associations between sTREM2 and amyloid abundance, providing important mechanistic insight into sTREM2 changes and highlighting the need to incorporate genetic context into the analysis of sTREM2 levels, particularly if leveraged as a clinical biomarker of disease in the future.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"38 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140953850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Alzheimer blood biomarkers: practical guidelines for study design, sample collection, processing, biobanking, measurement and result reporting","authors":"Xuemei Zeng, Yijun Chen, Anuradha Sehrawat, Jihui Lee, Tara K. Lafferty, Julia Kofler, Sarah B. Berman, Robert A. Sweet, Dana L. Tudorascu, William E. Klunk, Milos D. Ikonomovic, Anna Pfister, Henrik Zetterberg, Beth E. Snitz, Anne D. Cohen, Victor L. Villemagne, Tharick A. Pascoal, M. llyas Kamboh, Oscar I. Lopez, Kaj Blennow, Thomas K. Karikari","doi":"10.1186/s13024-024-00711-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00711-1","url":null,"abstract":"Alzheimer’s disease (AD), the most common form of dementia, remains challenging to understand and treat despite decades of research and clinical investigation. This might be partly due to a lack of widely available and cost-effective modalities for diagnosis and prognosis. Recently, the blood-based AD biomarker field has seen significant progress driven by technological advances, mainly improved analytical sensitivity and precision of the assays and measurement platforms. Several blood-based biomarkers have shown high potential for accurately detecting AD pathophysiology. As a result, there has been considerable interest in applying these biomarkers for diagnosis and prognosis, as surrogate metrics to investigate the impact of various covariates on AD pathophysiology and to accelerate AD therapeutic trials and monitor treatment effects. However, the lack of standardization of how blood samples and collected, processed, stored analyzed and reported can affect the reproducibility of these biomarker measurements, potentially hindering progress toward their widespread use in clinical and research settings. To help address these issues, we provide fundamental guidelines developed according to recent research findings on the impact of sample handling on blood biomarker measurements. These guidelines cover important considerations including study design, blood collection, blood processing, biobanking, biomarker measurement, and result reporting. Furthermore, the proposed guidelines include best practices for appropriate blood handling procedures for genetic and ribonucleic acid analyses. While we focus on the key blood-based AD biomarkers for the AT(N) criteria (e.g., amyloid-beta [Aβ]40, Aβ42, Aβ42/40 ratio, total-tau, phosphorylated-tau, neurofilament light chain, brain-derived tau and glial fibrillary acidic protein), we anticipate that these guidelines will generally be applicable to other types of blood biomarkers. We also anticipate that these guidelines will assist investigators in planning and executing biomarker research, enabling harmonization of sample handling to improve comparability across studies.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140924985","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: Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade","authors":"Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Walter Gulisano, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Luciano D’Adamio, Shi-Xian Deng, Daniela Puzzo, Ottavio Arancio, Jole Fiorito","doi":"10.1186/s13024-024-00729-5","DOIUrl":"https://doi.org/10.1186/s13024-024-00729-5","url":null,"abstract":"<p><b>Correction: Molecular Neurodegeneration (2019) 14:26</b></p><p><b>https://doi.org/10.1186/s13024-019-0326-4</b>.</p><p>After publication of this work, the authors noted that the tubulin and t-CREB bands in panel B and F were similar. This was due to errors in the panels which likely occurred at the time of assembling the figure during the preparation of the manuscript. After carefully going back to all the raw data and checking the 32 bands assembled in the figure, the authors found and selected exact and correct tubulin and t-CREB bands for both panels, thus correcting the image. The errors only pertain to the incorrect representative images in panels B and F and do not affect any of the analyses or conclusions presented in the paper.