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Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-16 Rowan Saloner, Kaitlin B. Casaletto, Sruti Rayaprolu, Louisa Cornelis, Paramita Chakrabarty, Jose F. Abisambra, Salvatore Spina, Lea T. Grinberg, William W. Seeley, Bruce L. Miller, Joel H. Kramer, Gil D. Rabinovici, Breton M. Asken
Exposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimer’s disease
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In Memoriam of Edward H. Koo, MD 1954–2025 Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-16 Hui Zheng, Douglas Galasko, Sangram S. Sisodia
Edward H. Koo, MD, left us on April 22, 2025. At the age of 70, he was gone too soon, but he lived a full life and left a lasting legacy: He was a devoted husband to his wife Nancy, a loving father to his son Jeremy and daughter Allison (both followed his path to Amherst College), an accomplished scientist, and a celebrated mentor. To many of us, he was an extraordinary human being, a wonderful colleague
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Myelin dysfunction in aging and brain disorders: mechanisms and therapeutic opportunities Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-15 Zhihai Huang, Yulan Zhang, Peibin Zou, Xuemei Zong, Quanguang Zhang
Myelin is a multilamellar membrane that surrounds axons in the vertebrate nervous system. Properly functioning myelin is essential for the rapid conduction of nerve impulses, and it metabolically supports axonal integrity. Emerging evidence indicates that myelin is also involved in various aspects of cognition, with adaptive myelination playing a critical role in memory consolidation and motor learning
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Extracellular vesicles in TDP-43 proteinopathies: pathogenesis and biomarker potential Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-10 Elizabeth R. Dellar, Lara Nikel, Stephanie Fowler, Björn F. Vahsen, Ruxandra Dafinca, Emily Feneberg, Kevin Talbot, Martin R. Turner, Alexander G. Thompson
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles released by most cell types, and from multiple sub-cellular compartments. They carry a range of cargo biomolecules, including protein and RNA that reflect the type and status of their cell of origin. EVs are associated with the 43 kDa trans-active response DNA binding protein (TDP-43), aggregates of which are a key pathological feature
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Alzheimer’s disease pathogenesis: standing at the crossroad of lipid metabolism and immune response Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-04 Zitong Wang, Ling Zhang, Chuan Qin
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by macroscopic features such as cortical atrophy, narrowing of the gyri, widening of the sulci, and enlargement of the ventricles. At the cellular level, the pathological characteristics include the extracellular aggregation of β-amyloid (Aβ) forming senile plaques, and the intracellular accumulation of hyperphosphorylated tau proteins
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The many connections of UFMylation with Alzheimer’s disease: a comprehensive review Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-04 Tingxiang Yan, Benjamin D. Clarkson, Zhenkun Lou, Wolfdieter Springer, Fabienne C. Fiesel
Alzheimer’s disease (AD) is a complex neurodegenerative disorder that is characterized by the accumulation of pathologic tau and beta-amyloid proteins. UFMylation is an emerging ubiquitin-like post-translational modification that is crucial for healthy brain development. The UFM1 cascade was recently identified as a major modifier of tau aggregation in vitro and in vivo. Moreover, post-mortem AD brain
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The UNC5C T835M mutation associated with Alzheimer’s disease leads to neurodegeneration involving oxidative stress and hippocampal atrophy in aged mice Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-04 Devi Krishna Priya Karunakaran, Makenna Ley, Joanna Guo, Ammaarah Khatri, Katherine Sadleir, Jelena Popovic, Arun Kumar Upadhyay, Jeffrey Savas, Daniele Procissi, Jasvinder Atwal, Robert Vassar
Alzheimer’s disease (AD) is characterized by amyloid plaques, neurofibrillary tangles, and synaptic and neuronal loss. Recently, a rare autosomal dominant coding mutation, T835M, in the Un-coordinated 5c (UNC5C) netrin receptor gene was segregated with late-onset AD (LOAD). Overexpression of T835M in primary hippocampal neurons increased cell death in response to neurotoxic stimuli including beta-amyloid
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RNA-binding proteins in ALS and FTD: from pathogenic mechanisms to therapeutic insights Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-04 Jens Rummens, Sandrine Da Cruz
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are devastating neurodegenerative disorders with overlapping clinical, genetic and pathological features. A large body of evidence highlights the critical role of RNA-binding proteins (RBPs) – in particular TAR DNA-binding protein 43 (TDP-43) and Fused in sarcoma (FUS) – in the pathogenesis of these diseases. These RBPs normally
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CD2AP at the junction of nephropathy and Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-06-04 Milene Vandal, Mohsen Janmaleki, Isabel Rea, Colin Gunn, Sotaro Hirai, Jeff Biernaskie, Justin Chun, Grant Gordon, Andrey Shaw, Amir Sanati-Nezhad, Gerald Pfeffer, Frederic Calon, Minh Dang Nguyen
