Molecular Neurodegeneration最新文献

{"title":"Proteomic analysis of APOEε4 carriers implicates lipid metabolism, complement and lymphocyte signaling in cognitive resilience","authors":"Keenan A. Walker, Yang An, Abhay Moghekar, Ruin Moaddel, Michael R. Duggan, Zhongsheng Peng, Qu Tian, Luke C. Pilling, Shannon M. Drouin, Mark A. Espeland, Stephen R Rapp, Kathleen M Hayden, Aladdin H. Shadyab, Ramon Casanova, Madhav Thambisetty, Peter R. Rapp, Dimitrios Kapogiannis, Luigi Ferrucci, Susan M. Resnick","doi":"10.1186/s13024-024-00772-2","DOIUrl":"https://doi.org/10.1186/s13024-024-00772-2","url":null,"abstract":"Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P < 0.05. While one of the candidate proteins, a marker of neuronal injury (NfL), also distinguished resilient from non-resilient APOEε3 homozygotes, the other three proteins, known to be involved in lipid metabolism (ANGPTL4) and immune signaling (PTX3, NCR1), only predicted resilient vs. non-resilient status among APOEε4 carriers (protein*genotype interaction-P < 0.05). Three of these four proteins also predicted 14-year dementia risk among APOEε4 carriers in the UK Biobank validation sample (N = 9420). While the candidate proteins showed little to no association with targeted biomarkers of AD pathology, protein network and enrichment analyses suggested that natural killer (NK) cell and T lymphocyte signaling (via PKC-θ) distinguished resilient from non-resilient APOEε4 carriers. We identified and replicated a plasma proteomic signature associated with cognitive resilience among APOEε4 carriers. These proteins implicate specific immune processes in the preservation of cognitive status despite elevated genetic risk for AD. Future studies in diverse cohorts will be needed to assess the generalizability of these results.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142555723","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":"Repetitive transcranial magnetic stimulation alleviates motor impairment in Parkinson’s disease: association with peripheral inflammatory regulatory T-cells and SYT6","authors":"Fen Xie, Bibiao Shen, Yuqi Luo, Hang Zhou, Zhenchao Xie, Shuzhen Zhu, Xiaobo Wei, Zihan Chang, Zhaohua Zhu, Changhai Ding, Kunlin Jin, Chengwu Yang, Lucia Batzu, K Ray Chaudhuri, Ling-Ling Chan, Eng-King Tan, Qing Wang","doi":"10.1186/s13024-024-00770-4","DOIUrl":"https://doi.org/10.1186/s13024-024-00770-4","url":null,"abstract":"Repetitive transcranial magnetic stimulation (rTMS) has been used to treat various neurological disorders. However, the molecular mechanism underlying the therapeutic effect of rTMS on Parkinson’s disease (PD) has not been fully elucidated. Neuroinflammation like regulatory T-cells (Tregs) appears to be a key modulator of disease progression in PD. If rTMS affects the peripheral Tregs in PD remains unknown. Here, we conducted a prospective clinical study (Chinese ClinicalTrials. gov: ChiCTR 2100051140) involving 54 PD patients who received 10-day rTMS (10 Hz) stimulation on the primary motor cortex (M1) region or sham treatment. Clinical and function assessment as well as flow cytology study were undertaken in 54 PD patients who were consecutively recruited from the department of neurology at Zhujiang hospital between September 2021 and January 2022. Subsequently, we implemented flow cytometry analysis to examine the Tregs population in spleen of MPTP-induced PD mice that received rTMS or sham treatment, along with quantitative proteomic approach reveal novel molecular targets for Parkinson's disease, and finally, the RNA interference method verifies the role of these new molecular targets in the treatment of PD. We demonstrated that a 10-day rTMS treatment on the M1 motor cortex significantly improved motor dysfunction in PD patients. The beneficial effects persisted for up to 40 days, and were associated with an increase in peripheral Tregs. There was a positive correlation between Tregs and motor improvements in PD cases. Similarly, a 10-day rTMS treatment on the brains of MPTP-induced PD mice significantly ameliorated motor symptoms. rTMS reversed the downregulation of circulating Tregs and tyrosine hydroxylase neurons in these mice. It also increased anti-inflammatory mediators, deactivated microglia, and decreased inflammatory cytokines. These effects were blocked by administration of a Treg inhibitor anti-CD25 antibody in MPTP-induced PD mice. Quantitative proteomic analysis identified TLR4, TH, Slc6a3 and especially Syt6 as the hub node proteins related to Tregs and rTMS