Molecular Neurodegeneration最新文献

{"title":"Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease","authors":"Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M. Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T. Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J. Riemenschneider, Nathalie L. Albert, Marc Beyer, Jonas J. Neher, Lars Paeger, Johannes Levin, Günter U. Höglinger, Robert Perneczky, Sibylle I. Ziegler, Matthias Brendel","doi":"10.1186/s13024-024-00752-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00752-6","url":null,"abstract":"Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"7 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138309","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":"Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease","authors":"Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger, Sudha Seshadri, Liang Ma","doi":"10.1186/s13024-024-00751-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00751-7","url":null,"abstract":"The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"17 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090162","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":"Pathological characteristics of axons and alterations of proteomic and lipidomic profiles in midbrain dopaminergic neurodegeneration induced by WDR45-deficiency.","authors":"Panpan Wang, Yaping Shao, Murad Al-Nusaif, Jun Zhang, Huijia Yang, Yuting Yang, Kunhyok Kim, Song Li, Cong Liu, Huaibin Cai, Weidong Le","doi":"10.1186/s13024-024-00746-4","DOIUrl":"10.1186/s13024-024-00746-4","url":null,"abstract":"<p><strong>Background: </strong>Although WD repeat domain 45 (WDR45) mutations have been linked to <math><mi>β</mi></math> -propeller protein-associated neurodegeneration (BPAN), the precise molecular and cellular mechanisms behind this disease remain elusive. This study aims to shed light on the impacts of WDR45-deficiency on neurodegeneration, specifically axonal degeneration, within the midbrain dopaminergic (DAergic) system. We hope to better understand the disease process by examining pathological and molecular alterations, especially within the DAergic system.</p><p><strong>Methods: </strong>To investigate the impacts of WDR45 dysfunction on mouse behaviors and DAergic neurons, we developed a mouse model in which WDR45 was conditionally knocked out in the midbrain DAergic neurons (WDR45<sup>cKO</sup>). Through a longitudinal study, we assessed alterations in the mouse behaviors using open field, rotarod, Y-maze, and 3-chamber social approach tests. We utilized a combination of immunofluorescence staining and transmission electron microscopy to examine the pathological changes in DAergic neuron soma and axons. Additionally, we performed proteomic and lipidomic analyses of the striatum from young and aged mice to identify the molecules and processes potentially involved in the striatal pathology during aging. Further more, primary midbrain neuronal culture was employed to explore the molecular mechanisms leading to axonal degeneration.</p><p><strong>Results: </strong>Our study of WDR45<sup>cKO</sup> mice revealed a range of deficits, including impaired motor function, emotional instability, and memory loss, coinciding with the profound reduction of midbrain DAergic neurons. The neuronal loss, we observed massive axonal enlargements in the dorsal and ventral striatum. These enlargements were characterized by the accumulation of extensively fragmented tubular endoplasmic reticulum (ER), a hallmark of axonal degeneration. Proteomic analysis of the striatum showed that the differentially expressed proteins were enriched in metabolic processes. The carbohydrate metabolic and protein catabolic processes appeared earlier, and amino acid, lipid, and tricarboxylic acid metabolisms were increased during aging. Of note, we observed a tremendous increase in the expression of lysophosphatidylcholine acyltransferase 1 (Lpcat1) that regulates phospholipid metabolism, specifically in the conversion of lysophosphatidylcholine (LPC) to phosphatidylcholine (PC) in the presence of acyl-CoA. The lipidomic results consistently suggested that differential lipids were concentrated on PC and LPC. Axonal degeneration was effectively ameliorated by interfering Lpcat1 expression in primary cultured WDR45-deficient DAergic neurons, proving that Lpcat1 and its regulated lipid metabolism, especially PC and LPC metabolism, participate in controlling the axonal degeneration induced by WDR45 deficits.