Pub Date : 2024-10-31DOI: 10.1186/s13024-024-00772-2
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
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.
{"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}
Pub Date : 2024-10-25DOI: 10.1186/s13024-024-00770-4
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
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
{"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}
Pub Date : 2024-10-25DOI: 10.1186/s13024-024-00768-y
Ellen A. Albagli, Anna Calliari, Tania F. Gendron, Yong-Jie Zhang
<p>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.</p><p>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 <i>STMN2</i> mRNA produces a truncated stathmin-2 protein at the expense of its full-length counterpart, whereas inclusion of a CE in <i>UNC13A</i> mRNA reduces UNC13A protein expression (Fig. 1A) [6]. While cryptic RNAs including <i>STMN2</i>-CE and <i>UNC13A</i>-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 <i>de novo</i> proteins.</p><figure><figcaption><b data-test="figure-caption-text">Fig. 1</b></figcaption><picture><source srcset="//media.springernature.com/lw685/springer-stat
随着我们进一步研究 HDGLF2-CE 作为生物标志物的作用，HDGFL2-CE 和其他隐性蛋白的功能也应得到阐明。Seddighi等人发现，HDGFL2-CE改变了HDGFL2的相互作用组，HDGFL2-CE与RNA结合蛋白的相互作用增加，而与细胞骨架蛋白的相互作用减少，这表明HDGFL2-CE诱导毒性增益和功能缺失，从而可能影响疾病的发生和发展[7]。破译转录本中隐性外显子内含物导致神经退行性变的病理机制将拓宽我们对疾病发病机制的认识，并可能为治疗 TDP-43 蛋白病提供更有针对性的方法。AD:阿尔茨海默病ALS:肌萎缩侧索硬化症CE:隐性外显子CNS:中枢神经系统CSF:脑脊液FTD:额颞叶痴呆FTLD:额颞叶变性HDGFL2:肝瘤衍生生长因子iPSC:诱导多能干细胞LATE：Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, et al.前颞叶变性和肌萎缩侧索硬化症中的泛素化 TDP-43。科学。2006;314(5796):130-3.Article CAS PubMed Google Scholar de Boer EMJ, Orie VK, Williams T, Baker MR, De Oliveira HM, Polvikoski T, et al. TDP-43 proteinopathies: a new wave of neurodegenerative diseases.J Neurol Neurosurg Psychiatry.2020;92(1):86-95.Article PubMed Google Scholar James BD, Wilson RS, Boyle PA, Trojanowski JQ, Bennett DA, Schneider JA.TDP-43阶段、混合病理和临床阿尔茨海默型痴呆。脑。2016;139(11):2983-93.Article PubMed Google Scholar Irwin KE, Sheth U, Wong PC, Gendron TF.肌萎缩侧索硬化症的体液生物标志物：综述。Mol Neurodegener.2024;19(1):9.Article PubMed Google Scholar Ling JP, Pletnikova O, Troncoso JC, Wong PC.TDP-43对非保守隐性外显子的抑制在ALS-FTD中受损。Science.2015;349(6248):650-5.Article CAS PubMed Google Scholar Mehta PR, Brown AL, Ward ME, Fratta P. The era of cryptic exons: implications for ALS-FTD.Mol Neurodegener.2023;18(1):16.Article CAS PubMed Google Scholar Seddighi S, Qi YA, Brown A-L, Wilkins OG, Bereda C, Belair C, et al. Mis-spliced transcripts generate de novo proteins in TDP-43-related ALS/FTD.Sci Transl Med.2024;16(734):eadg7162.Article CAS PubMed Google Scholar Irwin KE, Jasin P, Braunstein KE, Sinha IR, Garret MA, Bowden KD et al. A fluid biomarker reveals loss of TDP-43 splicing repression in presymptomatic ALS-FTD.Nat Med.2024:1-12.Calliari A, Daughrity LM, Albagli EA, Castellanos Otero P, Yue M, Jansen-West K, et al. HDGFL2隐性蛋白报告了神经退行性疾病中TDP-43病理的存在。Mol Neurodegeneration.2024;19(1):29.Article CAS Google Scholar Feng W, Beer JC, Hao Q, Ariyapala IS, Sahajan A, Komarov A, et al. NULISA: a proteomic liquid biopsy platform with attomolar sensitivity and high multiplexing.Nat Commun.2023;14(1):7238.Article CAS PubMed Google Scholar Britson KA, Ling JP, Braunstein KE, Montagne JM, Kastenschmidt JM, Wilson A, et al. 散发性包涵体肌炎异种移植模型中 T 细胞耗竭后 TDP-43 功能丧失和边缘空泡持续存在。Sci Transl Med.2022;14(628):eabi9196.Article CAS PubMed Google Scholar Estades Ayuso V, Pickles S, Todd T, Yue M, Jansen-West K, Song Y, et al. TDP-43-regulated cryptic RNAs accumulate in Alzheimer's disease brains.Mol Neurodegeneration.2023;18(1):57.Article CAS Google Scholar Agra Almeida Quadros AR, Li Z, Wang X, Ndayambaje IS, Aryal S, Ramesh N, et al. Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer's disease.Acta Neuropathol.2024;147(1):9.Article CAS PubMed Google Scholar Chung M, Carter EK, Veire AM, Dammer EB, Chang J, Duong DM, et al. Cryptic exon inclusion is a molecular signature of LATE-NC in aging brains.Acta Neuropathol.2024;147(1):29.Article CAS PubMed Google Scholar Download references作者得到了目标 ALS 基金会（Y.-J