</p><figure><picture><img alt=\"figure a\" aria-describedby=\"Figa\" height=\"1286\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00729-5/MediaObjects/13024_2024_729_Fig1_HTML.png\" width=\"685\"/></picture></figure><span>Author notes</span><ol><li><p>Erica Acquarone, Elentina K. Argyrousi and Manon van den Berg contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Institute for Research on Alzheimer’s Disease and the Aging Brain, 630 West 168th Street, P&S 12- 420D, New York, NY, 10032, USA</p><p>Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Ottavio Arancio & Jole Fiorito</p></li><li><p>DiMi Department of Internal Medicine and Medical Specialties, University of Genoa, Genoa, 16132, Italy</p><p>Erica Acquarone</p></li><li><p>Faculty of Psychology and Neuroscience, Maastricht University, Maastricht, 6229, Netherlands</p><p>Elentina K. Argyrousi & Manon van den Berg</p></li><li><p>Department of Biomedical and Biotechnological Sciences, Section of Physiology, University of Catania, Catania, 95125, Italy</p><p>Walter Gulisano & Daniela Puzzo</p></li><li><p>Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Genoa, 16132, Italy</p><p>Elisa Calcagno</p></li><li><p>Department of Pharmacology, Physiology and Neuroscience, Rutgers University, Newark, NJ, USA</p><p>Luciano D’Adamio</p></li><li><p>Department of Medicine, Columbia University, New York, NY, 10032, USA</p><p>Shi-Xian Deng & Ottavio Arancio</p></li><li><p>Oasi Research Institute-IRCCS, Troina, 94018, Italy</p><p>Daniela Puzzo</p></li><li><p>Department of Pathology and Cell Biology, Columbia University, New York, NY, 10032, USA</p><p>Ottavio Arancio</p></li><li><p>Department of Life Sciences, New York Institute of Technology, Northern Boulevard, Theobald Science Center, room 425, P.O. Box 8000, Old Westbury, NY, 11568, USA</p><p>Jole Fiorito</p></li></ol><span>Authors</span><ol><li><span>Erica Acquarone</span>View author publications<p>You can also search for this author in <span>PubMed<span> <","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"30 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140814617","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":"Regulation of human microglial gene expression and function via RNAase-H active antisense oligonucleotides in vivo in Alzheimer’s disease","authors":"Lina Vandermeulen, Ivana Geric, Laura Fumagalli, Mohamed Kreir, Ashley Lu, Annelies Nonneman, Jessie Premereur, Leen Wolfs, Rafaela Policarpo, Nicola Fattorelli, An De Bondt, Ilse Van Den Wyngaert, Bob Asselbergh, Mark Fiers, Bart De Strooper, Constantin d’Ydewalle, Renzo Mancuso","doi":"10.1186/s13024-024-00725-9","DOIUrl":"https://doi.org/10.1186/s13024-024-00725-9","url":null,"abstract":"Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo. We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD. This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"304 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140640417","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":"Adaptive immune changes associate with clinical progression of Alzheimer’s disease","authors":"Lynn van Olst, Alwin Kamermans, Sem Halters, Susanne M. A. van der Pol, Ernesto Rodriguez, Inge M. W. Verberk, Sanne G. S. Verberk, Danielle W. R. Wessels, Carla Rodriguez-Mogeda, Jan Verhoeff, Dorine Wouters, Jan Van den Bossche, Juan J. Garcia-Vallejo, Afina W. Lemstra, Maarten E. Witte, Wiesje M. van der Flier, Charlotte E. Teunissen, Helga E. de Vries","doi":"10.1186/s13024-024-00726-8","DOIUrl":"https://doi.org/10.1186/s13024-024-00726-8","url":null,"abstract":"Alzheimer’s disease (AD) is the most frequent cause of dementia. Recent evidence suggests the involvement of peripheral immune cells in the disease, but the underlying mechanisms remain unclear. We comprehensively mapped peripheral immune changes in AD patients with mild cognitive impairment (MCI) or dementia compared to controls, using cytometry by time-of-flight (CyTOF). We found an adaptive immune signature in AD, and specifically highlight the accumulation of PD1+ CD57+ CD8+ T effector memory cells re-expressing CD45RA in the MCI stage of AD. In addition, several innate and adaptive immune cell subsets correlated to cerebrospinal fluid (CSF) biomarkers of AD neuropathology and measures for cognitive decline. Intriguingly, subsets of memory T and B cells were negatively associated with CSF biomarkers for tau pathology, neurodegeneration and neuroinflammation in AD patients. Lastly, we established the influence of the APOE ε4 allele on peripheral immunity. Our findings illustrate significant peripheral immune alterations associated with both early and late clinical stages of AD, emphasizing the necessity for further investigation into how these changes influence underlying brain pathology. • Peripheral CD8+ TEMRA cells expressing markers associated with senescence accumulate in AD patients before dementia onset. • Peripheral immune cells correlate with AD biomarkers, varying by clinical AD stage. • APOE ε4 modifies peripheral immunity and its association with clinical AD measures.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"43 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140642595","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":"Melatonin: a ferroptosis inhibitor with potential therapeutic efficacy for the post-COVID-19 trajectory of accelerated brain aging and neurodegeneration","authors":"Asmaa Yehia, Osama A. Abulseoud","doi":"10.1186/s13024-024-00728-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00728-6","url":null,"abstract":"The unprecedented pandemic of COVID-19 swept millions of lives in a short period, yet its menace continues among its survivors in the form of post-COVID syndrome. An exponentially growing number of COVID-19 survivors suffer from cognitive impairment, with compelling evidence of a trajectory of accelerated aging and neurodegeneration. The novel and enigmatic nature of this yet-to-unfold pathology demands