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Rejuvenating aged microglia by p16ink4a-siRNA-loaded nanoparticles increases amyloid-β clearance in animal models of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-03-16 Hyo Jung Shin, In Soo Kim, Seung Gyu Choi, Kayoung Lee, Hyewon Park, Juhee Shin, Dayoung Kim, Jaewon Beom, Yoon Young Yi, Deepak Prasad Gupta, Gyun Jee Song, Won-Suk Chung, C. Justin Lee, Dong Woon Kim
Age-dependent accumulation of amyloid plaques in patients with sporadic Alzheimer’s disease (AD) is associated with reduced amyloid clearance. Older microglia have a reduced ability to phagocytose amyloid, so phagocytosis of amyloid plaques by microglia could be regulated to prevent amyloid accumulation. Furthermore, considering the aging-related disruption of cell cycle machinery in old microglia
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APOE4 genotype and aging impair injury-induced microglial behavior in brain slices, including toward Aβ, through P2RY12 Mol. Neurodegener. (IF 15.1) Pub Date : 2024-03-11 Jordy Sepulveda, Jennifer Yejean Kim, Joseph Binder, Stefano Vicini, G. William Rebeck
Microglia are highly dynamic cells that play a critical role in tissue homeostasis through the surveillance of brain parenchyma and response to cues associated with damage. Aging and APOE4 genotype are the strongest risk factors for Alzheimer’s disease (AD), but how they affect microglial dynamics remains unclear. Using ex vivo confocal microscopy, we analyzed microglial dynamic behaviors in the entorhinal
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Updates on mouse models of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-03-11 Michael Z. Zhong, Thomas Peng, Mariana Lemos Duarte, Minghui Wang, Dongming Cai
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the United States (US). Animal models, specifically mouse models have been developed to better elucidate disease mechanisms and test therapeutic strategies for AD. A large portion of effort in the field was focused on developing transgenic (Tg) mouse models through over-expression of genetic mutations associated with familial
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GBA1 inactivation in oligodendrocytes affects myelination and induces neurodegenerative hallmarks and lipid dyshomeostasis in mice Mol. Neurodegener. (IF 15.1) Pub Date : 2024-03-07 Ilaria Gregorio, Loris Russo, Enrica Torretta, Pietro Barbacini, Gabriella Contarini, Giada Pacinelli, Dario Bizzotto, Manuela Moriggi, Paola Braghetta, Francesco Papaleo, Cecilia Gelfi, Enrico Moro, Matilde Cescon
Mutations in the β-glucocerebrosidase (GBA1) gene do cause the lysosomal storage Gaucher disease (GD) and are among the most frequent genetic risk factors for Parkinson’s disease (PD). So far, studies on both neuronopathic GD and PD primarily focused on neuronal manifestations, besides the evaluation of microglial and astrocyte implication. White matter alterations were described in the central nervous
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Correction: The major TMEM106B dementia risk allele affects TMEM106B protein levels, fibril formation, and myelin lipid homeostasis in the ageing human hippocampus Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-27 Jun Yup Lee, Dylan J. Harney, Jonathan D. Teo, John B. Kwok, Greg T. Sutherland, Mark Larance, Anthony S. Don
Molecular Neurodegeneration (2023) 18:63 https://doi.org/10.1186/s13024-023-00650-3 The original article contains an error in Fig. 1C– the red label should instead indicate “Increased protein sets with ageing” and blue should instead indicate "Decreased protein sets with ageing". Authors and Affiliations Charles Perkins Centre, 2006, Camperdown, NSW, Australia Jun Yup Lee, Dylan J. Harney, Jonathan
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Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-20 Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo, Ryan Limbocker
The conversion of native peptides and proteins into amyloid aggregates is a hallmark of over 50 human disorders, including Alzheimer’s and Parkinson’s diseases. Increasing evidence implicates misfolded protein oligomers produced during the amyloid formation process as the primary cytotoxic agents in many of these devastating conditions. In this review, we analyze the processes by which oligomers are
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Plasma N-terminal containing tau fragments (NTA-tau): a biomarker of tau deposition in Alzheimer’s Disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-17 Juan Lantero-Rodriguez, Gemma Salvadó, Anniina Snellman, Laia Montoliu-Gaya, Wagner S. Brum, Andrea L. Benedet, Niklas Mattsson-Carlgren, Pontus Tideman, Shorena Janelidze, Sebastian Palmqvist, Erik Stomrud, Nicholas J. Ashton, Henrik Zetterberg, Kaj Blennow, Oskar Hansson
Novel phosphorylated-tau (p-tau) blood biomarkers (e.g., p-tau181, p-tau217 or p-tau231), are highly specific for Alzheimer’s disease (AD), and can track amyloid-β (Aβ) and tau pathology. However, because these biomarkers are strongly associated with the emergence of Aβ pathology, it is difficult to determine the contribution of insoluble tau aggregates to the plasma p-tau signal in blood. Therefore