{"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":"<p>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.</p><p>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 <i>STMN2</i> mRNA produces a truncated stathmin-2 protein at the expense of its full-length counterpart, whereas inclusion of a CE in <i>UNC13A</i> mRNA reduces UNC13A protein expression (Fig. 1A) [6]. While cryptic RNAs including <i>STMN2</i>-CE and <i>UNC13A</i>-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 <i>de novo</i> proteins.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 1</b></figcaption><picture><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}
Pub Date : 2024-10-24DOI: 10.1186/s13024-024-00766-0
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
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.
{"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}
Pub Date : 2024-10-21DOI: 10.1186/s13024-024-00758-0
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
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
{"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<sup>+</sup> 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<sup>+</sup> 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}
Pub Date : 2024-10-19DOI: 10.1186/s13024-024-00769-x
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
<p>To the Editor,</p><p>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.</p><p>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 (<i>n</i> = 4) or hippocampus (<i>n</i> = 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
作者和工作单位韩国首尔ADEL 科技研究所（AIST）Ha-Lim Song、Min-Seok Kim & Seung-Yong Yoon韩国首尔蔚山大学医学院牙山医疗中心脑科学系、韩国 21 世纪脑科学项目Woo-Young Cho、Ye-Seul Yoo、Jae-You Kim、Tae-Wook Kim、Dong-Hou Kim &；Seung-Yong YoonConvergence Medicine Research Center, Asan Institute for Life Sciences, Asan Medical Center, Seoul, South KoreaHyori KimStem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul、韩国Seung-Yong Yoon作者Ha-Lim Song查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Min-Seok Kim查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Woo-Young Cho查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Ye-Seul Yoo查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Jae- You Kim查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Jae- You Kim查看作者发表的论文您也可以在PubMed Google Scholar中搜索该作者Jae- You Kim查看作者发表的论文You KimView 发表作品您也可以在 PubMed Google Scholar中搜索该作者Tae-Wook KimView 发表作品您也可以在 PubMed Google Scholar中搜索该作者Hyori KimView 发表作品您也可以在 PubMed Google Scholar中搜索该作者Dong-Hou KimView 发表作品您也可以在 PubMed Google Scholar中搜索该作者Seung-Yong YoonView 发表作品您也可以在 PubMed Google Scholar中搜索该作者ContributionsH.L.S..、M.S.K.、D.H.K.和S.Y.Y.对本研究的构思和设计做出了贡献。H.L.S.、M.S.K.和 S.Y.Y. 参与了数据的获取和分析。伦理批准和参与同意书不适用。发表同意书不适用。利益冲突S.Y.Y.创立了ADEL公司；S.Y.Y.、D.H.K.、H.L.S.和M.S.K.拥有ADEL公司的股票或股票期权、以下是电子版补充材料的链接。补充材料1开放获取本文采用知识共享署名 4.0 国际许可协议，允许以任何媒介或格式使用、共享、改编、分发和复制，只要您适当注明原作者和来源，提供知识共享许可协议的链接，并说明是否进行了修改。本文中的图片或其他第三方材料均包含在文章的知识共享许可协议中，除非在材料的署名栏中另有说明。如果材料未包含在文章的知识共享许可协议中，且您打算使用的材料不符合法律规定或超出许可使用范围，则您需要直接从版权所有者处获得许可。要查看该许可的副本，请访问 http://creativecommons.org/licenses/by/4.0/。除非在数据的信用行中另有说明，否则创作共用公共领域专用免责声明 (http://creativecommons.org/publicdomain/zero/1.0/) 适用于本文提供的数据。转载与许可引用本文Song, HL., Kim, MS., Cho, WY. et al. 比较临床试验中的抗tau抗体及其在tau病理学上的表位。Mol Neurodegeneration 19, 76 (2024). https://doi.org/10.1186/s13024-024-00769-xDownload citationReceived：16 August 2024Accepted：11 October 2024Published: 19 October 2024DOI: https://doi.org/10.1186/s13024-024-00769-xShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative.
