journal
https://read.qxmd.com/read/38254150/nuclear-import-receptors-as-gatekeepers-of-pathological-phase-transitions-in-als-ftd
#21
REVIEW
Bilal Khalil, Miriam Linsenmeier, Courtney L Smith, James Shorter, Wilfried Rossoll
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are fatal neurodegenerative disorders on a disease spectrum that are characterized by the cytoplasmic mislocalization and aberrant phase transitions of prion-like RNA-binding proteins (RBPs). The common accumulation of TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), and other nuclear RBPs in detergent-insoluble aggregates in the cytoplasm of degenerating neurons in ALS/FTD is connected to nuclear pore dysfunction and other defects in the nucleocytoplasmic transport machinery...
January 22, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38245794/unravelling-cell-type-specific-responses-to-parkinson-s-disease-at-single-cell-resolution
#22
JOURNAL ARTICLE
Araks Martirosyan, Rizwan Ansari, Francisco Pestana, Katja Hebestreit, Hayk Gasparyan, Razmik Aleksanyan, Silvia Hnatova, Suresh Poovathingal, Catherine Marneffe, Dietmar R Thal, Andrew Kottick, Victor J Hanson-Smith, Sebastian Guelfi, William Plumbly, T Grant Belgard, Emmanouil Metzakopian, Matthew G Holt
Parkinson's Disease (PD) is the second most common neurodegenerative disorder. The pathological hallmark of PD is loss of dopaminergic neurons and the presence of aggregated α-synuclein, primarily in the substantia nigra pars compacta (SNpc) of the midbrain. However, the molecular mechanisms that underlie the pathology in different cell types is not currently understood. Here, we present a single nucleus transcriptome analysis of human post-mortem SNpc obtained from 15 sporadic Parkinson's Disease (PD) cases and 14 Controls...
January 20, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38238819/real-time-imaging-of-mitochondrial-redox-reveals-increased-mitochondrial-oxidative-stress-associated-with-amyloid-%C3%AE-aggregates-in-vivo-in-a-mouse-model-of-alzheimer-s-disease
#23
JOURNAL ARTICLE
Maria Calvo-Rodriguez, Elizabeth K Kharitonova, Austin C Snyder, Steven S Hou, Maria Virtudes Sanchez-Mico, Sudeshna Das, Zhanyun Fan, Hamid Shirani, K Peter R Nilsson, Alberto Serrano-Pozo, Brian J Bacskai
BACKGROUND: Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants...
January 18, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38229094/brain-clearance-of-protein-aggregates-a-close-up-on-astrocytes
#24
REVIEW
Veronica Giusti, Gurkirat Kaur, Elena Giusto, Laura Civiero
Protein misfolding and accumulation defines a prevailing feature of many neurodegenerative disorders, finally resulting in the formation of toxic intra- and extracellular aggregates. Intracellular aggregates can enter the extracellular space and be subsequently transferred among different cell types, thus spreading between connected brain districts.Although microglia perform a predominant role in the removal of extracellular aggregated proteins, mounting evidence suggests that astrocytes actively contribute to the clearing process...
January 16, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38195580/neuronal-and-glial-vulnerability-of-the-suprachiasmatic-nucleus-in-tauopathies-evidence-from-human-studies-and-animal-models
#25
REVIEW
Gowoon Son, Thomas C Neylan, Lea T Grinberg
Tauopathies, a group of neurodegenerative diseases that includes Alzheimer's disease, commonly lead to disturbances in sleep-wake patterns and circadian rhythm disorders. The circadian rhythm, a recurring 24-hour cycle governing human biological activity, is regulated by the hypothalamic suprachiasmatic nucleus (SCN) and endogenous transcriptional-translational feedback loops. Surprisingly, little attention has been given to investigating tauopathy-driven neuropathology in the SCN and the repercussions of SCN and circadian gene dysfunction in the human brain affected by tauopathies...