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Sodium oligomannate alters gut microbiota, reduces cerebral amyloidosis and reactive microglia in a sex-specific manner Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-17 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
It has recently become well-established that there is a connection between Alzheimer’s disease pathology and gut microbiome dysbiosis. We have previously demonstrated that antibiotic-mediated gut microbiota perturbations lead to attenuation of Aβ deposition, phosphorylated tau accumulation, and disease-associated glial cell phenotypes in a sex-dependent manner. In this regard, we were intrigued by
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Correction: Collusion of α-Synuclein and Aβ aggravating co-morbidities in a novel prion-type mouse model Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-16 Grace M. Lloyd, Jess-Karan S. Dhillon, Kimberly-Marie M. Gorion, Cara Riffe, Susan E. Fromholt, Yuxing Xia, Benoit I. Giasson, David R. Borchelt
Correction: Molecular Neurodegeneration 16, 63 (2021) https://doi.org/10.1186/s13024-021-00486-9 The authors wish to correct an error in Fig. 7A of the original article [1]. We have determined that the representative image of a hemibrain shown for 10 month-old, PBS-injected, nontransgenic (nTg) mice in panel A is incorrect. Due to a labeling error of the digital file name, the brain image shown was
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Unraveling the dual nature of brain CD8+ T cells in Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-14 Dan Hu, Howard L. Weiner
CD8+ T cells are essential components of adaptive immunity, and primarily function as cytotoxic T lymphocytes (CTLs) that recognize and eliminate infected or abnormal cells in the body. However, a small subpopulation of CD8+ T cells act as regulatory T cells (CD8+ Tregs) that suppress immune responses [1]. For a considerable period, it was widely held that the central nervous system (CNS) was immune
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CSF protein ratios with enhanced potential to reflect Alzheimer’s disease pathology and neurodegeneration Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-13 Sára Mravinacová, Vilma Alanko, Sofia Bergström, Claire Bridel, Yolande Pijnenburg, Göran Hagman, Miia Kivipelto, Charlotte Teunissen, Peter Nilsson, Anna Matton, Anna Månberg
Amyloid and tau aggregates are considered to cause neurodegeneration and consequently cognitive decline in individuals with Alzheimer’s disease (AD). Here, we explore the potential of cerebrospinal fluid (CSF) proteins to reflect AD pathology and cognitive decline, aiming to identify potential biomarkers for monitoring outcomes of disease-modifying therapies targeting these aggregates. We used a multiplex
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Cognitive, functional, and neuropsychiatric correlates of regional tau pathology in autopsy-confirmed chronic traumatic encephalopathy Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-06 Michael L. Alosco, Micaela White, Carter Bell, Farwa Faheem, Yorghos Tripodis, Eukyung Yhang, Zachary Baucom, Brett Martin, Joseph Palmisano, Kristen Dams-O’Connor, John F. Crary, Lee E. Goldstein, Douglas I. Katz, Brigid Dwyer, Daniel H. Daneshvar, Christopher Nowinski, Robert C. Cantu, Neil W. Kowall, Robert A. Stern, Victor E. Alvarez, Bertrand Russell Huber, Thor D. Stein, Ann C. McKee, Jesse Mez
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease characterized by hyperphosphorylated tau (p-tau) accumulation. The clinical features associated with CTE pathology are unclear. In brain donors with autopsy-confirmed CTE, we investigated the association of CTE p-tau pathology density and location with cognitive, functional, and neuropsychiatric symptoms. In 364 brain donors with
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Microglial ferroptotic stress causes non-cell autonomous neuronal death Mol. Neurodegener. (IF 15.1) Pub Date : 2024-02-05 Jeffrey R. Liddell, James B. W. Hilton, Kai Kysenius, Jessica L. Billings, Sara Nikseresht, Lachlan E. McInnes, Dominic J. Hare, Bence Paul, Stephen W. Mercer, Abdel A. Belaidi, Scott Ayton, Blaine R. Roberts, Joseph S. Beckman, Catriona A. McLean, Anthony R. White, Paul S. Donnelly, Ashley I. Bush, Peter J. Crouch
Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. To elucidate
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NMNAT2 supports vesicular glycolysis via NAD homeostasis to fuel fast axonal transport Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-29 Sen Yang, Zhen-Xian Niou, Andrea Enriquez, Jacob LaMar, Jui-Yen Huang, Karen Ling, Paymaan Jafar-Nejad, Jonathan Gilley, Michael P. Coleman, Jason M. Tennessen, Vidhya Rangaraju, Hui-Chen Lu