{"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":"<p>To the Editor,</p><p>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.</p><p>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 (<i>n</i> = 4) or hippocampus (<i>n</i> = 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}
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.
{"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}
Pub Date : 2024-10-16DOI: 10.1186/s13024-024-00762-4
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
This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s13024-022-00564-6.
{"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}
Pub Date : 2024-10-14DOI: 10.1186/s13024-024-00763-3
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..
<p><b>Correction</b><b>: </b><b>Mol Neurodegeneration 19, 61 (2024)</b></p><p><b>https://doi.org/10.1186/s13024-024-00747-3</b></p><br/><p>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.</p><ol data-track-component="outbound reference" data-track-context="references section"><li data-counter="1."><p>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.</p><p>Article CAS Google Scholar </p></li></ol><p>Download references<svg aria-hidden="true" focusable="false" height="16" role="img" width="16"><use xlink:href="#icon-eds-i-download-medium" xmlns:xlink="http://www.w3.org/1999/xlink"></use></svg></p><span>Author notes</span><ol><li><p>Hui Wang and Timothy S. Chang contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</p><p>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 & Wan-Ping Lee</p></li><li><p>Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</p><p>Hui Wang, Beth A. Dombroski, Po-Liang Cheng, Yuk Yee Leung, Adam C. Naj, Li-San Wang, Gerard D. Schellenberg & Wan-Ping Lee</p></li><li><p>Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA</p><p>Timothy S. Chang, Vishakha Patil, Leopoldo Valiente-Banuet, Giovanni Coppola & Daniel H. Geschwind</p></li><li><p>Department of Pathology, Department of Artificial Intelligence & Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain, Institute, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA</p><p>Kurt Farrell & John F. Crary</p></li><li><p>Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia</p><p>Catriona Mclean</p></li><li><p>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</p><p>Laura Molina-Porcel</p></li><li><p>Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain</p><p>Laura Molina-Porcel</p></li><li><p>Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, SK, Canada</p><p>Alex Rajput</p></li>
SerranoUniversity McGill, Montreal, QC, CanadaLili-Naz HazratiDepartment of Neuroscience, University of California, San Diego, CA, USAIrene Litvan & Douglas GalaskoVIB Center for Molecular Neurology, University of Antwerp, Antwerp, BelgiumRosa RademakersDepartment of Neuroscience, Mayo Clinic Jacksonville, Jacksonville, FL, USARosa Rademakers, Owen A.Ross & Dennis W. Dickson美国加州大学旧金山分校记忆与衰老中心Adam L. Boxer, Bruce L. Miller & Willian W. Seeley神经退化中心SeeleyCenter for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, PA, USAEdward B. LeeUniversity of Texas Southwestern Medical Center, Dallas, TX, USACharles L.White II英国伦敦，伦敦大学学院临床与运动神经学系Huw MorrisReta Lila Weston 研究所，英国伦敦，UCL 皇后广场神经学研究所Rohan de Silva美国纽约，遗传学与基因组科学系；美国纽约，西奈山伊坎医学院Alison M. GoateFriedman Bioventure, Inc、美国加利福尼亚州德尔马市杰弗里-弗里德曼（Jeffrey S. Friedman）加利福尼亚大学塞梅尔神经科学与人类行为研究所精神病学系美国加利福尼亚州洛杉矶市乔瓦尼-科波拉（Agiovanni Coppola）宾夕法尼亚大学佩雷尔曼医学院生物统计学、流行病学和信息学系美国宾夕法尼亚州费城亚当-C.NajDepartment of Anatomy Physiology and Genetics, the American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USAClifton DalgardDepartment of Neurology, LMU University