Polymorphisms in the gene encoding CD2-associated protein (CD2AP) are associated with an increased risk for developing Alzheimer’s disease (AD). Intriguingly, variants in the gene also cause a pattern of kidney injury termed focal segmental glomerulosclerosis. Recent studies have investigated the cell types and mechanisms by which CD2AP gene dosage contributes to the key pathological features of AD
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Early transcriptional and cellular abnormalities in choroid plexus of a mouse model of Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-31 Zhong-Jiang Yan, Maosen Ye, Jiexi Li, Deng-Feng Zhang, Yong-Gang Yao
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, tau hyperphosphorylation, and neuroinflammation. The choroid plexus (ChP), serving as the blood-cerebrospinal fluid-brain barrier, plays essential roles in immune response to stress and brain homeostasis. However, the cellular and molecular contributions of the ChP to AD progression
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Bridging systemic metabolic dysfunction and Alzheimer’s disease: the liver interface Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-28 Dan Song, Yang Li, Ling-Ling Yang, Ya-Xi Luo, Xiu-Qing Yao
Alzheimer’s disease (AD) is increasingly recognized as a systemic disorder with a substantial metabolic disorder component, where the liver significantly impacts the brain via the liver-brain axis. Key mechanisms include the liver’s role in clearing peripheral β-amyloid (Aβ), the influence of hepatic enzymes and metabolites on cognitive decline, and the systemic effects of metabolic disorders on AD
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Immunotherapy against tau fragment diminishes AD pathology, improving synaptic function and cognition Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-27 Jie Xiang, Zhengjiang Qian, Ye Xi, Yanuo Wei, Guangxing Wang, Xia Liu, Zhi-Hao Wang, Zhentao Zhang, Shengxi Wu, Keqiang Ye
Asparagine endopeptidase (AEP) is implicated in the pathogenesis of Alzheimer’s disease (AD) by cleaving Tau at residue N368, accelerating its hyperphosphorylation and aggregation. The Tau N368/t-Tau ratio in cerebrospinal fluid (CSF) serves as a superior biomarker compared to established biomarkers (p-Tau 181/217) for correlating with tau pathology and synaptic dysfunction in patients with AD, highlighting
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Mutations in NEK1 cause ciliary dysfunction as a novel pathogenic mechanism in amyotrophic lateral sclerosis Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-20 Min-Young Noh, Seong-il Oh, Young-Eun Kim, Sun Joo Cha, Wonjae Sung, Ki-Wook Oh, Yurim Park, Ji Young Mun, Chang-Seok Ki, Minyeop Nahm, Seung Hyun Kim
Neuronal primary cilia, vital for signaling and cell-cycle regulation, have been implicated in maintaining neuronal identity. While a link between primary ciliary defects and neurodegenerative diseases is emerging, the precise pathological mechanisms remain unclear. We studied the genetic contribution of NEK1 to ALS pathogenesis by analyzing the exome sequences of 920 Korean patients with ALS. To understand
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Network analysis of the cerebrospinal fluid proteome reveals shared and unique differences between sporadic and familial forms of amyotrophic lateral sclerosis Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-15 Adam N. Trautwig, Edward J. Fox, Eric B. Dammer, Anantharaman Shantaraman, Lingyan Ping, Duc M. Duong, Caroline M. Watson, Fang Wu, Seneshaw Asress, Qi Guo, Allan I. Levey, James J. Lah, Federico Verde, Alberto Doretti, Antonia Ratti, Nicola Ticozzi, Cindy V. Ly, Timothy M. Miller, Mark A. Garret, James D. Berry, Eleanor V. Thomas, Christina N. Fournier, Zachary T. McEachin, Nicholas T. Seyfried, Jonathan
Amyotrophic Lateral Sclerosis (ALS), a neurodegenerative disease involving loss of motor neurons, typically results in death within 3–5 years of disease onset. Although roughly 10% of cases can be linked to a specific inherited mutation (e.g., C9orf72 hexanucleotide repeat expansion or SOD1 mutation), the cause(s) of most cases are unknown. Consequently, there is a critical need for biomarkers that
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Mouse models of Anti-Aβ immunotherapies Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-13 Philip Pikus, R. Scott Turner, G. William Rebeck
The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer’s Disease (AD) is a breakthrough of basic research and translational science. Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination
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Cellular and molecular mechanisms of pathological tau phosphorylation in traumatic brain injury: implications for chronic traumatic encephalopathy Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-10 Neil Donison, Jacqueline Palik, Kathryn Volkening, Michael J. Strong
Tau protein plays a critical role in the physiological functioning of the central nervous system by providing structural integrity to the cytoskeletal architecture of neurons and glia through microtubule assembly and stabilization. Under certain pathological conditions, tau is aberrantly phosphorylated and aggregates into neurotoxic fibrillary tangles. The aggregation and cell-to-cell propagation of
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Evidence suggesting that microglia make amyloid from neuronally expressed APP: a hypothesis Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-09 John Hardy, Patrick Lewis
While APP is largely neuonally expressed, Aβ amyloid is largely produced by microglia as the clearance mechanisms for damaged membranes becomes overwhelmed.