therapy. Lastly, we validated the role of Treg and rTMS-related protein syt6 in MPTP mice using the virus interference method. Our clinical and experimental studies suggest that rTMS improves motor function by modulating the function of Tregs and suppressing toxic neuroinflammation. Hub node proteins (especially Syt6) may be potential therapeutic targets. Chinese ClinicalTrials, ChiCTR2100051140. Registered 15 December 2021, https://www.chictr.org.cn/bin/project/edit?pid=133691 rTMS is a safe and non-invasive method for Parkinson's disease. In this study, we showed the proportion of CD4+CD25+CD127- regulatory T-cells (Tregs) in the peripheral blood was significantly increased after rTMS treatment. Similar effects of rTMS treatment were verified in MPTP-induced PD mice. Proteomic analysis and RNA interference analyses identified TLR4, TH, Slc6a3 and especially Syt6 as hub ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142490289","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":"HDGFL2 cryptic protein: a portal to detection and diagnosis in neurodegenerative disease","authors":"Ellen A. Albagli, Anna Calliari, Tania F. Gendron, Yong-Jie Zhang","doi":"10.1186/s13024-024-00768-y","DOIUrl":"https://doi.org/10.1186/s13024-024-00768-y","url":null,"abstract":"&lt;p&gt;In 2006, TAR DNA-binding protein of 43 kDa (TDP-43) was discovered as the major ubiquitinated and aggregated protein in approximately 95% of amyotrophic lateral sclerosis (ALS) cases and 45% of frontotemporal lobar degeneration (FTLD) cases [1]. Since then, TDP-43 pathology has been identified in Alzheimer’s disease (AD), limbic-predominant age-related TDP-43 encephalopathy (LATE), and other neurodegenerative diseases [2]. This discovery initiated copious studies uncovering the pathomechanisms through which TDP-43, an RNA-binding protein with roles in alternative splicing, causes neurodegeneration [2] – chief among them, its loss of function owing to its aggregation in the cytoplasm and concurrent depletion from the nucleus.&lt;/p&gt;&lt;p&gt;TDP-43 proteinopathies share clinical, genetic, and pathological features, and this is particularly true of frontotemporal dementia (FTD) and ALS. While no treatments for FTD, ALS, or other TDP-43 proteinopathies yet exist, developing effective therapies for these fatal neurodegenerative diseases would benefit from biomarkers that facilitate an early and accurate diagnosis. Indeed, therapies are expected to be most effective when initiated early in the disease course. Biomarkers that identify the underlying pathology of patients with FTD in life would also aid in selecting appropriate participants for clinical trials targeting TDP-43 proteinopathy. As patients with behavioral variant FTD are essentially just as likely to develop TDP-43 or tau pathology, biomarkers that inform the presence of TDP-43 pathology would be particularly useful for this group, as would patients with AD who often develop mixed pathologies [3]. Although studies have examined whether TDP-43 itself could fulfill these biomarker needs, multiple efforts in detecting pathological TDP-43 species in biofluids have so far been unsuccessful [4]. Nevertheless, an exciting avenue being pursued harnesses the consequences of TDP-43 loss of function; more specifically, TDP-43’s inability to repress the splicing of non-conserved cryptic exons (CE) [5]. This engenders the production of novel RNA isoforms bearing non-conserved intronic sequences that often introduce frameshifts, premature stop codons, or premature polyadenylation sequences. For example, inclusion of a CE in &lt;i&gt;STMN2&lt;/i&gt; mRNA produces a truncated stathmin-2 protein at the expense of its full-length counterpart, whereas inclusion of a CE in &lt;i&gt;UNC13A&lt;/i&gt; mRNA reduces UNC13A protein expression (Fig. 1A) [6]. While cryptic RNAs including &lt;i&gt;STMN2&lt;/i&gt;-CE and &lt;i&gt;UNC13A&lt;/i&gt;-CE have been detected in postmortem brain tissue [6], they have yet to be detected in biofluids, hindering their application for biomarker development. Perhaps most pertinent to biomarker development, consequently, are the cryptic transcripts that generate &lt;i&gt;de novo&lt;/i&gt; proteins.