Bioenergetic maladaptations and axonopathy are often found in the early stages of neurodegeneration. Nicotinamide adenine dinucleotide (NAD), an essential cofactor for energy metabolism, is mainly synthesized by Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) in CNS neurons. NMNAT2 mRNA levels are reduced in the brains of Alzheimer’s, Parkinson’s, and Huntington’s disease. Here we addressed
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Mitochondrial CISD1/Cisd accumulation blocks mitophagy and genetic or pharmacological inhibition rescues neurodegenerative phenotypes in Pink1/parkin models Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-25 Aitor Martinez, Alvaro Sanchez-Martinez, Jake T. Pickering, Madeleine J. Twyning, Ana Terriente-Felix, Po-Lin Chen, Chun-Hong Chen, Alexander J. Whitworth
Mitochondrial dysfunction and toxic protein aggregates have been shown to be key features in the pathogenesis of neurodegenerative diseases, such as Parkinson’s disease (PD). Functional analysis of genes linked to PD have revealed that the E3 ligase Parkin and the mitochondrial kinase PINK1 are important factors for mitochondrial quality control. PINK1 phosphorylates and activates Parkin, which in
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Collagen in the central nervous system: contributions to neurodegeneration and promise as a therapeutic target Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-25 Lauren K. Wareham, Robert O. Baratta, Brian J. Del Buono, Eric Schlumpf, David J. Calkins
The extracellular matrix is a richly bioactive composition of substrates that provides biophysical stability, facilitates intercellular signaling, and both reflects and governs the physiological status of the local microenvironment. The matrix in the central nervous system (CNS) is far from simply an inert scaffold for mechanical support, instead conducting an active role in homeostasis and providing
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Fluid biomarkers for amyotrophic lateral sclerosis: a review Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-24 Katherine E. Irwin, Udit Sheth, Philip C. Wong, Tania F. Gendron
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of upper and lower motor neurons. Presently, three FDA-approved drugs are available to help slow functional decline for patients with ALS, but no cure yet exists. With an average life expectancy of only two to five years after diagnosis, there is a clear need for biomarkers to improve the care of patients
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Nuclear-import receptors as gatekeepers of pathological phase transitions in ALS/FTD Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-22 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
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Unravelling cell type-specific responses to Parkinson’s Disease at single cell resolution Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-20 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
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Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-18 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
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
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Brain clearance of protein aggregates: a close-up on astrocytes Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-16 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
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Neuronal and glial vulnerability of the suprachiasmatic nucleus in tauopathies: evidence from human studies and animal models Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-10 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
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Blood platelet factor 4: the elixir of brain rejuvenation Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-07 José M. Izquierdo
Aging is invariably associated with some form of cognitive impairment. Three recently published articles in Nature family journals from independent groups reported that the plasma levels of platelet factor four (PF4) are negatively associated with brain aging and neurodegeneration phenotypes and positively associated with cognitive performance, brain rejuvenation and health. These studies identify
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Comparison of immunoassay- with mass spectrometry-derived p-tau quantification for the detection of Alzheimer’s disease pathology Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-07 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
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
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Proteo-genomics of soluble TREM2 in cerebrospinal fluid provides novel insights and identifies novel modulators for Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2024-01-03 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
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
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Untargeted serum metabolomics reveals novel metabolite associations and disruptions in amino acid and lipid metabolism in Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-19 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