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Cautions on utilizing plasma GFAP level as a biomarker for reactive astrocytes in neurodegenerative diseases Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-09 Wongu Youn, Mijin Yun, C. Justin Lee, Michael Schöll
In the recent decade, there has been a surge of efforts to develop scalable, specific and cost-effective biomarkers in blood to diagnose neurodegenerative diseases and prognose their progress even before overt symptoms manifest. Among an array of brain-associated proteins, glial fibrillary acidic protein (GFAP) has emerged as a compelling biomarker candidate, often in conjunction with other biomarkers
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Molecular mechanisms and consequences of TDP-43 phosphorylation in neurodegeneration Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-08 Elise A. Kellett, Adekunle T. Bademosi, Adam K. Walker
Increased phosphorylation of TDP-43 is a pathological hallmark of several neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). However, the regulation and roles of TDP-43 phosphorylation remain incompletely understood. A variety of techniques have been utilized to understand TDP-43 phosphorylation, including kinase/phosphatase manipulation, phosphomimic
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Cerebrospinal fluid proteome profiling across the Alzheimer’s disease continuum: a step towards solving the equation for ‘X’ Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-06 Sophia Weiner, Mathias Sauer, Laia Montoliu-Gaya, Andrea L. Benedet, Nicholas J. Ashton, Fernando Gonzalez-Ortiz, Joel Simrén, Nesrine Rahmouni, Cecile Tissot, Joseph Therriault, Stijn Servaes, Jenna Stevenson, Ville Leinonen, Tuomas Rauramaa, Mikko Hiltunen, Pedro Rosa-Neto, Kaj Blennow, Henrik Zetterberg, Johan Gobom
While the temporal profile of amyloid (Aβ) and tau cerebrospinal fluid (CSF) biomarkers along the Alzheimer’s disease (AD) continuum is well-studied, chronological changes of CSF proteins reflecting other disease-relevant processes, denoted ‘X’ in the ATX(N) framework, remain poorly understood. Using an untargeted mass spectrometric approach termed tandem mass tag (TMT), we quantified over 1500 CSF
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Alzheimer’s disease protective allele of Clusterin modulates neuronal excitability through lipid-droplet-mediated neuron-glia communication Mol. Neurodegener. (IF 14.9) Pub Date : 2025-05-03 Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J. Moulton, Lindsey D. Goodman, Zhiping P. Pang, Alan R. Sanders, Hugo J. Bellen, Gopal Thinakaran, Jubao Duan
Genome-wide association studies (GWAS) of Alzheimer’s disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied. Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated
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Monoallelic TYROBP deletion is a novel risk factor for Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-29 Henna Martiskainen, Roosa-Maria Willman, Päivi Harju, Sami Heikkinen, Mette Heiskanen, Stephan A. Müller, Rosa Sinisalo, Mari Takalo, Petra Mäkinen, Teemu Kuulasmaa, Viivi Pekkala, Ana Galván del Rey, Sini-Pauliina Juopperi, Heli Jeskanen, Inka Kervinen, Kirsi Saastamoinen, Marja Niiranen, Sami V. Heikkinen, Mitja I. Kurki, Jarkko Marttila, Petri I. Mäkinen, Hannah Rostalski, Tomi Hietanen, Tiia Ngandu
Biallelic loss-of-function variants in TYROBP and TREM2 cause autosomal recessive presenile dementia with bone cysts known as Nasu-Hakola disease (NHD, alternatively polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy, PLOSL). Some other TREM2 variants contribute to the risk of Alzheimer’s disease (AD) and frontotemporal dementia, while deleterious TYROBP variants are globally
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TDP-43 seeding activity in the olfactory mucosa of patients with amyotrophic lateral sclerosis Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-26 Maria Vizziello, Ilaria Linda Dellarole, Arianna Ciullini, Riccardo Pascuzzo, Annalisa Lombardo, Floriana Bellandi, Luigi Celauro, Claudia Battipaglia, Emilio Ciusani, Ambra Rizzo, Marcella Catania, Grazia Devigili, Sara Adriana Della Seta, Valentina Margiotta, Monica Consonni, Veronica Faltracco, Pietro Tiraboschi, Nilo Riva, Sara Maria Silvia Portaleone, Gianluigi Zanusso, Giuseppe Legname, Giuseppe
In recent years, the seed amplification assay (SAA) has enabled the identification of pathological TDP-43 in the cerebrospinal fluid (CSF) and olfactory mucosa (OM) of patients with genetic forms of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Here, we investigated the seeding activity of TDP-43 in OM samples collected from patients with sporadic ALS. OM samples were collected
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Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-26 Sara Gutiérrez Fernández, Cristina Gan Oria, Dieter Petit, Wim Annaert, John M. Ringman, Nick C. Fox, Natalie S. Ryan, Lucía Chávez-Gutiérrez
Autosomal Dominant Alzheimer's Disease (ADAD), caused by mutations in Presenilins (PSEN1/2) and Amyloid Precursor Protein (APP) genes, typically manifests with early onset (< 65 years). Age at symptom onset (AAO) is relatively consistent among carriers of the same PSEN1 mutation, but more variable for PSEN2 and APP variants, with these mutations associated with later AAOs than PSEN1. Understanding