Hospital, Ludwig-Maximilians-Universität (LMU) München; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany; and Munich Cluster for Systems Neurology (SyNergy), Munich, GermanyFranziska Hopfner & Günter U.HöglingerDepartment of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USADaniel H. GeschwindInstitute of Precision Health, University of California, Los Angeles, Los Angeles, CA, USADaniel H. GeschwindAuthorsHui WangView author publications您也可以在PubMed Google Scholar中搜索该作者Timothy S. ChangView author publications您也可以在PubMed Google Scholar中搜索该作者Beth A. Dombroski查看作者发表的文章DombroskiView 作者发表作品您也可以在PubMed Google Scholar中搜索该作者Po-Liang ChengView 作者发表作品您也可以在PubMed Google Scholar中搜索该作者Vishakha PatilView 作者发表作品您也可以在PubMed Google Scholar中搜索该作者Leopoldo Valiente-BanuetView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Kurt FarrellView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Catriona McleanView 作者发表作品您也可以在 PubMed Google Scholar中搜索该作者Laura Molina-PorcelView 作者发表作品您也可以在 PubMed Google ScholarAlex RajputView 作者发表作品您也可以在 PubMed Google ScholarPeter Paul De DeynView 作者发表作品您也可以在 PubMed Google ScholarNathalieLe Bastard查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Marla Gearing查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Laura Donker Kaat查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者John C. Van Swieten查看作者发表作品Van Swieten查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Elise Dopper查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Bernardino F. Ghetti查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Kathy L. Newell查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Claire Troakes查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Justo G. de Yébenes 查看作者发表作品de Yébenes查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Alberto Rábano-Gutierrez 查看作者发表作品您也可以在PubMed Google Scholar中搜索该作者Tina Meller查看作者发表作品您也可以
{"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":"<p><b>Correction</b><b>: </b><b>Mol Neurodegeneration 19, 61 (2024)</b></p><p><b>https://doi.org/10.1186/s13024-024-00747-3</b></p><br/><p>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.</p><ol data-track-component=\"outbound reference\" data-track-context=\"references section\"><li data-counter=\"1.\"><p>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.</p><p>Article CAS Google Scholar </p></li></ol><p>Download references<svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-download-medium\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></p><span>Author notes</span><ol><li><p>Hui Wang and Timothy S. Chang contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</p><p>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 & Wan-Ping Lee</p></li><li><p>Penn Neurodegeneration Genomics Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA</p><p>Hui Wang, Beth A. Dombroski, Po-Liang Cheng, Yuk Yee Leung, Adam C. Naj, Li-San Wang, Gerard D. Schellenberg & Wan-Ping Lee</p></li><li><p>Movement Disorders Programs, Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA</p><p>Timothy S. Chang, Vishakha Patil, Leopoldo Valiente-Banuet, Giovanni Coppola & Daniel H. Geschwind</p></li><li><p>Department of Pathology, Department of Artificial Intelligence & Human Health, Nash Family, Department of Neuroscience, Ronald M. Loeb Center for Alzheimer’s Disease, Friedman Brain, Institute, Neuropathology Brain Bank & Research CoRE, Icahn School of Medicine at Mount Sinai, New York, NY, USA</p><p>Kurt Farrell & John F. Crary</p></li><li><p>Victorian Brain Bank, The Florey Institute of Neuroscience and Mental Health, Parkville, VIC, Australia</p><p>Catriona Mclean</p></li><li><p>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</p><p>Laura Molina-Porcel</p></li><li><p>Neurological Tissue Bank of the Biobanc-Hospital Clínic-IDIBAPS, Barcelona, Spain</p><p>Laura Molina-Porcel</p></li><li><p>Movement Disorders Program, Division of Neurology, University of Saskatchewan, Saskatoon, SK, Canada</p><p>Alex Rajput</p></li>","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}
