Molecular Neurodegeneration最新文献

{"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}

{"title":"Correction: Network proteomics of the Lewy body dementia brain reveals presynaptic signatures distinct from Alzheimer’s disease","authors":"Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, Luming Yin, E. Kathleen Carter, Marla Gearing, Alice Chen-Plotkin, Edward B. Lee, John Q. Trojanowski, David A. Bennett, James J. Lah, Allan I. Levey, Nicholas T. Seyfried, Lenora Higginbotham","doi":"10.1186/s13024-024-00765-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00765-1","url":null,"abstract":"<p><b>Molecular Neurodegeneration (2024) 19:60</b></p><p><b>https://doi.org/10.1186/s13024-024-00749-1</b></p><p>The authors mistakenly omitted two funding sources - The BrightFocus Foundation and The American Brain Foundation (both for Lenora Higginbotham - in the original article which they wish to acknowledge via this Correction article.</p><h3>Authors and Affiliations</h3><ol><li><p>Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA</p><p>Anantharaman Shantaraman, Eric B. Dammer, Obiadada Ugochukwu, Duc M. Duong, E. Kathleen Carter, Marla Gearing, James J. Lah, Allan I. Levey, Nicholas T. Seyfried & Lenora Higginbotham</p></li><li><p>Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA</p><p>Anantharaman Shantaraman, Eric B. Dammer, Duc M. Duong, Luming Yin, E. Kathleen Carter & Nicholas T. Seyfried</p></li><li><p>Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA</p><p>E. Kathleen Carter, Marla Gearing, James J. Lah, Allan I. Levey, Nicholas T. Seyfried & Lenora Higginbotham</p></li><li><p>Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA</p><p>Marla Gearing</p></li><li><p>Department of Neurology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA</p><p>Alice Chen-Plotkin</p></li><li><p>Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA</p><p>Edward B. Lee & John Q. Trojanowski</p></li><li><p>Rush Alzheimer’s Disease Center, Rush University Medical Center, Chicago, IL, USA</p><p>David A. Bennett</p></li></ol><span>Authors</span><ol><li><span>Anantharaman Shantaraman</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Eric B. Dammer</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Obiadada Ugochukwu</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Duc M. Duong</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Luming Yin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>E. Kathleen Carter</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Marla Gearing</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Alice Chen-Plotkin</span>View author publications<p>You can also search for this author in <span>PubMed<span> </span>Google Scholar</span></p></li><li><span>Edward","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405260","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: Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner","authors":"Megan E. Bosch, Hemraj B. Dodiya, Julia Michalkiewicz, Choonghee Lee, Shabana M. Shaik, Ian Q. Weigle, Can Zhang, Jack Osborn, Aishwarya Nambiar, Priyam Patel, Samira Parhizkar, Xiaoqiong Zhang, Marie L. Laury, Prasenjit Mondal, Ashley Gomm, Matthew John Schipma, Dania Mallah, Oleg Butovsky, Eugene B. Chang, Rudolph E. Tanzi, Jack A. Gilbert, David M. Holtzman, Sangram S. Sisodia","doi":"10.1186/s13024-024-00764-2","DOIUrl":"https://doi.org/10.1186/s13024-024-00764-2","url":null,"abstract":"<p>Molecular Neurodegeneration (2024) 19:18</p><p>https://doi.org/10.1186/s13024-023-00700-w</p><p>The original article erroneously presents incorrect graph labels in the caption of Fig. 4. The corrected Fig. 4 caption alongside its respective figure can be viewed ahead in this Correction article.</p><figure><figcaption><b data-test=\"figure-caption-text\">Fig. 4</b></figcaption><picture><img alt=\"figure 4\" aria-describedby=\"Fig4\" height=\"577\" loading=\"lazy\" src=\"//media.springernature.com/lw685/springer-static/image/art%3A10.1186%2Fs13024-024-00764-2/MediaObjects/13024_2024_764_Fig4_HTML.png\" width=\"685\"/></picture><p>GV-971 modifies cytokine and chemokine levels in peripheral blood and cortical tissues. (<b>a</b>) Quantification of cytokine and chemokine concentrations in the serum of APPPS1-21 male mice treated with 160mg/kg GV-971 or vehicle from the University of Chicago (n = 10–11). (<b>b</b>) Quantification of cytokine and chemokine concentrations in the serum of APPPS1-21 female mice treated with 160mg/kg GV-971 or vehicle (n = 8–10). (<b>c</b>) Quantification of cytokine and chemokine concentrations in the serum of 5XFAD male mice treated with 100mg/kg GV-971 or vehicle from Washington University in St. Louis (n = 12–13). (<b>d</b>) Quantification