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Multi-region brain transcriptomic analysis of amyotrophic lateral sclerosis reveals widespread RNA alterations and substantial cerebellum involvement Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-25 Natalie Grima, Andrew N. Smith, Claire E. Shepherd, Lyndal Henden, Thiri Zaw, Luke Carroll, Dominic B. Rowe, Matthew C. Kiernan, Ian P. Blair, Kelly L. Williams
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects the motor neurons, causing progressive muscle weakness and paralysis. While research has focused on understanding pathological mechanisms in the motor cortex and spinal cord, there is growing evidence that extra-motor brain regions may also play a role in the pathogenesis or progression of ALS. We generated 165
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Apolipoprotein E in Alzheimer’s disease: molecular insights and therapeutic opportunities Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-24 Abdel Ali Belaidi, Ashley I. Bush, Scott Ayton
Apolipoprotein E (APOE- gene; apoE- protein) is the strongest genetic modulator of late-onset Alzheimer’s disease (AD), with its three major isoforms conferring risk for disease ε2 < ε3 < ε4. Emerging protective gene variants, such as APOE Christchurch and the COLBOS variant of REELIN, an alternative target of certain apoE receptors, offer novel insights into resilience against AD. In recent years
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Research models to study lewy body dementia Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-23 Suelen Lucio Boschen, Aarushi A. Mukerjee, Ayman H. Faroqi, Ben E. Rabichow, John Fryer
Lewy body dementia (LBD) encompasses neurodegenerative dementias characterized by cognitive fluctuations, visual hallucinations, and parkinsonism. Clinical differentiation of LBD from Alzheimer’s disease (AD) remains complex due to symptom overlap, yet approximately 25% of dementia cases are diagnosed as LBD postmortem, primarily identified by the presence of α-synuclein aggregates, tau tangles, and
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Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-23 Jolien Perneel, Miranda Lastra Osua, Sara Alidadiani, Nele Peeters, Linus De Witte, Bavo Heeman, Simona Manzella, Riet De Rycke, Mieu Brooks, Ralph B. Perkerson, Elke Calus, Wouter De Coster, Manuela Neumann, Ian R. A. Mackenzie, Debby Van Dam, Bob Asselbergh, Tommas Ellender, Xiaolai Zhou, Rosa Rademakers
Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear
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Inhibition of soluble epoxide hydrolase confers neuroprotection and restores microglial homeostasis in a tauopathy mouse model Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-23 Shuo Wang, Chuangye Qi, Chetan Rajpurohit, Baijayanti Ghosh, Wen Xiong, Baiping Wang, Yanyan Qi, Sung Hee Hwang, Bruce D. Hammock, Hongjie Li, Li Gan, Hui Zheng
The epoxyeicosatrienoic acids (EETs) are derivatives of the arachidonic acid metabolism with anti-inflammatory activities. However, their efficacy is limited due to the rapid hydrolysis by soluble epoxide hydrolase (sEH). Inhibition of sEH has been shown to stabilize the EETs and reduce neuroinflammation in Aβ mouse models of Alzheimer’s disease (AD). However, the role of the sEH-EET signaling pathway
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TREM2 and sTREM2 in Alzheimer’s disease: from mechanisms to therapies Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-17 Lianshuai Zhang, Xianyuan Xiang, Yahui Li, Guojun Bu, Xiao-Fen Chen
Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor predominantly expressed by microglia in the brain. Recent studies have established TREM2 as a central immune signaling hub in neurodegeneration, where it triggers immune responses upon sensing pathological development and tissue damages. TREM2 binds diverse ligands and activates downstream pathways that regulate microglial
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Therapeutic effects of adipose-derived mesenchymal stem cells combined with glymphatic system activation in prion disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-17 Mohammed Zayed, Yong-Chan Kim, Byung-Hoon Jeong
There is currently no effective therapy for prion diseases. The glymphatic system is an organized system of perivascular spaces that facilitates the removal of metabolic waste from the brain. This study demonstrates the therapeutic potential of a combination therapy of adipose-derived mesenchymal stem cells (AdMSCs) and a glymphatic system-activated drug, clonidine, against prion disease. The therapy
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ASO-mediated knock-down of GPNMB in mutant-GRN and in Grn-deficient peripheral myeloid cells disrupts lysosomal function and immune responses Mol. Neurodegener. (IF 14.9) Pub Date : 2025-04-08 Rebecca L. Wallings, Drew A. Gillett, Hannah A. Staley, Savanna Mahn, Julian Mark, Noelle Neighbarger, Holly Kordasiewicz, Warren D. Hirst, Malú Gámez Tansey