</p><p><strong>Conclusions: </strong>In this study, we uncovered the molecul","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"62"},"PeriodicalIF":14.9,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11346282/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142056058","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":"Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy","authors":"Hui Wang, Timothy S. Chang, Beth A. Dombroski, Po-Liang Cheng, Vishakha Patil, Leopoldo Valiente-Banuet, Kurt Farrell, Catriona Mclean, Laura Molina-Porcel, Alex Rajput, Peter Paul De Deyn, Nathalie Le Bastard, Marla Gearing, Laura Donker Kaat, John C. Van Swieten, Elise Dopper, Bernardino F. Ghetti, Kathy L. Newell, Claire Troakes, Justo G. de Yébenes, Alberto Rábano-Gutierrez, Tina Meller, Wolfgang H. Oertel, Gesine Respondek, Maria Stamelou, Thomas Arzberger, Sigrun Roeber, Ulrich Müller, Franziska Hopfner, Pau Pastor, Alexis Brice, Alexandra Durr, Isabelle Le Ber, Thomas G. Beach, Geidy E. Serrano, Lili-Naz Hazrati, Irene Litvan, Rosa Rademakers, Owen A. Ross, Douglas Galasko, Adam L. Boxer, Bruce L. Miller, Willian W. Seeley, Vivanna M. Van Deerlin, Edward B. Lee, Charles L. White, Huw Morris, Rohan de Silva, John F. Crary, Alison M. Goate, Jeffrey S. Friedman, Yuk Yee Leung, Giovanni Coppola, Adam C. Naj, Li-San Wang, Clifton Dalgard, Dennis W. Dickson, Günter U. Höglin..","doi":"10.1186/s13024-024-00747-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00747-3","url":null,"abstract":"Progressive supranuclear palsy (PSP) is a rare neurodegenerative disease characterized by the accumulation of aggregated tau proteins in astrocytes, neurons, and oligodendrocytes. Previous genome-wide association studies for PSP were based on genotype array, therefore, were inadequate for the analysis of rare variants as well as larger mutations, such as small insertions/deletions (indels) and structural variants (SVs). In this study, we performed whole genome sequencing (WGS) and conducted association analysis for single nucleotide variants (SNVs), indels, and SVs, in a cohort of 1,718 cases and 2,944 controls of European ancestry. Of the 1,718 PSP individuals, 1,441 were autopsy-confirmed and 277 were clinically diagnosed. Our analysis of common SNVs and indels confirmed known genetic loci at MAPT, MOBP, STX6, SLCO1A2, DUSP10, and SP1, and further uncovered novel signals in APOE, FCHO1/MAP1S, KIF13A, TRIM24, TNXB, and ELOVL1. Notably, in contrast to Alzheimer’s disease (AD), we observed the APOE ε2 allele to be the risk allele in PSP. Analysis of rare SNVs and indels identified significant association in ZNF592 and further gene network analysis identified a module of neuronal genes dysregulated in PSP. Moreover, seven common SVs associated with PSP were observed in the H1/H2 haplotype region (17q21.31) and other loci, including IGH, PCMT1, CYP2A13, and SMCP. In the H1/H2 haplotype region, there is a burden of rare deletions and duplications (P = 6.73 × 10–3) in PSP. Through WGS, we significantly enhanced our understanding of the genetic basis of PSP, providing new targets for exploring disease mechanisms and therapeutic interventions.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"40 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994519","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":"Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease","authors":"Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham","doi":"10.1186/s13024-024-00749-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00749-1","url":null,"abstract":"Lewy body dementia (LBD), a class of disorders comprising Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB), features substantial clinical and pathological overlap with Alzheimer’s disease (AD). The identification of biomarkers unique to LBD pathophysiology could meaningfully advance its diagnosis, monitoring, and treatment. Using quantitative mass spectrometry (MS), we measured over 9,000 proteins across 138 dorsolateral prefrontal cortex (DLPFC) tissues from a University of Pennsylvania autopsy collection comprising control, Parkinson’s disease (PD), PDD, and DLB diagnoses. We then analyzed co-expression network protein alterations in those with LBD, validated these disease signatures in two independent LBD datasets, and compared these findings to those observed in network analyses of AD cases. The LBD network revealed numerous groups or “modules” of co-expressed proteins significantly altered in PDD and DLB, representing synaptic, metabolic, and inflammatory pathophysiology. A comparison of validated LBD signatures to those of AD identified distinct differences between the two diseases. Notably, synuclein-associated presynaptic modules were elevated in LBD but decreased in AD relative to controls. We also found that glial-associated matrisome signatures consistently elevated in AD were more variably altered in LBD, ultimately stratifying those LBD cases with low versus high burdens of concurrent beta-amyloid deposition. In conclusion, unbiased network proteomic analysis revealed diverse pathophysiological changes in the LBD frontal cortex distinct from alterations in AD. These results highlight the LBD brain network proteome as a promising source of biomarkers that could enhance clinical recognition and management.