January 10, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38185677/comparison-of-immunoassay-with-mass-spectrometry-derived-p-tau-quantification-for-the-detection-of-alzheimer-s-disease-pathology
#26
JOURNAL ARTICLE
Joseph Therriault, Marcel S Woo, Gemma Salvadó, Johan Gobom, Thomas K Karikari, Shorena Janelidze, Stijn Servaes, Nesrine Rahmouni, Cécile Tissot, Nicholas J Ashton, Andréa Lessa Benedet, Laia Montoliu-Gaya, Arthur C Macedo, Firoza Z Lussier, Jenna Stevenson, Paolo Vitali, Manuel A Friese, Gassan Massarweh, Jean-Paul Soucy, Tharick A Pascoal, Erik Stomrud, Sebastian Palmqvist, Niklas Mattsson-Carlgren, Serge Gauthier, Henrik Zetterberg, Oskar Hansson, Kaj Blennow, Pedro Rosa-Neto
BACKGROUND: Antibody-based immunoassays have enabled quantification of very low concentrations of phosphorylated tau (p-tau) protein forms in cerebrospinal fluid (CSF), aiding in the diagnosis of AD. Mass spectrometry enables absolute quantification of multiple p-tau variants within a single run. The goal of this study was to compare the performance of mass spectrometry assessments of p-tau181 , p-tau217 and p-tau231 with established immunoassay techniques. METHODS: We measured p-tau181 , p-tau217 and p-tau231 concentrations in CSF from 173 participants from the TRIAD cohort and 394 participants from the BioFINDER-2 cohort using both mass spectrometry and immunoassay methods...
January 7, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38185628/blood-platelet-factor-4-the-elixir-of-brain-rejuvenation
#27
LETTER
José M Izquierdo
No abstract text is available yet for this article.
January 7, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38172904/proteo-genomics-of-soluble-trem2-in-cerebrospinal-fluid-provides-novel-insights-and-identifies-novel-modulators-for-alzheimer-s-disease
#28
JOURNAL ARTICLE
Lihua Wang, Niko-Petteri Nykänen, Daniel Western, Priyanka Gorijala, Jigyasha Timsina, Fuhai Li, Zhaohua Wang, Muhammad Ali, Chengran Yang, Menghan Liu, William Brock, Marta Marquié, Mercè Boada, Ignacio Alvarez, Miquel Aguilar, Pau Pastor, Agustín Ruiz, Raquel Puerta, Adelina Orellana, Jarod Rutledge, Hamilton Oh, Michael D Greicius, Yann Le Guen, Richard J Perrin, Tony Wyss-Coray, Angela Jefferson, Timothy J Hohman, Neill Graff-Radford, Hiroshi Mori, Alison Goate, Johannes Levin, Yun Ju Sung, Carlos Cruchaga
Triggering receptor expressed on myeloid cells 2 (TREM2) plays a critical role in microglial activation, survival, and apoptosis, as well as in Alzheimer's disease (AD) pathogenesis. We previously reported the MS4A locus as a key modulator for soluble TREM2 (sTREM2) in cerebrospinal fluid (CSF). To identify additional novel genetic modifiers of sTREM2, we performed the largest genome-wide association study (GWAS) and identified four loci for CSF sTREM2 in 3,350 individuals of European ancestry. Through multi-ethnic fine mapping, we identified two independent missense variants (p...
January 3, 2024: Molecular Neurodegeneration
https://read.qxmd.com/read/38115077/microglial-apoe4-more-is-less-and-less-is-more
#29
EDITORIAL
Ghazaleh Eskandari-Sedighi, Mathew Blurton-Jones
Apolipoprotein E (APOE) is the single greatest genetic risk factor for late onset Alzheimer's disease (AD). Yet, the cell-specific effects of APOE on microglia function have remained unclear. Fortunately, two comprehensive new studies published in the latest issue of Nature Immunology have employed complementary gain-of-function and loss-of-function approaches to provide critical new insight into the impact of microglial APOE on AD pathogenesis.
December 19, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38115046/untargeted-serum-metabolomics-reveals-novel-metabolite-associations-and-disruptions-in-amino-acid-and-lipid-metabolism-in-parkinson-s-disease
#30
JOURNAL ARTICLE
Kimberly C Paul, Keren Zhang, Douglas I Walker, Janet Sinsheimer, Yu Yu, Cynthia Kusters, Irish Del Rosario, Aline Duarte Folle, Adrienne M Keener, Jeff Bronstein, Dean P Jones, Beate Ritz
BACKGROUND: Untargeted high-resolution metabolomic profiling provides simultaneous measurement of thousands of metabolites. Metabolic networks based on these data can help uncover disease-related perturbations across interconnected pathways. OBJECTIVE: Identify metabolic disturbances associated with Parkinson's disease (PD) in two population-based studies using untargeted metabolomics. METHODS: We performed a metabolome-wide association study (MWAS) of PD using serum-based untargeted metabolomics data derived from liquid chromatography with high-resolution mass spectrometry (LC-HRMS) using two distinct population-based case-control populations...