GPNMB has been discussed as a potential therapeutic target in GRN-mediated neurodegeneration, based on the observed reproducible upregulation in FTD-GRN cerebrospinal fluid (CSF) and post-mortem brain. However, the functional impacts of up-regulated GPNMB are currently unknown, and it is currently unclear if targeting GPNMB will be protective or deleterious. Increases in GPNMB seen in FTD-GRN are reproduced
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Immune modulation to treat Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-31 Michael R. Duggan, David G. Morgan, Brittani R. Price, Binita Rajbanshi, Alfonso Martin-Peña, Malú Gámez Tansey, Keenan A. Walker
Immune mechanisms play a fundamental role in Alzheimer’s disease (AD) pathogenesis, suggesting that approaches which target immune cells and immunologically relevant molecules can offer therapeutic opportunities beyond the recently approved amyloid beta monoclonal therapies. In this review, we provide an overview of immunomodulatory therapeutics in development, including their preclinical evidence
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A stress-dependent TDP-43 SUMOylation program preserves neuronal function Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-28 Terry R. Suk, Caroline E. Part, Jenny L. Zhang, Trina T. Nguyen, Meghan M. Heer, Alejandro Caballero-Gómez, Veronica S. Grybas, Paul M. McKeever, Benjamin Nguyen, Tahir Ali, Steve M. Callaghan, John M. Woulfe, Janice Robertson, Maxime W. C. Rousseaux
Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD) are overwhelmingly linked to TDP-43 dysfunction. Mutations in TDP-43 are rare, indicating that the progressive accumulation of exogenous factors – such as cellular stressors – converge on TDP-43 to play a key role in disease pathogenesis. Post translational modifications such as SUMOylation play essential roles in response to such
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Decoding microglial immunometabolism: a new frontier in Alzheimer's disease research Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-27 Eun Sun Jung, Hayoung Choi, Inhee Mook-Jung
Alzheimer’s disease (AD) involves a dynamic interaction between neuroinflammation and metabolic dysregulation, where microglia play a central role. These immune cells undergo metabolic reprogramming in response to AD-related pathology, with key genes such as TREM2, APOE, and HIF-1α orchestrating these processes. Microglial metabolism adapts to environmental stimuli, shifting between oxidative phosphorylation
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Immune cell metabolic dysfunction in Parkinson’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-24 Julian R. Mark, Malú Gámez Tansey
Parkinson’s disease (PD) is a multi-system disorder characterized histopathologically by degeneration of dopaminergic neurons in the substantia nigra pars compacta. While the etiology of PD remains multifactorial and complex, growing evidence suggests that cellular metabolic dysfunction is a critical driver of neuronal death. Defects in cellular metabolism related to energy production, oxidative stress
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The role of n-3-derived specialised pro-resolving mediators (SPMs) in microglial mitochondrial respiration and inflammation resolution in Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-21 Mary Slayo, Christoph Rummel, Pasindu Hansana Singhaarachchi, Martin Feldotto, Sarah J. Spencer
Alzheimer’s disease (AD) is the most common form of dementia globally and is characterised by reduced mitochondrial respiration and cortical deposition of amyloid-β plaques and neurofibrillary tangles comprised of hyper-phosphorylated tau. Despite its characterisation more than 110 years ago, the mechanisms by which AD develops are still unclear. Dysregulation of microglial phagocytosis of amyloid-β
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A reciprocal relationship between markers of genomic DNA damage and alpha-synuclein pathology in dementia with Lewy bodies Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-20 David J. Koss, Olivia Todd, Hariharan Menon, Zoe Anderson, Tamsin Yang, Lucas Findlay, Ben Graham, Pawel Palmowski, Andrew Porter, Nicola Morrice, Lauren Walker, Johannes Attems, Simona S. Ghanem, Omar El-Agnaf, Fiona EN. LeBeau, Daniel Erskine, Tiago F. Outeiro
DNA damage and DNA damage repair (DDR) dysfunction are insults with broad implications for cellular physiology and have been implicated in various neurodegenerative diseases. Alpha-synuclein (aSyn), a pre-synaptic and nuclear protein associated with neurodegenerative disorders known as synucleinopathies, has been associated with DNA double strand break (DSB) repair. However, although nuclear aSyn pathology
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Alpha synuclein co-pathology is associated with accelerated amyloid-driven tau accumulation in Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-18 Nicolai Franzmeier, Sebastian Niclas Roemer-Cassiano, Alexander Maximilian Bernhardt, Amir Dehsarvi, Anna Dewenter, Anna Steward, Davina Biel, Lukas Frontzkowski, Zeyu Zhu, Johannes Gnörich, Julia Pescoller, Fabian Wagner, Fabian Hirsch, Hannah de Bruin, Rik Ossenkoppele, Carla Palleis, Felix Strübing, Michael Schöll, Johannes Levin, Matthias Brendel, Günter U. Höglinger