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"22 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141895350","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":"Single-cell peripheral immunoprofiling of lewy body and Parkinson's disease in a multi-site cohort.","authors":"Thanaphong Phongpreecha, Kavita Mathi, Brenna Cholerton, Eddie J Fox, Natalia Sigal, Camilo Espinosa, Momsen Reincke, Philip Chung, Ling-Jen Hwang, Chandresh R Gajera, Eloise Berson, Amalia Perna, Feng Xie, Chi-Hung Shu, Debapriya Hazra, Divya Channappa, Jeffrey E Dunn, Lucas B Kipp, Kathleen L Poston, Kathleen S Montine, Holden T Maecker, Nima Aghaeepour, Thomas J Montine","doi":"10.1186/s13024-024-00748-2","DOIUrl":"10.1186/s13024-024-00748-2","url":null,"abstract":"<p><strong>Background: </strong>Multiple lines of evidence support peripheral organs in the initiation or progression of Lewy body disease (LBD), a spectrum of neurodegenerative diagnoses that include Parkinson's Disease (PD) without or with dementia (PDD) and dementia with Lewy bodies (DLB). However, the potential contribution of the peripheral immune response to LBD remains unclear. This study aims to characterize peripheral immune responses unique to participants with LBD at single-cell resolution to highlight potential biomarkers and increase mechanistic understanding of LBD pathogenesis in humans.</p><p><strong>Methods: </strong>In a case-control study, peripheral mononuclear cell (PBMC) samples from research participants were randomly sampled from multiple sites across the United States. The diagnosis groups comprise healthy controls (HC, n = 159), LBD (n = 110), Alzheimer's disease dementia (ADD, n = 97), other neurodegenerative disease controls (NDC, n = 19), and immune disease controls (IDC, n = 14). PBMCs were activated with three stimulants (LPS, IL-6, and IFNa) or remained at basal state, stained by 13 surface markers and 7 intracellular signal markers, and analyzed by flow cytometry, which generated 1,184 immune features after gating.</p><p><strong>Results: </strong>The model classified LBD from HC with an AUROC of 0.87 ± 0.06 and AUPRC of 0.80 ± 0.06. Without retraining, the same model was able to distinguish LBD from ADD, NDC, and IDC. Model predictions were driven by pPLCγ2, p38, and pSTAT5 signals from specific cell populations under specific activation. The immune responses characteristic for LBD were not associated with other common medical conditions related to the risk of LBD or dementia, such as sleep disorders, hypertension, or diabetes.</p><p><strong>Conclusions and relevance: </strong>Quantification of PBMC immune response from multisite research participants yielded a unique pattern for LBD compared to HC, multiple related neurodegenerative diseases, and autoimmune diseases thereby highlighting potential biomarkers and mechanisms of disease.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"59"},"PeriodicalIF":14.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11295553/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141875304","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":"Astrocyte reactivity is associated with tau tangle load and cortical thinning in Alzheimer's disease.","authors":"Tengfei Guo, Anqi Li, Pan Sun, Zhengbo He, Yue Cai, Guoyu Lan, Lin Liu, Jieyin Li, Jie Yang, Yalin Zhu, Ruiyue Zhao, Xuhui Chen, Dai Shi, Zhen Liu, Qingyong Wang, Linsen Xu, Liemin Zhou, Pengcheng Ran, Xinlu Wang, Kun Sun, Jie Lu, Ying Han","doi":"10.1186/s13024-024-00750-8","DOIUrl":"10.1186/s13024-024-00750-8","url":null,"abstract":"<p><strong>Background: </strong>It is not fully established whether plasma β-amyloid(Aβ)₄₂/Aβ₄₀ and phosphorylated Tau₁₈₁ (p-Tau₁₈₁) can effectively detect Alzheimer's disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.