of cytokine and chemokine concentrations in the serum of 5XFAD female mice treated with 100mg/kg GV-971 or vehicle (n = 9–12). (<b>e</b>) Quantification of cytokine and chemokine concentrations in the cortical tissue of 5XFAD male mice treated with 100mg/kg GV-971 or vehicle (n = 12–13). Data presented as SEM. Significance determined using unpaired t-test. *, P<0.05; **, P<0.01; ***, P<0.001; ****, P<0.0001</p><span>Full size image</span><svg aria-hidden=\"true\" focusable=\"false\" height=\"16\" role=\"img\" width=\"16\"><use xlink:href=\"#icon-eds-i-chevron-right-small\" xmlns:xlink=\"http://www.w3.org/1999/xlink\"></use></svg></figure><span>Author notes</span><ol><li><p>Megan E. Bosch and Hemraj B. Dodiya contributed equally to this work.</p></li><li><p>Julia Michalkiewicz, Choonghee Lee and Shabana M. Shaik contributed equally to this work.</p></li></ol><h3>Authors and Affiliations</h3><ol><li><p>Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer’s Disease Research Center, Washington University in St. Louis, St. Louis, USA</p><p>Megan E. Bosch, Choonghee Lee, Aishwarya Nambiar, Samira Parhizkar & David M. Holtzman</p></li><li><p>Department of Neurobiology, University of Chicago, Chicago, USA</p><p>Hemraj B. Dodiya, Julia Michalkiewicz, Shabana M. Shaik, Ian Q. Weigle, Jack Osborn, Xiaoqiong Zhang & Sangram S. Sisodia</p></li><li><p>Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA</p><p>Can Zhang, Prasenjit Mondal, Ashley Gomm & Rudolph E. Tanzi</p></li><li><p>Center for Genetic Medicine,","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398041","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":"Multi-analyte proteomic analysis identifies blood-based neuroinflammation, cerebrovascular and synaptic biomarkers in preclinical Alzheimer's disease.","authors":"Xuemei Zeng, Tara K Lafferty, Anuradha Sehrawat, Yijun Chen, Pamela C L Ferreira, Bruna Bellaver, Guilherme Povala, M Ilyas Kamboh, William E Klunk, Ann D Cohen, Oscar L Lopez, Milos D Ikonomovic, Tharick A Pascoal, Mary Ganguli, Victor L Villemagne, Beth E Snitz, Thomas K Karikari","doi":"10.1186/s13024-024-00753-5","DOIUrl":"10.1186/s13024-024-00753-5","url":null,"abstract":"<p><strong>Background: </strong>Blood-based biomarkers are gaining grounds for the detection of Alzheimer's disease (AD) and related disorders (ADRDs). However, two key obstacles remain: the lack of methods for multi-analyte assessments and the need for biomarkers for related pathophysiological processes like neuroinflammation, vascular, and synaptic dysfunction. A novel proteomic method for pre-selected analytes, based on proximity extension technology, was recently introduced. Referred to as the NULISAseq CNS disease panel, the assay simultaneously measures ~ 120 analytes related to neurodegenerative diseases, including those linked to both core (i.e., tau and amyloid-beta (Aβ)) and non-core AD processes. This study aimed to evaluate the technical and clinical performance of this novel targeted proteomic panel.</p><p><strong>Methods: </strong>The NULISAseq CNS disease panel was applied to 176 plasma samples from 113 individuals in the MYHAT-NI cohort of predominantly cognitively normal participants from an economically underserved region in southwestern Pennsylvania, USA. Classical AD biomarkers, including p-tau181, p-tau217, p-tau231, GFAP, NEFL, Aβ40, and Aβ42, were independently measured using Single Molecule Array (Simoa) and correlations and diagnostic performances compared. Aβ pathology, tau pathology, and neurodegeneration (AT(N) statuses) were evaluated with [<sup>11</sup>C] PiB PET, [<sup>18</sup>F]AV-1451 PET, and an MRI-based AD-signature composite cortical thickness index, respectively. Linear mixed models were used to examine cross-sectional and Wilcoxon rank sum tests for longitudinal associations between NULISA and neuroimaging-determined AT(N) biomarkers.</p><p><strong>Results: </strong>NULISA concurrently measured 116 plasma biomarkers with good technical performance (97.2 ± 13.9% targets gave signals above assay limits of detection), and significant correlation with Simoa assays for the classical biomarkers. Cross-sectionally, p-tau217 was the top hit to identify Aβ pathology, with age, sex, and APOE genotype-adjusted AUC of 0.930 (95%CI: 0.878-0.983). Fourteen markers were significantly decreased in Aβ-PET + participants, including TIMP3, BDNF, MDH1, and several cytokines. Longitudinally, FGF2, IL4, and IL9 exhibited Aβ PET-dependent yearly increases in Aβ-PET + participants. Novel plasma biomarkers with tau PET-dependent longitudinal changes included proteins associated with neuroinflammation, synaptic function, and cerebrovascular integrity, such as CHIT1, CHI3L1, NPTX1, PGF, PDGFRB, and VEGFA; all previously linked to AD but only reliable when measured in cerebrospinal fluid. The autophagosome cargo protein SQSTM1 exhibited significant association with neurodegeneration after adjusting age, sex, and APOE ε4 genotype.