&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaption&gt;&lt;picture&gt;&lt;source srcset=\"//media.springernature.com/lw685/springer-stat","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489521","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-first Parkinson’s disease is encoded by gut dysbiome","authors":"Mário F. Munoz-Pinto, Emanuel Candeias, Inês Melo-Marques, A. Raquel Esteves, Ana Maranha, João D. Magalhães, Diogo Reis Carneiro, Mariana Sant’Anna, A. Raquel Pereira-Santos, António E Abreu, Daniela Nunes-Costa, Susana Alarico, Igor Tiago, Ana Morgadinho, João Lemos, Pedro N. Figueiredo, Cristina Januário, Nuno Empadinhas, Sandra Morais Cardoso","doi":"10.1186/s13024-024-00766-0","DOIUrl":"https://doi.org/10.1186/s13024-024-00766-0","url":null,"abstract":"In Parkinson's patients, intestinal dysbiosis can occur years before clinical diagnosis, implicating the gut and its microbiota in the disease. Recent evidence suggests the gut microbiota may trigger body-first Parkinson Disease (PD), yet the underlying mechanisms remain unclear. This study aims to elucidate how a dysbiotic microbiome through intestinal immune alterations triggers PD-related neurodegeneration. To determine the impact of gut dysbiosis on the development and progression of PD pathology, wild-type male C57BL/6 mice were transplanted with fecal material from PD patients and age-matched healthy donors to challenge the gut-immune-brain axis. This study demonstrates that patient-derived intestinal microbiota caused midbrain tyrosine hydroxylase positive (TH +) cell loss and motor dysfunction. Ileum-associated microbiota remodeling correlates with a decrease in Th17 homeostatic cells. This event led to an increase in gut inflammation and intestinal barrier disruption. In this regard, we found a decrease in CD4 + cells and an increase in pro-inflammatory cytokines in the blood of PD transplanted mice that could contribute to an increase in the permeabilization of the blood–brain-barrier, observed by an increase in mesencephalic Ig-G-positive microvascular leaks and by an increase of mesencephalic IL-17 levels, compatible with systemic inflammation. Furthermore, alpha-synuclein aggregates can spread caudo-rostrally, causing fragmentation of neuronal mitochondria. This mitochondrial damage subsequently activates innate immune responses in neurons and triggers microglial activation. We propose that the dysbiotic gut microbiome (dysbiome) in PD can disrupt a healthy microbiome and Th17 homeostatic immunity in the ileum mucosa, leading to a cascade effect that propagates to the brain, ultimately contributing to PD pathophysiology. Our landmark study has successfully identified new peripheral biomarkers that could be used to develop highly effective strategies to prevent the progression of PD into the brain. ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142489593","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":"Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer's disease.","authors":"Xavier Taylor, Harun N Noristani, Griffin J Fitzgerald, Herold Oluoch, Nick Babb, Tyler McGathey, Lindsay Carter, Justin T Hole, Pascale N Lacor, Ronald B DeMattos, Yaming Wang","doi":"10.1186/s13024-024-00758-0","DOIUrl":"10.1186/s13024-024-00758-0","url":null,"abstract":"<p><strong>Background: </strong>Anti-amyloid-β (Aβ) immunotherapy trials have revealed amyloid-related imaging abnormalities (ARIA) as the most prevalent and serious adverse events linked to pathological changes in cerebral vasculature. Recent studies underscore the critical involvement of perivascular macrophages and the infiltration of peripheral immune cells in regulating cerebrovascular damage. Specifically, Aβ antibodies engaged at cerebral amyloid angiopathy (CAA) deposits trigger perivascular macrophage activation and the upregulation of genes associated with vascular permeability. Nevertheless, further research is needed to understand the immediate downstream consequences of macrophage activation, potentially exacerbating CAA-related vascular permeability and microhemorrhages linked to Aβ immunotherapy.</p><p><strong>Methods: </strong>This study investigates immune responses induced by amyloid-targeting antibodies and CAA-induced microhemorrhages using RNA in situ hybridization, histology and digital spatial profiling in an Alzheimer's disease (AD) mouse model of microhemorrhage.</p><p><strong>Results: </strong>In the present study, we have demonstrated that bapineuzumab murine surrogate (3D6) induces profound vascular damage, leading to smooth muscle cell loss and blood-brain barrier (BBB) breakdown. In addition, digital spatial profiling (DSP) reveals that distinct immune responses contribute to vascular damage with peripheral immune responses and perivascular macrophage activation linked to smooth muscle cell loss and vascular fibrosis, respectively. Finally, RNA in situ hybridization identifies two distinct subsets of Trem2⁺ macrophages representing tissue-resident and monocyte-derived macrophages around vascular amyloid deposits. Overall, these findings highlight multifaceted roles of immune activation and vascular damage in driving the development of microhemorrhage.