</p><p><strong>Methods: </strong>We recruited 470 older adults and analyzed plasma Aβ₄₂/Aβ₄₀, p-Tau₁₈₁, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ₄₂/Aβ₄₀ and p-Tau₁₈₁ thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ₄₂/Aβ₄₀ (A) and p-Tau₁₈₁ (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.</p><p><strong>Results: </strong>Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau₁₈₁ and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau₁₈₁ and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ₄₂/Aβ₄₀ and higher plasma p-Tau₁₈₁ in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.</p><p><strong>Discussion: </strong>This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":"58"},"PeriodicalIF":14.9,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11290175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141856026","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":"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":"&lt;p&gt;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.&lt;/p&gt;&lt;p&gt;Compared to mAb-mediated immunotherapies, antisense oligonucleotides (ASOs) aimed at lowering levels of Aβ either by targeting &lt;i&gt;APP&lt;/i&gt; 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 &lt;i&gt;APP&lt;/i&gt; 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 &lt;i&gt;APP&lt;/i&gt; exon encoding proteolytic cleavage sites required for Aβ peptide production [3]. Similarly, tau plays a key role in AD pathophysiology [4]. MAPTR&lt;sub&gt;x&lt;/sub&gt; 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].&lt;/p&gt;&lt;p&gt;In the latest issue of &lt;i&gt;Brain&lt;/i&gt;, 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 &lt;i&gt;APP&lt;/i&gt; 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.&lt;/p&gt;&lt;p&gt;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":"&lt;p&gt;&lt;b&gt;Correction: Molecular Neurodegeneration (2024) 19:29&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s13024-024-00718-8&lt;/b&gt;&lt;/p&gt;&lt;p&gt;The original article contains an error in Figure 1A.&lt;/p&gt;&lt;figure&gt;&lt;picture&gt;&lt;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\"/&gt;&lt;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\"/&gt;&lt;/picture&gt;&lt;/figure&gt;&lt;p&gt;The corrected figure amends the statistical significance annotation of ‘ns’ to ‘*’ and can be viewed ahead.&lt;/p&gt;&lt;span&gt;Author notes&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt; Anna Calliari and Lillian M. Daughrity contributed equally to this work.&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;h3&gt;Authors and Affiliations&lt;/h3&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA&lt;/p&gt;&lt;p&gt;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 &amp; Leonard Petrucelli&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Neurobiology of Disease Graduate Program, Mayo Graduate School, Mayo Clinic College of Medicine, Rochester, MN, USA&lt;/p&gt;&lt;p&gt;Michael DeTure, Casey Cook, Dennis W. Dickson, Tania F. Gendron, Mercedes Prudencio, Yong-Jie Zhang &amp; Leonard Petrucelli&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Neurology, Mayo Clinic, Jacksonville, FL, USA&lt;/p&gt;&lt;p&gt;Neill R. Graff-Radford, Gregory S. Day &amp; Björn Oskarsson&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Neurology, Mayo Clinic, Rochester, MN, USA&lt;/p&gt;&lt;p&gt;Bradley F. Boeve, David S. Knopman, Ronald C. Petersen &amp; Keith A. Josephs&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA&lt;/p&gt;&lt;p&gt;Aaron D. Gitler&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA&lt;/p&gt;&lt;p&gt;Michael E. Ward&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;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&lt;/p&gt;&lt;p&gt;Michael E. Ward&lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;span&gt;Authors&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;span&gt;Anna Calliari&lt;/span&gt;View author publications&lt;p&gt;You can also search for this author in &lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Lillian M. Daughrity&lt;/span&gt;View author publications&lt;p&gt;You can also search for this author in &lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Ellen A. Albagli&lt;/span&gt;View author publications&lt;p&gt;You can also search for this author in &lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Paula Castellanos Otero&lt;/span&gt;View author publications&lt;p&gt;You can also search for this author in &lt;span&gt;PubMed&lt;span&gt; &lt;/span&gt;Google Scholar&lt;/span&gt;&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;span&gt;Mei Yue&lt;/span&gt;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}