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. Identify metabolic disturbances associated with Parkinson’s disease (PD) in two population-based studies using untargeted metabolomics. We performed a metabolome-wide association
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Microglial APOE4: more is less and less is more Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-19 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
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Advanced structural brain aging in preclinical autosomal dominant Alzheimer disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-19 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
“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. We modeled BAG in 257 deeply-phenotyped
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Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-18 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
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
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Correction: Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-18 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
Molecular Neurodegeneration (2023) 18:87 https://doi.org/10.1186/s13024-023-00673-w The original article [1] contained an erroneous duplication of Fig. 1 over Fig. 3 during proofing. The corrected Fig. 3 has since been restored in the original article. Hasan S, Fernandopulle MS, Humble SW, et al. Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient
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Translational profiling identifies sex-specific metabolic and epigenetic reprogramming of cortical microglia/macrophages in APPPS1-21 mice with an antibiotic-perturbed-microbiome Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-16 Shabana M. Shaik, Yajun Cao, Joseph V. Gogola, Hemraj B. Dodiya, Xulun Zhang, Hejer Boutej, Weinong Han, Jasna Kriz, Sangram S. Sisodia
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
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MLKL deficiency alleviates neuroinflammation and motor deficits in the α-synuclein transgenic mouse model of Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-01 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,
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Sleep restoration by optogenetic targeting of GABAergic neurons reprograms microglia and ameliorates pathological phenotypes in an Alzheimer’s disease model Mol. Neurodegener. (IF 15.1) Pub Date : 2023-12-01 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
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. We generated a mouse model where GABAergic interneurons could be targeted in the presence of APPswe/PS1dE9 (APP) amyloidosis, APP-GAD-Cre
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Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-29 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
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Characterization of APOE Christchurch carriers in 455,306 UK Biobank participants Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-28 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
To the editor The APOE gene is a known genetic risk factor for neurodegeneration and cardiovascular disease (CVD) [1, 2]. Beyond the known effects of APOE ε2 and APOE ε4, several rare and protective APOE variants (R154S Christchurch (APOECh), V236E Jacksonville, and R251G) have been identified recently [3, 4]. The ultra-rare APOECh mutation (NM_000041.4(APOE):c.460C > A (p.Arg154Ser)), also known as
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Non-invasive systemic viral delivery of human alpha-synuclein mimics selective and progressive neuropathology of Parkinson’s disease in rodent brains Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-27 Morgan Bérard, Laura Martínez-Drudis, Razan Sheta, Omar M. A. El-Agnaf, Abid Oueslati
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
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Alzheimer’s genes in microglia: a risk worth investigating Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-20 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
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Donald Lowell Price, M.D. In memoriam Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-20 Sangram Sisodia, Philip C. Wong
Dr. Donald L. Price, one of the most prolific and distinguished neuroscientists in the field of Alzheimer’s disease and neurodegeneration, has passed. Don was a pioneer in clinical and experimental neuropathology, a devoted husband, father and grandfather, and a mentor to a legion of scientists who followed him. Don was a quintessential renaissance man who read literature in college and thereafter
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Multi-modal proteomic characterization of lysosomal function and proteostasis in progranulin-deficient neurons Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-16 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