</p><p><strong>Conclusions: </strong>In summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2⁺ macrophage populations in response to Aβ immunotherapy.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11494988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142470236","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":"Comparing anti-tau antibodies under clinical trials and their epitopes on tau pathologies","authors":"Ha-Lim Song, Min-Seok Kim, Woo-Young Cho, Ye-Seul Yoo, Jae-You Kim, Tae-Wook Kim, Hyori Kim, Dong-Hou Kim, Seung-Yong Yoon","doi":"10.1186/s13024-024-00769-x","DOIUrl":"https://doi.org/10.1186/s13024-024-00769-x","url":null,"abstract":"&lt;p&gt;To the Editor,&lt;/p&gt;&lt;p&gt;Tauopathies, including Alzheimer’s disease (AD), are characterized by the accumulation of abnormal tau protein deposits in the brain. Tau exists in multiple heterogenous forms of various polypeptide fragments by enzymatic cleavage and post-translational modifications (PTMs) [1]. Insights from clinical trials of anti-β-amyloid (Aβ) antibodies highlight the importance of epitope selection, as targeting Aβ protofibrils or N-terminus influenced both target engagement and downstream pathogenic processes [2]. Initially, anti-tau antibodies targeting the N-terminus were developed because these N-terminal fragments predominated in AD cerebrospinal fluid (CSF) and were implicated in tau spread [3]. However, these trials ultimately failed [4], aligning with earlier findings that indicated insufficient inhibition of tau seeding [5]. Although other epitopes, such as mid-region, microtubule-binding region (MTBR) and C-terminus, are being explored, the most effective target remains unclear. Certain tau fragments are suggested to play critical roles in tau pathology development [1] and studies in the interstitial fluid (ISF) of tau transgenic mice brains show that secreted tau is primarily truncated during disease progression [6]. The complexity of tau cleavage and PTMs emphasizes the significance of epitope selection, especially in the context of low brain penetration of antibodies, to effectively bind seed-competent forms and counteract propagation.&lt;/p&gt;&lt;p&gt;To investigate this issue, the potency of various anti-tau antibodies under clinical trials was compared using sarkosyl-insoluble fractions isolated from AD patient brains. Inhibition of tau seeding by antibodies targeting the N-terminus (antibody A), mid-region (antibody B), and MTBR (antibody C and D) (Fig. 1a and table S1) was tested using tau fluorescence resonance energy transfer (FRET) cells. Initial study using fraction from a single patient to determine adequate concentration yielded dose-dependent inhibition of tau seeding with anti-tau antibody treatment. Cells treated with anti-acetylated lysine-280 (acK280) antibody, antibody C, showed the most significant decrease in FRET signal at 1 µg/mL (Fig. S1a). Using this concentration as baseline, subsequent tests with insoluble tau fractions from the entorhinal cortex (&lt;i&gt;n&lt;/i&gt; = 4) or hippocampus (&lt;i&gt;n&lt;/i&gt; = 5) of AD patients revealed that antibody C induced a statistically significant inhibitory effect on tau seeding (Fig. 1b and c, and table S2). With the entorhinal cortex, both antibodies targeting the MTBR, C and D, inhibited tau seeding, with antibody C showing superior effects (Fig. 1b). With the hippocampus, only antibody C was effective (Fig. 1c). Further analysis by Braak stages showed that only antibody C significantly reduced tau seeding in both Braak 3–4 (Fig. S1b) and Braak 5–6 (Fig. S1c). These results indicate that the anti-tau antibody targeting acK280 on MTBR was most potent in inhibiting tau seeding from AD bra","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451406","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":"Increased expression of mesencephalic astrocyte-derived neurotrophic factor (MANF) contributes to synapse loss in Alzheimer’s disease","authors":"Yiran Zhang, Xiusheng Chen, Laiqiang Chen, Mingting Shao, Wenzhen Zhu, Tingting Xing, Tingting Guo, Qingqing Jia, Huiming Yang, Peng Yin, Xiao-Xin Yan, Jiandong Yu, Shihua Li, Xiao-Jiang Li, Su