</p><p><strong>Conclusions: </strong>Together, our results demonstrate the feasibility and potential of immunoassay-based multiplexing to provide a comprehensive view of AD-associated proteomic changes, consist","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":14.9,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11465638/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391901","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":"α-Synuclein pathology disrupts mitochondrial function in dopaminergic and cholinergic neurons at-risk in Parkinson’s disease","authors":"Fanni F. Geibl, Martin T. Henrich, Zhong Xie, Enrico Zampese, Jun Ueda, Tatiana Tkatch, David L. Wokosin, Elena Nasiri, Constantin A. Grotmann, Valina L. Dawson, Ted M. Dawson, Navdeep S. Chandel, Wolfgang H. Oertel, D. James Surmeier","doi":"10.1186/s13024-024-00756-2","DOIUrl":"https://doi.org/10.1186/s13024-024-00756-2","url":null,"abstract":"Pathological accumulation of aggregated α-synuclein (aSYN) is a common feature of Parkinson’s disease (PD). However, the mechanisms by which intracellular aSYN pathology contributes to dysfunction and degeneration of neurons in the brain are still unclear. A potentially relevant target of aSYN is the mitochondrion. To test this hypothesis, genetic and physiological methods were used to monitor mitochondrial function in substantia nigra pars compacta (SNc) dopaminergic and pedunculopontine nucleus (PPN) cholinergic neurons after stereotaxic injection of aSYN pre-formed fibrils (PFFs) into the mouse brain. aSYN PFFs were stereotaxically injected into the SNc or PPN of mice. Twelve weeks later, mice were studied using a combination of approaches, including immunocytochemical analysis, cell-type specific transcriptomic profiling, electron microscopy, electrophysiology and two-photon-laser-scanning microscopy of genetically encoded sensors for bioenergetic and redox status. In addition to inducing a significant neuronal loss, SNc injection of PFFs induced the formation of intracellular, phosphorylated aSYN aggregates selectively in dopaminergic neurons. In these neurons, PFF-exposure decreased mitochondrial gene expression, reduced the number of mitochondria, increased oxidant stress, and profoundly disrupted mitochondrial adenosine triphosphate production. Consistent with an aSYN-induced bioenergetic deficit, the autonomous spiking of dopaminergic neurons slowed or stopped. PFFs also up-regulated lysosomal gene expression and increased lysosomal abundance, leading to the formation of Lewy-like inclusions. Similar changes were observed in PPN cholinergic neurons following aSYN PFF exposure. Taken together, our findings suggest that disruption of mitochondrial function, and the subsequent bioenergetic deficit, is a proximal step in the cascade of events induced by aSYN pathology leading to dysfunction and degeneration of neurons at-risk in PD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385576","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":"Clarifying the association of CSF Aβ, tau, BACE1, and neurogranin with AT(N) stages in Alzheimer disease","authors":"Sylvain Lehmann, Susanna Schraen-Maschke, Luc Buée, Jean-Sébastien Vidal, Constance Delaby, Christophe Hirtz, Frédéric Blanc, Claire Paquet, Bernadette Allinquant, Stéphanie Bombois, Audrey Gabelle, Olivier Hanon","doi":"10.1186/s13024-024-00755-3","DOIUrl":"https://doi.org/10.1186/s13024-024-00755-3","url":null,"abstract":"Current AT(N) stratification for Alzheimer’s disease (AD) accounts for complex combinations of amyloid (A), tau proteinopathy (T) and neurodegeneration (N) signatures. Understanding the transition between these different stages is a major challenge, especially in view of the recent development of disease modifying therapy. This is an observational study, CSF levels of Tau, pTau181, pTau217, Aβ38/40/42, sAPPα/β, BACE1 and neurogranin were measured in the BALTAZAR cohort of cognitively impaired patients and in the Alzheimer's Disease Neuroimaging Initiative (ADNI). Biomarkers levels were related to the AT(N) framework. (A) and (T) were defined in BALTAZAR with CSF Aβ42/40 ratio and pTau217 respectively, and in ADNI with amyloid and tau PET. (N) was defined using total CSF tau in both cohorts. As expected, CSF Aβ42 decreased progressively with the AD continuum going from the A-T-N- to the A + T + N + profile. On the other hand, Tau and pTau181 increased progressively with the