Progranulin (PGRN) is a lysosomal glycoprotein implicated in various neurodegenerative diseases, including frontotemporal dementia and neuronal ceroid lipofuscinosis. Over 70 mutations discovered in the GRN gene all result in reduced expression of the PGRN protein. Genetic and functional studies point toward a regulatory role for PGRN in lysosome functions. However, the detailed molecular function
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Roles of peripheral lipoproteins and cholesteryl ester transfer protein in the vascular contributions to cognitive impairment and dementia Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-16 Tetiana Poliakova, Cheryl L. Wellington
This narrative review focuses on the role of cholesteryl ester transfer protein (CETP) and peripheral lipoproteins in the vascular contributions to cognitive impairment and dementia (VCID). Humans have a peripheral lipoprotein profile where low-density lipoproteins (LDL) represent the dominant lipoprotein fraction and high-density lipoproteins (HDL) represent a minor lipoprotein fraction. Elevated
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Altered plasma protein profiles in genetic FTD – a GENFI study Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-15 Abbe Ullgren, Linn Öijerstedt, Jennie Olofsson, Sofia Bergström, Julia Remnestål, John C. van Swieten, Lize C. Jiskoot, Harro Seelaar, Barbara Borroni, Raquel Sanchez-Valle, Fermin Moreno, Robert Laforce, Matthis Synofzik, Daniela Galimberti, James B. Rowe, Mario Masellis, Maria Carmela Tartaglia, Elizabeth Finger, Rik Vandenberghe, Alexandre de Mendonça, Pietro Tirabosch, Isabel Santana, Simon Ducharme
Plasma biomarkers reflecting the pathology of frontotemporal dementia would add significant value to clinical practice, to the design and implementation of treatment trials as well as our understanding of disease mechanisms. The aim of this study was to explore the levels of multiple plasma proteins in individuals from families with genetic frontotemporal dementia. Blood samples from 693 participants
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α-Synuclein serine129 phosphorylation – the physiology of pathology Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-13 Nagendran Ramalingam, Ulf Dettmer
The study that found phospho-serine129 in the Parkinson’s-linked protein alpha-synuclein over two decades ago proposed a physiological role in regulating protein function, but this notion was neglected when alpha-synuclein serine129 phosphorylation was identified in Lewy bodies/neurites, the hallmark pathology of synucleinopathies. Recent work suggests that both are relevant: pathological phospho-serine129
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Mitochondrial dysfunction in Parkinson’s disease – a key disease hallmark with therapeutic potential Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-11 Martin T. Henrich, Wolfgang H. Oertel, D. James Surmeier, Fanni F. Geibl
Mitochondrial dysfunction is strongly implicated in the etiology of idiopathic and genetic Parkinson’s disease (PD). However, strategies aimed at ameliorating mitochondrial dysfunction, including antioxidants, antidiabetic drugs, and iron chelators, have failed in disease-modification clinical trials. In this review, we summarize the cellular determinants of mitochondrial dysfunction, including impairment
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Simple model systems reveal conserved mechanisms of Alzheimer’s disease and related tauopathies Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-10 Yuwei Jiang, Lesley T. MacNeil
The lack of effective therapies that slow the progression of Alzheimer’s disease (AD) and related tauopathies highlights the need for a more comprehensive understanding of the fundamental cellular mechanisms underlying these diseases. Model organisms, including yeast, worms, and flies, provide simple systems with which to investigate the mechanisms of disease. The evolutionary conservation of cellular
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Correction: Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-09 John J. Alam, Ralph A. Nixon
Molecular Neurodegeneration (2023) 18:74 https://doi.org/10.1186/s13024-023-00663-y In the original article [1] the following statement of funding acknowledgement was mistakenly omitted: “Preclinical studies have been supported by NIH grants P01AG017617 and R01AG062376 grants to RAN.” Authors and Affiliations CervoMed Inc, 20 Park Plaza, Suite 424, Boston, MA, 02116, USA John J. Alam Center for Dementia
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Peptide-based approaches to directly target alpha-synuclein in Parkinson’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-09 Scott G. Allen, Richard M. Meade, Lucy L. White Stenner, Jody M. Mason
Peptides and their mimetics are increasingly recognised as drug-like molecules, particularly for intracellular protein-protein interactions too large for inhibition by small molecules, and inaccessible to larger biologics. In the past two decades, evidence associating the misfolding and aggregation of alpha-synuclein strongly implicates this protein in disease onset and progression of Parkinson’s disease