December 19, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38111006/advanced-structural-brain-aging-in-preclinical-autosomal-dominant-alzheimer-disease
#31
JOURNAL ARTICLE
Peter R Millar, Brian A Gordon, Julie K Wisch, Stephanie A Schultz, Tammie Ls Benzinger, Carlos Cruchaga, Jason J Hassenstab, Laura Ibanez, Celeste Karch, Jorge J Llibre-Guerra, John C Morris, Richard J Perrin, Charlene Supnet-Bell, Chengjie Xiong, Ricardo F Allegri, Sarah B Berman, Jasmeer P Chhatwal, Patricio A Chrem Mendez, Gregory S Day, Anna Hofmann, Takeshi Ikeuchi, Mathias Jucker, Jae-Hong Lee, Johannes Levin, Francisco Lopera, Yoshiki Niimi, Victor J Sánchez-González, Peter R Schofield, Ana Luisa Sosa-Ortiz, Jonathan Vöglein, Randall J Bateman, Beau M Ances, Eric M McDade
BACKGROUND: "Brain-predicted age" estimates biological age from complex, nonlinear features in neuroimaging scans. The brain age gap (BAG) between predicted and chronological age is elevated in sporadic Alzheimer disease (AD), but is underexplored in autosomal dominant AD (ADAD), in which AD progression is highly predictable with minimal confounding age-related co-pathology. METHODS: We modeled BAG in 257 deeply-phenotyped ADAD mutation-carriers and 179 non-carriers from the Dominantly Inherited Alzheimer Network using minimally-processed structural MRI scans...
December 19, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38111033/correction-multi-modal-proteomic-characterization-of-lysosomal-function-and-proteostasis-in-progranulin-deficient-neurons
#32
Saadia Hasan, Michael S Fernandopulle, Stewart W Humble, Ashley M Frankenfield, Haorong Li, Ryan Prestil, Kory R Johnson, Brent J Ryan, Richard Wade-Martins, Michael E Ward, Ling Hao
No abstract text is available yet for this article.
December 18, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38111016/amyloid-%C3%AE-specific-regulatory-t-cells-attenuate-alzheimer-s-disease-pathobiology-in-app-ps1-mice
#33
JOURNAL ARTICLE
Pravin Yeapuri, Jatin Machhi, Yaman Lu, Mai Mohamed Abdelmoaty, Rana Kadry, Milankumar Patel, Shaurav Bhattarai, Eugene Lu, Krista L Namminga, Katherine E Olson, Emma G Foster, R Lee Mosley, Howard E Gendelman
BACKGROUND: Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRA β )...
December 18, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38104136/translational-profiling-identifies-sex-specific-metabolic-and-epigenetic-reprogramming-of-cortical-microglia-macrophages-in-appps1-21-mice-with-an-antibiotic-perturbed-microbiome
#34
JOURNAL ARTICLE
Shabana M Shaik, Yajun Cao, Joseph V Gogola, Hemraj B Dodiya, Xulun Zhang, Hejer Boutej, Weinong Han, Jasna Kriz, Sangram S Sisodia
BACKGROUND: Microglia, the brain-resident macrophages perform immune surveillance and engage with pathological processes resulting in phenotype changes necessary for maintaining homeostasis. In preceding studies, we showed that antibiotic-induced perturbations of the gut microbiome of APPPS1-21 mice resulted in significant attenuation in Aβ amyloidosis and altered microglial phenotypes that are specific to male mice. The molecular events underlying microglial phenotypic transitions remain unclear...
December 16, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38041169/mlkl-deficiency-alleviates-neuroinflammation-and-motor-deficits-in-the-%C3%AE-synuclein-transgenic-mouse-model-of-parkinson-s-disease
#35
JOURNAL ARTICLE
Lu Geng, Wenqing Gao, Hexige Saiyin, Yuanyuan Li, Yu Zeng, Zhifei Zhang, Xue Li, Zuolong Liu, Qiang Gao, Ping An, Ning Jiang, Xiaofei Yu, Xiangjun Chen, Suhua Li, Lei Chen, Boxun Lu, Aiqun Li, Guoyuan Chen, Yidong Shen, Haibing Zhang, Mei Tian, Zhuohua Zhang, Jixi Li
Parkinson's disease (PD), one of the most devastating neurodegenerative brain disorders, is characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. Currently, pharmacological interventions for PD remain inadequate. The cell necroptosis executor protein MLKL (Mixed-lineage kinase domain-like) is involved in various diseases, including inflammatory bowel disease and neurodegenerative diseases; however, its precise role in PD remains unclear...