disease. The final transition from A + T + N- to A + T + N + led to a sharp increase in Aβ38, Aβ42 and sAPP levels. Synaptic CSF biomarkers BACE1 and neurogranin, were lowest in the initial A + T-N- stage and increased with T + and N + . CSF pTau181 and total tau were closely related in both cohorts. The early transition to an A + phenotype (A + T-N-) primarily impacts synaptic function. The appearance of T + and then N + is associated with a significant and progressive increase in pathological Alzheimer's disease biomarkers. Our main finding is that CSF pTau181 is an indicator of N + rather than T + , and that N + is associated with elevated levels of BACE1 protein and beta-amyloid peptides. This increase may potentially fuel the amyloid cascade in a positive feedback loop. Overall, our data provide further insights into understanding the interconnected pathological processes of amyloid, tau, and neurodegeneration underlying Alzheimer's disease.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384483","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":"Heparin-enriched plasma proteome is significantly altered in Alzheimer’s disease","authors":"Qi Guo, Lingyan Ping, Eric B. Dammer, Duc M. Duong, Luming Yin, Kaiming Xu, Anantharaman Shantaraman, Edward J. Fox, Todd E Golde, Erik C.B. Johnson, Blaine R. Roberts, James J. Lah, Allan I. Levey, Nicholas T. Seyfried","doi":"10.1186/s13024-024-00757-1","DOIUrl":"https://doi.org/10.1186/s13024-024-00757-1","url":null,"abstract":"Heparin binding proteins (HBPs) with roles in extracellular matrix assembly are strongly correlated to β-amyloid (Aβ) and tau pathology in Alzheimer’s disease (AD) brain and cerebrospinal fluid (CSF). However, it remains challenging to detect these proteins in plasma using standard mass spectrometry-based proteomic approaches. We employed heparin-affinity chromatography, followed by off-line fractionation and tandem mass tag mass spectrometry (TMT-MS), to enrich HBPs from plasma obtained from AD (n = 62) and control (n = 47) samples. These profiles were then correlated to Aβ, tau and phosphorylated tau (pTau) CSF biomarkers and plasma pTau181 from the same individuals, as well as a consensus brain proteome network to assess the overlap with AD brain pathophysiology. Heparin enrichment from plasma was highly reproducible, enriched well-known HBPs like APOE and thrombin, and depleted high-abundant proteins such as albumin. A total of 2865 proteins, spanning 10 orders of magnitude in abundance, were measured across 109 samples. Compared to the consensus AD brain protein co-expression network, we observed that specific plasma proteins exhibited consistent direction of change in both brain and plasma, whereas others displayed divergent changes, highlighting the complex interplay between the two compartments. Elevated proteins in AD plasma, when compared to controls, included members of the matrisome module in brain that accumulate with Aβ deposits, such as SMOC1, SMOC2, SPON1, MDK, OLFML3, FRZB, GPNMB, and the APOE4 proteoform. Additionally, heparin-enriched proteins in plasma demonstrated significant correlations with conventional AD CSF biomarkers, including Aβ, total tau, pTau, and plasma pTau181. A panel of five plasma proteins classified AD from control individuals with an area under the curve (AUC) of 0.85. When combined with plasma pTau181, the panel significantly improved the classification performance of pTau181 alone, increasing the AUC from 0.93 to 0.98. This suggests that the heparin-enriched plasma proteome captures additional variance in cognitive dementia beyond what is explained by pTau181. These findings support the utility of a heparin-affinity approach coupled with TMT-MS for enriching amyloid-associated proteins, as well as a wide spectrum of plasma biomarkers that reflect pathological changes in the AD brain.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384482","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":"One immune cell to bind them all: platelet contribution to neurodegenerative disease","authors":"Gabriela Rodriguez Moore, Isabel Melo-Escobar, David Stegner, Oliver Bracko","doi":"10.1186/s13024-024-00754-4","DOIUrl":"https://doi.org/10.1186/s13024-024-00754-4","url":null,"abstract":"Alzheimer’s disease (AD) and related dementias (ADRD) collectively affect a significant portion of the aging population worldwide. The pathological progression of AD involves not only the classical hallmarks of amyloid beta (Aβ) plaque buildup and neurofibrillary tangle development but also the effects of vasculature and chronic inflammatory processes. Recently, platelets have emerged as central players in systemic and neuroinflammation. Studies have