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Mechanism and therapeutic potential of targeting cGAS-STING signaling in neurological disorders Mol. Neurodegener. (IF 15.1) Pub Date : 2023-11-08 Yige Huang, Bangyan Liu, Subhash C. Sinha, Sadaf Amin, Li Gan
DNA sensing is a pivotal component of the innate immune system that is responsible for detecting mislocalized DNA and triggering downstream inflammatory pathways. Among the DNA sensors, cyclic GMP-AMP synthase (cGAS) is a primary player in detecting cytosolic DNA, including foreign DNA from pathogens and self-DNA released during cellular damage, culminating in a type I interferon (IFN-I) response through
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cGAS-STING triggers inflammaging-associated neurodegeneration Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-23 José M. Izquierdo
In their recent article in Nature, Gulen et al. [1] established the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway as a regulatory driver of inflammaging-associated neurodegeneration in mice. Pharmacological blockade of this pathway in aged mice prevented inflammaging and improved cognitive and motor performance. In the same vein, chemical intervention attenuated a toxic
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Genome-wide analyses identify NEAT1 as genetic modifier of age at onset of amyotrophic lateral sclerosis Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-23 Chunyu Li, Qianqian Wei, Yanbing Hou, Junyu Lin, Ruwei Ou, Lingyu Zhang, Qirui Jiang, Yi Xiao, Kuncheng Liu, Xueping Chen, TianMi Yang, Wei Song, Bi Zhao, Ying Wu, Huifang Shang
Patients with amyotrophic lateral sclerosis (ALS) demonstrate great heterogeneity in the age at onset (AAO), which is closely related to the course of disease. However, most genetic studies focused on the risk of ALS, while the genetic background underlying AAO of ALS is still unknown. To identify genetic determinants influencing AAO of ALS, we performed genome-wide association analysis using a Cox
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Mechanisms of ARIA: is it time to focus on the unique immune environment of the neurovascular unit? Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-20 Kate E. Foley, Erica M. Weekman, Donna M. Wilcock
Microhemorrhages as a consequence of anti-Ab immunotherapy were first identified over 20 years ago in a single page report in Science by Pfeifer et al. [1]. Following on from that, both Wilcock and Racke reported microhemorrhages in 2004 and 2005 respectively, in different animal models and with different Ab antibodies [2, 3]. When vasogenic edema and microhemorrhages were identified in clinical trials
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Regulation of cortical hyperexcitability in amyotrophic lateral sclerosis: focusing on glial mechanisms Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-19 Manling Xie, Praveen N. Pallegar, Sebastian Parusel, Aivi T. Nguyen, Long-Jun Wu
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the loss of both upper and lower motor neurons, resulting in muscle weakness, atrophy, paralysis, and eventually death. Motor cortical hyperexcitability is a common phenomenon observed at the presymptomatic stage of ALS. Both cell-autonomous (the intrinsic properties of motor neurons) and non-cell-autonomous
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Drug development targeting degeneration of the basal forebrain cholinergic system: its time has come Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-04 John J. Alam, Ralph A. Nixon
Recent advances in understanding the pathogenic mechanisms underlying basal forebrain cholinergic (BFC) neuronal degeneration and MRI-based studies provide insight on the contribution of such degeneration at various stages of Alzheimer’s disease (AD) and related dementias and have renewed interest in disease-modifying approaches to treat BFC degeneration. Herein we comment on two recent related publications
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Border-associated macrophages promote cerebral amyloid angiopathy and cognitive impairment through vascular oxidative stress Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-03 Ken Uekawa, Yorito Hattori, Sung Ji Ahn, James Seo, Nicole Casey, Antoine Anfray, Ping Zhou, Wenjie Luo, Josef Anrather, Laibaik Park, Costantino Iadecola
Cerebral amyloid angiopathy (CAA) is a devastating condition common in patients with Alzheimer’s disease but also observed in the general population. Vascular oxidative stress and neurovascular dysfunction have been implicated in CAA but the cellular source of reactive oxygen species (ROS) and related signaling mechanisms remain unclear. We tested the hypothesis that brain border-associated macrophages
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Correction: Predominant expression of Alzheimer’s disease-associated BIN1 in mature oligodendrocytes and localization to white matter tracts Mol. Neurodegener. (IF 15.1) Pub Date : 2023-10-02 Pierre De Rossi, Virginie Buggia-Prévot, Benjamin L. L. Clayton, Jared B. Vasquez, Carson van Sanford, Robert J. Andrew, Ruben Lesnick, Alexandra Botté, Carole Deyts, Someya Salem, Eshaan Rao, Richard C. Rice, Angèle Parent, Satyabrata Kar, Brian Popko, Peter Pytel, Steven Estus, Gopal Thinakaran