Aggregated alpha-Synuclein (αSyn) is a hallmark pathology in Parkinson’s disease but also one of the most common co-pathologies in Alzheimer’s disease (AD). Preclinical studies suggest that αSyn can exacerbate tau aggregation, implying that αSyn co-pathology may specifically contribute to the Aβ-induced aggregation of tau that drives neurodegeneration and cognitive decline in AD. To investigate this
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Alzheimer's disease neuropathology and its estimation with fluid and imaging biomarkers Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-14 Dietmar Rudolf Thal, Koen Poesen, Rik Vandenberghe, Steffi De Meyer
Alzheimer’s disease (AD) is neuropathologically characterized by the extracellular deposition of the amyloid-β peptide (Aβ) and the intraneuronal accumulation of abnormal phosphorylated tau (τ)-protein (p-τ). Most frequently, these hallmark lesions are accompanied by other co-pathologies in the brain that may contribute to cognitive impairment, such as vascular lesions, intraneuronal accumulation of
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Probe-dependent Proximity Profiling (ProPPr) Uncovers Similarities and Differences in Phospho-Tau-Associated Proteomes Between Tauopathies Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-13 Dmytro Morderer, Melissa C. Wren, Feilin Liu, Naomi Kouri, Anastasiia Maistrenko, Bilal Khalil, Nora Pobitzer, Michelle R. Salemi, Brett S. Phinney, Guojun Bu, Na Zhao, Dennis W. Dickson, Melissa E. Murray, Wilfried Rossoll
Tauopathies represent a diverse group of neurodegenerative disorders characterized by the abnormal aggregation of the microtubule-associated protein tau. Despite extensive research, the mechanisms underlying the diversity of neuronal and glial tau pathology in different tauopathies are poorly understood. While there is a growing understanding of tauopathy-specific differences in tau isoforms and fibrillar
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Comprehensive cross-sectional and longitudinal comparisons of plasma glial fibrillary acidic protein and neurofilament light across FTD spectrum disorders Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-12 Udit Sheth, Linn Öijerstedt, Michael G. Heckman, Launia J. White, Hilary W. Heuer, Argentina Lario Lago, Leah K. Forsberg, Kelley M. Faber, Tatiana M. Foroud, Rosa Rademakers, Eliana Marisa Ramos, Brian S. Appleby, Andrea C. Bozoki, R. Ryan Darby, Bradford C. Dickerson, Kimiko Domoto-Reilly, Douglas R. Galasko, Nupur Ghoshal, Neill R. Graff-Radford, Ian M. Grant, Chadwick M. Hales, Ging-Yuek Robin
Therapeutic development for frontotemporal dementia (FTD) is hindered by the lack of biomarkers that inform susceptibility/risk, prognosis, and the underlying causative pathology. Blood glial fibrillary acidic protein (GFAP) has garnered attention as a FTD biomarker. However, investigations of GFAP in FTD have been hampered by symptomatic and histopathologic heterogeneity and small cohort sizes contributing
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A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-11 Lutgarde Serneels, Annerieke Sierksma, Emanuela Pasciuto, Ivana Geric, Arya Nair, Anna Martinez-Muriana, An Snellinx, Bart De Strooper
Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation
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Srebf2 mediates successful optic nerve axon regeneration via the mevalonate synthesis pathway Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-05 Mengming Hu, Matthew B. Veldman
Axon regeneration within the mammalian central nervous system is extremely limited. In optic neuropathy conditions like glaucoma, the inability of retinal ganglion cell (RGC) axons to regenerate is a major impediment to functional recovery. In contrast, adult teleost fish such as zebrafish can fully regenerate RGC axons enabling visual recovery from optic nerve (ON) injury making it an ideal model
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Inactivation of NLRP3 inflammasome by dephosphorylation at Serine 658 alleviates glial inflammation in the mouse model of Parkinson’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-05 Rong-Xin Zhu, Rui-Xue Han, Yue-Han Chen, Lei Huang, Ting Liu, Jingwei Jiang, Cong Wang, Lei Cao, Yang Liu, Ming Lu
Parkinson’s disease (PD) is a leading neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons, contributing to considerable disability worldwide. Current treatments offer only symptomatic relief, highlighting the need for novel therapeutic strategies targeting disease progression. Neuroinflammation plays a pivotal role in PD pathogenesis, with the NLRP3 inflammasome
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Age-dependent progression from clearance to vulnerability in the early response of periventricular microglia to α-synuclein toxic species Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-05 Mª Salomé Sirerol-Piquer, Ana Perez-Villalba, Pere Duart-Abadia, Germán Belenguer, Ulises Gómez-Pinedo, Laura Blasco-Chamarro, Pau Carrillo-Barberà, Azucena Pérez-Cañamás, Victoria Navarro-Garrido, Benjamin Dehay, Miquel Vila, Javier Vitorica, Francisco Pérez-Sánchez, Isabel Fariñas