extensive research seeking answers for both the molecular underpinnings and potential therapeutic targets. Ferroptosis, an iron-dependent cell death, is a strongly proposed underlying mechanism in post-COVID-19 aging and neurodegeneration discourse. COVID-19 incites neuroinflammation, iron dysregulation, reactive oxygen species (ROS) accumulation, antioxidant system repression, renin-angiotensin system (RAS) disruption, and clock gene alteration. These events pave the way for ferroptosis, which shows its signature in COVID-19, premature aging, and neurodegenerative disorders. In the search for a treatment, melatonin shines as a promising ferroptosis inhibitor with its repeatedly reported safety and tolerability. According to various studies, melatonin has proven efficacy in attenuating the severity of certain COVID-19 manifestations, validating its reputation as an anti-viral compound. Melatonin has well-documented anti-aging properties and combating neurodegenerative-related pathologies. Melatonin can block the leading events of ferroptosis since it is an efficient anti-inflammatory, iron chelator, antioxidant, angiotensin II antagonist, and clock gene regulator. Therefore, we propose ferroptosis as the culprit behind the post-COVID-19 trajectory of aging and neurodegeneration and melatonin, a well-fitting ferroptosis inhibitor, as a potential treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140620293","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":"Gut microbiota-host lipid crosstalk in Alzheimer’s disease: implications for disease progression and therapeutics","authors":"Ya-Xi Luo, Ling-Ling Yang, Xiu-Qing Yao","doi":"10.1186/s13024-024-00720-0","DOIUrl":"https://doi.org/10.1186/s13024-024-00720-0","url":null,"abstract":"Trillions of intestinal bacteria in the human body undergo dynamic transformations in response to physiological and pathological changes. Alterations in their composition and metabolites collectively contribute to the progression of Alzheimer’s disease. The role of gut microbiota in Alzheimer’s disease is diverse and complex, evidence suggests lipid metabolism may be one of the potential pathways. However, the mechanisms that gut microbiota mediate lipid metabolism in Alzheimer’s disease pathology remain unclear, necessitating further investigation for clarification. This review highlights the current understanding of how gut microbiota disrupts lipid metabolism and discusses the implications of these discoveries in guiding strategies for the prevention or treatment of Alzheimer’s disease based on existing data.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"41 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140557201","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":"Mitovesicles secreted into the extracellular space of brains with mitochondrial dysfunction impair synaptic plasticity","authors":"Pasquale D’Acunzo, Elentina K. Argyrousi, Jonathan M. Ungania, Yohan Kim, Steven DeRosa, Monika Pawlik, Chris N. Goulbourne, Ottavio Arancio, Efrat Levy","doi":"10.1186/s13024-024-00721-z","DOIUrl":"https://doi.org/10.1186/s13024-024-00721-z","url":null,"abstract":"Hypometabolism tied to mitochondrial dysfunction occurs in the aging brain and in neurodegenerative disorders, including in Alzheimer’s disease, in Down syndrome, and in mouse models of these conditions. We have previously shown that mitovesicles, small extracellular vesicles (EVs) of mitochondrial origin, are altered in content and abundance in multiple brain conditions characterized by mitochondrial dysfunction. However, given their recent discovery, it is yet to be explored what mitovesicles regulate and modify, both under physiological conditions and in the diseased brain. In this study, we investigated the effects of mitovesicles on synaptic function, and the molecular players involved. Hippocampal slices from wild-type mice were perfused with the three known types of EVs, mitovesicles, microvesicles, or exosomes, isolated from the brain of a mouse model of Down syndrome or of a diploid control and long-term potentiation (LTP) recorded. The role of the monoamine oxidases type B (MAO-B) and type A (MAO-A) in mitovesicle-driven LTP impairments was addressed by treatment of mitovesicles with the irreversible MAO inhibitors pargyline and clorgiline prior to perfusion of the hippocampal slices. Mitovesicles from the brain of the Down syndrome model reduced LTP within minutes of mitovesicle addition. Mitovesicles isolated from control brains did not trigger electrophysiological effects, nor did other types of brain EVs (microvesicles and exosomes) from any genotype tested. Depleting mitovesicles of their MAO-B, but not MAO-A, activity eliminated their ability to alter LTP. Mitovesicle impairment of LTP is a previously undescribed paracrine-like mechanism by which EVs modulate synaptic activity, demonstrating that mitovesicles are active participants in the propagation of cellular and functional homeostatic changes in the context of neurodegenerative disorders.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"66 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140553638","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}