Correction: Mol Neurodegeneration 11, 59 (2016) https://doi.org/10.1186/s13024-016-0124-1 Correction The original article [1] contains an error whereby, in the Methods section on page 3, the last sentence on the left column (continuing to the right column) reads: ‘D7-BIN1 reactions used the same exon 5 sense primer and a junctional antisense primer, 5’-GCTTTCTCAAGCAGCGAGAC-3’, corresponding to the
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TDP-43 pathology is associated with increased tau burdens and seeding Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-30 Sandra O. Tomé, Grigoria Tsaka, Alicja Ronisz, Simona Ospitalieri, Klara Gawor, Luis Aragão Gomes, Markus Otto, Christine A. F. von Arnim, Philip Van Damme, Ludo Van Den Bosch, Estifanos Ghebremedhin, Celeste Laureyssen, Kristel Sleegers, Rik Vandenberghe, Frederic Rousseau, Joost Schymkowitz, Dietmar Rudolf Thal
Most Alzheimer’s Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-β plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD
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A microglial activity state biomarker panel differentiates FTD-granulin and Alzheimer’s disease patients from controls Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-29 Ida Pesämaa, Stephan A. Müller, Sophie Robinson, Alana Darcher, Dominik Paquet, Henrik Zetterberg, Stefan F. Lichtenthaler, Christian Haass
With the emergence of microglia-modulating therapies there is an urgent need for reliable biomarkers to evaluate microglial activation states. Using mouse models and human induced pluripotent stem cell-derived microglia (hiMGL), genetically modified to yield the most opposite homeostatic (TREM2-knockout) and disease-associated (GRN-knockout) states, we identified microglia activity-dependent markers
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Correction: Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-29 Jihoon Lee, Ki Woon Sung, Eun-Jin Bae, Dabin Yoon, Dasarang Kim, Jin Saem Lee, Da-ha Park, Daniel Youngjae Park, Su Ran Mun, Soon Chul Kwon, Hye Yeon Kim, Joo-Ok Min, Seung-Jae Lee, Young Ho Suh, Yong Tae Kwon
Molecular Neurodegeneration (2023) 18:41 https://doi.org/10.1186/s13024-023-00630-7. The original article [1] contained errors in the Funding section. The correct Funding information can be viewed ahead: Funding This work was supported by the National Research Foundation of Korea (NRF) grants funded by the Ministry of Science, ICT and Future Planning (MSIP) (NRF-2020R1A5A1019023 to Y.T.K., NRF-2021R1A2B5B03002614
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The Q/R editing site of AMPA receptor GluA2 subunit acts as an epigenetic switch regulating dendritic spines, neurodegeneration and cognitive deficits in Alzheimer’s disease Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-28 Amanda L. Wright, Lyndsey M. Konen, Bruce G. Mockett, Gary P. Morris, Anurag Singh, Lisseth Estefania Burbano, Luke Milham, Monica Hoang, Raphael Zinn, Rose Chesworth, Richard P. Tan, Gordon A. Royle, Ian Clark, Steven Petrou, Wickliffe C. Abraham, Bryce Vissel
RNA editing at the Q/R site of GluA2 occurs with ~99% efficiency in the healthy brain, so that the majority of AMPARs contain GluA2(R) instead of the exonically encoded GluA2(Q). Reduced Q/R site editing infcreases AMPA receptor calcium permeability and leads to dendritic spine loss, neurodegeneration, seizures and learning impairments. Furthermore, GluA2 Q/R site editing is impaired in Alzheimer’s
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Astrocytes of the optic nerve exhibit a region-specific and temporally distinct response to elevated intraocular pressure Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-27 Arpan G. Mazumder, Amélie M. Julé, Daniel Sun
The optic nerve is an important tissue in glaucoma and the unmyelinated nerve head region remains an important site of many early neurodegenerative changes. In both humans and mice, astrocytes constitute the major glial cell type in the region, and in glaucoma they become reactive, influencing the optic nerve head (ONH) microenvironment and disease outcome. Despite recognizing their importance in the
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BAX activation in mouse retinal ganglion cells occurs in two temporally and mechanistically distinct steps Mol. Neurodegener. (IF 15.1) Pub Date : 2023-09-26 Margaret E. Maes, Ryan J. Donahue, Cassandra L. Schlamp, Olivia J. Marola, Richard T. Libby, Robert W. Nickells
Pro-apoptotic BAX is a central mediator of retinal ganglion cell (RGC) death after optic nerve damage. BAX activation occurs in two stages including translocation of latent BAX to the mitochondrial outer membrane (MOM) and then permeabilization of the MOM to facilitate the release of apoptotic signaling molecules. As a critical component of RGC death, BAX is an attractive target for neuroprotective