shown that patients with altered platelet receptor expression exhibit accelerated cognitive decline independent of traditional risk factors. Additionally, platelets from AD patients exhibit heightened unstimulated activation compared to control groups. Platelet granules contain crucial AD-related proteins like tau and amyloid precursor protein (APP). Dysregulation of platelet exocytosis contributes to disease phenotypes characterized by increased bleeding, stroke, and cognitive decline risk. Recent studies have indicated that these effects are not associated with the quantity of platelets present in circulation. This underscores the hypothesis that disruptions in platelet-mediated inflammation and healing processes may play a crucial role in the development of ADRD. A thorough look at platelets, encompassing their receptors, secreted molecules, and diverse roles in inflammatory interactions with other cells in the circulatory system in AD and ADRD, holds promising prospects for disease management and intervention. This review discusses the pivotal roles of platelets in ADRD.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142328686","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":"Regional desynchronization of microglial activity is associated with cognitive decline in Alzheimer’s disease","authors":"Artem Zatcepin, Johannes Gnörich, Boris-Stephan Rauchmann, Laura M. Bartos, Stephan Wagner, Nicolai Franzmeier, Maura Malpetti, Xianyuan Xiang, Yuan Shi, Samira Parhizkar, Maximilian Grosch, Karin Wind-Mark, Sebastian T. Kunte, Leonie Beyer, Carolin Meyer, Desirée Brösamle, Ann-Christin Wendeln, Collins Osei-Sarpong, Steffanie Heindl, Arthur Liesz, Sophia Stoecklein, Gloria Biechele, Anika Finze, Florian Eckenweber, Simon Lindner, Axel Rominger, Peter Bartenstein, Michael Willem, Sabina Tahirovic, Jochen Herms, Katharina Buerger, Mikael Simons, Christian Haass, Rainer Rupprecht, Markus J. Riemenschneider, Nathalie L. Albert, Marc Beyer, Jonas J. Neher, Lars Paeger, Johannes Levin, Günter U. Höglinger, Robert Perneczky, Sibylle I. Ziegler, Matthias Brendel","doi":"10.1186/s13024-024-00752-6","DOIUrl":"https://doi.org/10.1186/s13024-024-00752-6","url":null,"abstract":"Microglial activation is one hallmark of Alzheimer disease (AD) neuropathology but the impact of the regional interplay of microglia cells in the brain is poorly understood. We hypothesized that microglial activation is regionally synchronized in the healthy brain but experiences regional desynchronization with ongoing neurodegenerative disease. We addressed the existence of a microglia connectome and investigated microglial desynchronization as an AD biomarker. To validate the concept, we performed microglia depletion in mice to test whether interregional correlation coefficients (ICCs) of 18 kDa translocator protein (TSPO)-PET change when microglia are cleared. Next, we evaluated the influence of dysfunctional microglia and AD pathophysiology on TSPO-PET ICCs in the mouse brain, followed by translation to a human AD-continuum dataset. We correlated a personalized microglia desynchronization index with cognitive performance. Finally, we performed single-cell radiotracing (scRadiotracing) in mice to ensure the microglial source of the measured desynchronization. Microglia-depleted mice showed a strong ICC reduction in all brain compartments, indicating microglia-specific desynchronization. AD mouse models demonstrated significant reductions of microglial synchronicity, associated with increasing variability of cellular radiotracer uptake in pathologically altered brain regions. Humans within the AD-continuum indicated a stage-depended reduction of microglia synchronicity associated with cognitive decline. scRadiotracing in mice showed that the increased TSPO signal was attributed to microglia. Using TSPO-PET imaging of mice with depleted microglia and scRadiotracing in an amyloid model, we provide first evidence that a microglia connectome can be assessed in the mouse brain. Microglia synchronicity is closely associated with cognitive decline in AD and could serve as an independent personalized biomarker for disease progression.\u0000","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142138309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease","authors":"Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger, Sudha Seshadri, Liang Ma","doi":"10.1186/s13024-024-00751-7","DOIUrl":"https://doi.org/10.1186/s13024-024-00751-7","url":null,"abstract":"The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":null,"pages":null},"PeriodicalIF":15.1,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142090162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}