Cytoplasmic alpha-synuclein (αSyn) aggregates are a typical feature of Parkinson’s disease (PD). Extracellular insoluble αSyn can induce pathology in healthy neurons suggesting that PD neurodegeneration may spread through cell-to-cell transfer of αSyn proteopathic seeds. Early pro-homeostatic reaction of microglia to toxic forms of αSyn remains elusive, which is especially relevant considering the
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The neuroimmune nexus: unraveling the role of the mtDNA-cGAS-STING signal pathway in Alzheimer’s disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-03-04 Shuiyue Quan, Xiaofeng Fu, Huimin Cai, Ziye Ren, Yinghao Xu, Longfei Jia
The relationship between Alzheimer's disease (AD) and neuroimmunity has gradually begun to be unveiled. Emerging evidence indicates that cyclic GMP-AMP synthase (cGAS) acts as a cytosolic DNA sensor, recognizing cytosolic damage-associated molecular patterns (DAMPs), and inducing the innate immune response by activating stimulator of interferon genes (STING). Dysregulation of this pathway culminates
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Preclinical studies and transcriptome analysis in a model of Parkinson’s disease with dopaminergic ZNF746 expression Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-28 Ji Hun Kim, Sumin Yang, Hyojung Kim, Dang-Khoa Vo, Han-Joo Maeng, Areum Jo, Joo-Heon Shin, Joo-Ho Shin, Hyeon-Man Baek, Gum Hwa Lee, Sung-Hyun Kim, Key-Hwan Lim, Valina L. Dawson, Ted M. Dawson, Jae-Yeol Joo, Yunjong Lee
The parkin-interacting substrate (PARIS, also known as ZNF746) is a transcriptional repressor, whose accumulation and phosphorylation play central pathological roles in Parkinson’s disease (PD). PARIS-induced transcriptional repression of PGC-1α or MDM4 contributes to mitochondrial dysfunction and p53-dependent neuron loss in PD. Despite the important role of PARIS in PD pathogenesis, unbiased transcriptomic
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18F-MK-6240 tau PET in patients at-risk for chronic traumatic encephalopathy Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-25 Michael L. Alosco, Jhony Mejía Pérez, Julia E. Culhane, Ranjani Shankar, Christopher J. Nowinski, Samantha Bureau, Nidhi Mundada, Karen Smith, Alinda Amuiri, Breton Asken, Jenna R. Groh, Annalise Miner, Erika Pettway, Sydney Mosaheb, Yorghos Tripodis, Charles Windon, Gustavo Mercier, Robert A. Stern, Lea T. Grinberg, David N. Soleimani-Meigooni, Bradley T. Christian, Tobey J. Betthauser, Thor D. Stein
Molecular biomarkers of chronic traumatic encephalopathy (CTE) are lacking. We evaluated 18F-MK-6240 tau PET as a biomarker for CTE. Two studies were done: (1) 3H-MK-6240 autoradiography and an in-vitro brain homogenate binding studies on postmortem CTE tissue, (2) an in-vivo 18F-MK-6240 tau PET study in former American football players. Autoradiography and in-vitro binding studies were done using
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Peripheral and central neuroimmune mechanisms in Alzheimer’s disease pathogenesis Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-21 Shuo Zhang, Yue Gao, Yini Zhao, Timothy Y. Huang, Qiuyang Zheng, Xin Wang
Alzheimer’s disease (AD) poses a growing global health challenge as populations age. Recent research highlights the crucial role of peripheral immunity in AD pathogenesis. This review explores how blood-brain barrier disruption allows peripheral immune cells to infiltrate the central nervous system (CNS), worsening neuroinflammation and disease progression. We examine recent findings on interactions
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Mechanisms of astrocyte aging in reactivity and disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-21 Holly K. Gildea, Shane A. Liddelow
Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are heterogenous, responsive to their environments, and
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The integrated stress response in neurodegenerative diseases Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-19 Maria Astrid Bravo-Jimenez, Shivangi Sharma, Soheila Karimi-Abdolrezaee
The integrated stress response (ISR) is a conserved network in eukaryotic cells that mediates adaptive responses to diverse stressors. The ISR pathway ensures cell survival and homeostasis by regulating protein synthesis in response to internal or external stresses. In recent years, the ISR has emerged as an important regulator of the central nervous system (CNS) development, homeostasis and pathology
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From mechanisms to future therapy: a synopsis of isolated REM sleep behavior disorder as early synuclein-related disease Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-11 Ambra Stefani, Elena Antelmi, Dario Arnaldi, Isabelle Arnulf, Emmanuel During, Birgit Högl, Michele M. T. Hu, Alex Iranzo, Russell Luke, John Peever, Ronald B. Postuma, Aleksandar Videnovic, Ziv Gan-Or
Parkinson disease (PD), dementia with Lewy bodies (DLB) and multiple system atrophy are synucleinopathies, characterized by neuronal loss, gliosis and the abnormal deposition of α-synuclein in vulnerable areas of the nervous system. Neurodegeneration begins however several years before clinical onset of motor, cognitive or autonomic symptoms. The isolated form of REM sleep behavior disorder (RBD),