December 1, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38041158/sleep-restoration-by-optogenetic-targeting-of-gabaergic-neurons-reprograms-microglia-and-ameliorates-pathological-phenotypes-in-an-alzheimer-s-disease-model
#36
JOURNAL ARTICLE
Qiuchen Zhao, Megi Maci, Morgan R Miller, Heng Zhou, Fang Zhang, Moustafa Algamal, Yee Fun Lee, Steven S Hou, Stephen J Perle, Hoang Le, Alyssa N Russ, Eng H Lo, Dmitry Gerashchenko, Stephen N Gomperts, Brian J Bacskai, Ksenia V Kastanenka
BACKGROUND: Alzheimer's disease (AD) patients exhibit memory disruptions and profound sleep disturbances, including disruption of deep non-rapid eye movement (NREM) sleep. Slow-wave activity (SWA) is a major restorative feature of NREM sleep and is important for memory consolidation. METHODS: We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre mice. An electroencephalography (EEG) / electromyography (EMG) telemetry system was used to monitor sleep disruptions in these animals...
December 1, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38017562/microglial-function-inpp5d-ship1-signaling-and-nlrp3-inflammasome-activation-implications-for-alzheimer-s-disease
#37
REVIEW
Gizem Terzioglu, Tracy L Young-Pearse
Recent genetic studies on Alzheimer's disease (AD) have brought microglia under the spotlight, as loci associated with AD risk are enriched in genes expressed in microglia. Several of these genes have been recognized for their central roles in microglial functions. Increasing evidence suggests that SHIP1, the protein encoded by the AD-associated gene INPP5D, is an important regulator of microglial phagocytosis and immune response. A recent study from our group identified SHIP1 as a negative regulator of the NLRP3 inflammasome in human iPSC-derived microglial cells (iMGs)...
November 29, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38017580/characterization-of-apoe-christchurch-carriers-in-455-306-uk-biobank-participants
#38
LETTER
Karen Y He, Ekaterina A Khramtsova, Alfredo Cabrera-Socorro, Yanfei Zhang, Shuwei Li, Brice A J Sarver, Bart Smets, Qingqin S Li, Louis De Muynck, Antonio R Parrado, Simon Lovestone, Mary Helen Black
No abstract text is available yet for this article.
November 28, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/38012703/non-invasive-systemic-viral-delivery-of-human-alpha-synuclein-mimics-selective-and-progressive-neuropathology-of-parkinson-s-disease-in-rodent-brains
#39
JOURNAL ARTICLE
Morgan Bérard, Laura Martínez-Drudis, Razan Sheta, Omar M A El-Agnaf, Abid Oueslati
BACKGROUND: Alpha-synuclein (α-syn) aggregation into proteinaceous intraneuronal inclusions, called Lewy bodies (LBs), is the neuropathological hallmark of Parkinson's disease (PD) and related synucleinopathies. However, the exact role of α-syn inclusions in PD pathogenesis remains elusive. This lack of knowledge is mainly due to the absence of optimal α-syn-based animal models that recapitulate the different stages of neurodegeneration. METHODS: Here we describe a novel approach for a systemic delivery of viral particles carrying human α-syn allowing for a large-scale overexpression of this protein in the mouse brain...
November 27, 2023: Molecular Neurodegeneration
https://read.qxmd.com/read/37986179/alzheimer-s-genes-in-microglia-a-risk-worth-investigating
#40
REVIEW
Ari Sudwarts, Gopal Thinakaran
Despite expressing many key risk genes, the role of microglia in late-onset Alzheimer's disease pathophysiology is somewhat ambiguous, with various phenotypes reported to be either harmful or protective. Herein, we review some key findings from clinical and animal model investigations, discussing the role of microglial genetics in mediating perturbations from homeostasis. We note that impairment to protective phenotypes may include prolonged or insufficient microglial activation, resulting in dysregulated metabolomic (notably lipid-related) processes, compounded by age-related inflexibility in dynamic responses...
November 20, 2023: Molecular Neurodegeneration
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