Pub Date : 2024-10-12DOI: 10.1186/s13024-024-00761-5
Cong Lin, Xiubo Du, Xiaohui Wang
<p>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.</p><p>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
总之，临终/悖论性清醒现象以及对使用迷幻药的新兴研究，为了解注意力缺失症认知能力衰退的潜在可逆性和可塑性提供了突破性的见解。这些观察结果不仅对我们现有的神经变性范式提出了挑战，而且开辟了创新的治疗途径，可显著提高注意力缺失症患者的生活质量。通过探索潜在的神经机制和迷幻药对大脑功能的影响，我们正在超越传统的方法，开启新的策略，从而在治疗阿兹海默症（尤其是晚期）方面取得实质性进展。AD:阿尔茨海默病LSD:麦角酰二乙胺BDNF:脑源性神经营养因子DMT:N, N-二甲基色胺Aβ:淀粉样蛋白-βPET:正电子发射断层扫描DeTure MA, Dickson DW.阿尔茨海默病的神经病理学诊断。Mol Neurodegener.2019;14:32.Article PubMed PubMed Central Google Scholar Guo T, Zhang D, Zeng Y, Huang TY, Xu H, Zhao Y. Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer's disease.Mol Neurodegener.2020;15:40.Article PubMed PubMed Central Google Scholar Ferrari C, Sorbi S. The complexity of Alzheimer's disease: an evolving puzzle.Physiol Rev. 2021;101:1047-81.Article PubMed Google Scholar Peterson A, Clapp J, Harkins K, Kleid M, Largent EA, Stites SD, et al. Is there a difference between terminal lucidity and paradoxical lucidity?阿尔茨海默氏痴呆症。2022;18:540-1.Article PubMed Google Scholar Habashi M, Vutla S, Tripathi K, Senapati S, Chauhan PS, Haviv-Chesner A, et al.Proc Natl Acad Sci U S A. 2022;119:e2210766119.Article PubMed PubMed Central Google Scholar Peterson A, Clapp J, Largent EA, Harkins K, Stites SD, Karlawish J. What is paradoxical lucidity?答案从定义开始。Alzheimers Dement.2022;18:513-21.Article PubMed Google Scholar Vardalaki D, Chung K, Harnett MT.丝状体是成人新皮质中无声突触的结构基质。自然。2022;612:323-7.Article PubMed Google Scholar Ji X, Zhou Y, Gao Q, He H, Wu Z, Feng B, et al. Functional reconstruction of the basal ganglia neural circuit by human striatal neurons in hypoxic-ischaemic injured brain.脑。2023;146:612-28.Article PubMed Google Scholar Cheng D, Lei ZG, Chu K, Lam OJH, Chiang CY, Zhang ZJ.N，N-二甲基色胺，一种天然致幻剂，通过恢复神经元 Sigma-1 受体介导的内质网-线粒体串联改善阿尔茨海默病。Alzheimers Res Ther.2024;16:95.Article PubMed PubMed Central Google Scholar Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB.Nat Neurosci.2023;26:1032-41.Article PubMed PubMed Central Google Scholar Nardou R, Sawyer E, Song YJ, Wilkinson M, Padovan-Hernandez Y, de Deus JL, et al. Psychedelics reopen the social reward learning critical period.自然》。2023;618:790-8.Article PubMed PubMed Central Google Scholar Ly C, Greb AC, Cameron LP, Wong JM, Barragan EV, Wilson PC, et al. Psychedelics promote structural and functional neural plasticity.Cell Rep. 2018;23:3170-82.Article PubMed PubMed Central Google Scholar Huang YY, Gan YH, Yang L, Cheng W, Yu JT.阿尔茨海默病中的抑郁症：流行病学、机制和治疗。生物精神病学》。2024;95:992-1005.Article PubMed Google Scholar Vann Jones SA, O'Kelly A. Psychedelics as a treatment for Alzheimer's Disease Dementia.Front Synaptic Neurosci.2020;12:34.Article PubMed PubMed Central Google Scholar Download referencesNot applicable.This work was supported by the National Natural Science Foundation of China (T2241028), STI2030-Major Projects [2021ZD0203000(2021ZD0203003)], and the Chinese Academy (CAS) Hundred Talents Program.作者及工作单位中国科学院长春应用化学研究所化学生物学实验室，长春，130022 林聪&；王晓辉深圳大学生命科学与海洋学院，深圳，518060杜秀波作者简介林聪查看作者发表
{"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":"<p>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.</p><p>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}
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