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The transcription factor combination MEF2 and KLF7 promotes axonal sprouting in the injured spinal cord with functional improvement and regeneration-associated gene expression Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-08 Callan L. Attwell, Inés Maldonado-Lasunción, Ruben Eggers, Bastiaan A. Bijleveld, Ward M. Ellenbroek, Natascha Siersema, Lotte Razenberg, Dédé Lamme, Nitish D. Fagoe, Ronald E. van Kesteren, August B. Smit, Joost Verhaagen, Matthew R. J. Mason
Axon regeneration after injury to the central nervous system (CNS) is limited by an inhibitory environment but also because injured neurons fail to initiate expression of regeneration associated genes (RAGs). The potential of strong RAG expression to promote regeneration in the CNS is exemplified by the conditioning lesion model, whereby peripheral nerve injury promotes regeneration of centrally projecting
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Disparate and shared transcriptomic signatures associated with cortical atrophy in genetic behavioral variant frontotemporal degeneration Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-07 Ting Shen, Jacob W. Vogel, Vivianna M. Van Deerlin, EunRan Suh, Laynie Dratch, Jeffrey S. Phillips, Lauren Massimo, Edward B. Lee, David J. Irwin, Corey T. McMillan
Cortical atrophy is a common manifestation in behavioral variant frontotemporal degeneration (bvFTD), exhibiting spatial heterogeneity across various genetic subgroups, which may be driven by distinct biological mechanisms. We employed an integrative imaging transcriptomics approach to identify both disparate and shared transcriptomic signatures associated with cortical thickness in bvFTD with C9orf72
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Loss of MEF2C function by enhancer mutation leads to neuronal mitochondria dysfunction and motor deficits in mice Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-07 Ali Yousefian-Jazi, Suhyun Kim, Jiyeon Chu, Seung-Hye Choi, Phuong Thi Thanh Nguyen, Uiyeol Park, Min-gyeong Kim, Hongik Hwang, Kyungeun Lee, Yeyun Kim, Seung Jae Hyeon, Hyewhon Rhim, Hannah L. Ryu, Grewo Lim, Thor D. Stein, Kayeong Lim, Hoon Ryu, Junghee Lee
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, leading to progressive paralysis. Both genetic alterations and epigenetic modifications contribute to neuronal dysfunction in the pathogenesis of ALS. However, the mechanism behind genetic mutations in the non-coding region of genes that affect epigenetic modifications
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Cellular senescence induced by cholesterol accumulation is mediated by lysosomal ABCA1 in APOE4 and AD Mol. Neurodegener. (IF 14.9) Pub Date : 2025-02-04 Shaowei Wang, Boyang Li, Jie Li, Zhiheng Cai, Cristelle Hugo, Yi Sun, Lu Qian, Julia TCW, Helena C. Chui, Dante Dikeman, Isaac Asante, Stan G. Louie, David A. Bennett, Zoe Arvanitakis, Alan T. Remaley, Bilal E. Kerman, Hussein N. Yassine
Cellular senescence, a hallmark of aging, has been implicated in Alzheimer’s disease (AD) pathogenesis. Cholesterol accumulation is known to drive cellular senescence; however, its underlying mechanisms are not fully understood. ATP-binding cassette transporter A1 (ABCA1) plays an important role in cholesterol homeostasis, and its expression and trafficking are altered in APOE4 and AD models. However
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Lewy body diseases and the gut Mol. Neurodegener. (IF 14.9) Pub Date : 2025-01-30 Timothy R. Sampson, Malú Gámez Tansey, Andrew B. West, Rodger A. Liddle
Gastrointestinal (GI) involvement in Lewy body diseases (LBDs) has been observed since the initial descriptions of patients by James Parkinson. Recent experimental and human observational studies raise the possibility that pathogenic alpha-synuclein (⍺-syn) might develop in the GI tract and subsequently spread to susceptible brain regions. The cellular and mechanistic origins of ⍺-syn propagation in
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Molecular and cellular characteristics of cerebrovascular cell types and their contribution to neurodegenerative diseases Mol. Neurodegener. (IF 14.9) Pub Date : 2025-01-29 Francisco J. Garcia, Myriam Heiman
Many diseases and disorders of the nervous system suffer from a lack of adequate therapeutics to halt or slow disease progression, and to this day, no cure exists for any of the fatal neurodegenerative diseases. In part this is due to the incredible diversity of cell types that comprise the brain, knowledge gaps in understanding basic mechanisms of disease, as well as a lack of reliable strategies
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Cell-specific transcriptional signatures of vascular cells in Alzheimer’s disease: perspectives, pathways, and therapeutic directions Mol. Neurodegener. (IF 14.9) Pub Date : 2025-01-29 Soumilee Chaudhuri, Minyoung Cho, Julia C. Stumpff, Paula J. Bice, Özkan İş, Nilüfer Ertekin-Taner, Andrew J. Saykin, Kwangsik Nho
Alzheimer’s disease (AD) is a debilitating neurodegenerative disease that is marked by profound neurovascular dysfunction and significant cell-specific alterations in the brain vasculature. Recent advances in high throughput single-cell transcriptomics technology have enabled the study of the human brain vasculature at an unprecedented depth. Additionally, the understudied niche of cerebrovascular