Yang","doi":"10.1186/s13024-024-00771-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00771-3","url":null,"abstract":"The activation of endoplasmic reticulum (ER) stress is an early pathological hallmark of Alzheimer’s disease (AD) brain, but how ER stress contributes to the onset and development of AD remains poorly characterized. Mesencephalic astrocyte-derived neurotrophic factor (MANF) is a non-canonical neurotrophic factor and an ER stress inducible protein. Previous studies reported that MANF is increased in the brains of both pre-symptomatic and symptomatic AD patients, but the consequence of the early rise in MANF protein is unknown. We examined the expression of MANF in the brain of AD mouse models at different pathological stages. Through behavioral, electrophysiological, and neuropathological analyses, we assessed the level of synaptic dysfunctions in the MANF transgenic mouse model which overexpresses MANF in the brain and in wild type (WT) mice with MANF overexpression in the hippocampus. Using proteomic and transcriptomic screening, we identified and validated the molecular mechanism underlying the effects of MANF on synaptic function. We found that increased expression of MANF correlates with synapse loss in the hippocampus of AD mice. The ectopic expression of MANF in mice via transgenic or viral approaches causes synapse loss and defects in learning and memory. We also identified that MANF interacts with ELAV like RNA-binding protein 2 (ELAVL2) and affects its binding to RNA transcripts that are involved in synaptic functions. Increasing or decreasing MANF expression in the hippocampus of AD mice exacerbates or ameliorates the behavioral deficits and synaptic pathology, respectively. Our study established MANF as a mechanistic link between ER stress and synapse loss in AD and hinted at MANF as a therapeutic target in AD treatment.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142449475","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":"Retraction Note: Aging exacerbates the brain inflammatory micro-environment contributing to α-synuclein pathology and functional deficits in a mouse model of DLB/PD","authors":"Michiyo Iba, Ross A. McDevitt, Changyoun Kim, Roshni Roy, Dimitra Sarantopoulou, Ella Tommer, Byron Siegars, Michelle Sallin, Somin Kwon, Jyoti Misra Sen, Ranjan Sen, Eliezer Masliah","doi":"10.1186/s13024-024-00762-4","DOIUrl":"https://doi.org/10.1186/s13024-024-00762-4","url":null,"abstract":"This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13024-022-00564-6.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440133","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: 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/s13024-024-00763-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00763-3","url":null,"abstract":"&lt;p&gt;&lt;b&gt;Correction&lt;/b&gt;&lt;b&gt;: &lt;/b&gt;&lt;b&gt;Mol Neurodegeneration 19, 61 (2024)&lt;/b&gt;&lt;/p&gt;&lt;p&gt;&lt;b&gt;https://doi.org/10.1186/s13024-024-00747-3&lt;/b&gt;&lt;/p&gt;&lt;br/&gt;&lt;p&gt;The original article [1] erroneously gives a wrong affiliation for Ulrich Müller. His correct affiliation is Institute of Human Genetics, Justus-Liebig University Giessen, 35392 Giessen, Germany.&lt;/p&gt;&lt;ol data-track-component=\"outbound reference\" data-track-context=\"references section\"&gt;&lt;li data-counter=\"1.\"&gt;&lt;p&gt;Wang H, Chang TS, Dombroski BA, et al. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy. Mol Neurodegeneration. 2024;19:61. https://doi.org/10.1186/s13024-024-00747-3.&lt;/p&gt;&lt;p&gt;Article CAS Google Scholar &lt;/p&gt;&lt;/li&gt;&lt;/ol&gt;&lt;p&gt;Download references&lt;svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"&gt;&lt;use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"&gt;&lt;/use&gt;&lt;/svg&gt;&lt;/p&gt;&lt;span&gt;Author notes&lt;/span&gt;&lt;ol&gt;&lt;li&gt;&lt;p&gt;Hui Wang and Timothy S. Chang 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 Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA&lt;/p&gt;&lt;p&gt;Hui Wang, Beth A. Dombroski, Po-Liang Cheng, Vivanna M. Van Deerlin, Edward B. Lee, Yuk Yee Leung, Adam C. Naj, Li-San Wang, Gerard D. Schellenberg &amp; Wan-Ping Lee&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA&lt;/p&gt;&lt;p&gt;Hui Wang, Beth A. Dombroski, Po-Liang Cheng, Yuk Yee Leung, Adam C. Naj, Li-San Wang, Gerard D. Schellenberg &amp; Wan-Ping Lee&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA&lt;/p&gt;&lt;p&gt;Timothy S. Chang, Vishakha Patil, Leopoldo Valiente-Banuet, Giovanni Coppola &amp; Daniel H. Geschwind&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Department of Pathology, Department of Artificial Intelligence &amp; Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain, Institute, Neuropathology Brain Bank &amp; Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA&lt;/p&gt;&lt;p&gt;Kurt Farrell &amp; John F. Crary&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia&lt;/p&gt;&lt;p&gt;Catriona Mclean&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Alzheimer’s Disease and Other Cognitive Disorders Unit. Neurology Service, Hospital Clínic, Fundació Recerca Clínic Barcelona (FRCB). Institut d’Investigacions Biomediques August Pi I Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain&lt;/p&gt;&lt;p&gt;Laura Molina-Porcel&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain&lt;/p&gt;&lt;p&gt;Laura Molina-Porcel&lt;/p&gt;&lt;/li&gt;&lt;li&gt;&lt;p&gt;Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, SK, Canada&lt;/p&gt;&lt;p&gt;Alex Rajput&lt;/p&gt;&lt;/li&gt;","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431639","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":"A perspective on Alzheimer’s disease: exploring the potential of terminal/paradoxical lucidity and psychedelics","authors":"Cong Lin, Xiubo Du, Xiaohui Wang","doi":"10.1186/s13024-024-00761-5","DOIUrl":"https://doi.org/10.1186/s13024-024-00761-5","url":null,"abstract":"&lt;p&gt;Alzheimer’s disease (AD) remains a formidable challenge in the field of neurodegenerative disorders, characterized by an insidious onset of memory impairment and a gradual cognitive decline. The molecular pathologies underlying AD are complex and multifactorial, involving a combination of genetic, biochemical, and immunological factors that contribute to its progression [1, 2]. The challenges in treating AD are exacerbated by the molecular complexity of the disease, which has hindered the development of target-based therapeutics. Most existing medications are primarily beneficial only in the early stages of AD, where they can slow the disease’s progression. However, a significant treatment gap exists for late-stage AD, characterized by extensive neuronal damage and severe cognitive decline [3]. This extensive damage complicates efforts to reverse or significantly improve symptoms, posing a major challenge in developing effective interventions for this advanced stage.&lt;/p&gt;&lt;p&gt;Recent observations of terminal/paradoxical lucidity in patients with severe dementia have challenged the longstanding belief that cognitive decline in AD is irreversible. Terminal/paradoxical lucidity refers to unexpected episodes in which individuals with severe dementia temporarily regain cognitive abilities, such as clear communication, emotional expression, and memory recall, typically occurring shortly before death [4]. A recent study indicates that insights into the basis of terminal/paradoxical lucidity may be enhanced by the possibility of regional fluctuations in amyloid-β (Aβ) oligomerization occurring on the appropriate timescale, as shown by cyclic azapeptide oligomer positron emission tomography (PET) ligands. Unlike the continuous amyloid accumulation seen with standard fibrillar amyloid PET, the oligomer tracer shows fluctuations over time without a clear pattern. At certain moments, the ligand illuminates the parietal cortex, but later that area becomes inactive while another region becomes active [5]. Traditionally, it has been thought that once neural pathways are damaged in AD, the decline is permanent due to irreparable pathway damage. However, terminal lucidity suggests that cognitive decline might be reversible, at least momentarily. This phenomenon is unlikely to result from the repair of damaged pathways, as previously assumed in dementia research. Instead, it seems more plausible that these lucidity episodes arise from the spontaneous formation of neural bypasses. These bypasses could temporarily restore connectivity at the network level, facilitating a transient resurgence of cognitive functions in patients with severe dementia [6]. Evidence suggests that it is possible to establish new pathways or circuits, with even silent synapses serving as potential starting points, to circumvent damaged areas and temporarily restore original functions. The abundance of silent synapses in the adult cortex was found to be significantly higher, by an order of ma","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142415691","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}