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Microglia are the tissue resident macrophages of the brain and their contribution to tau pathology progression remains to be fully understood. In this study, we developed a quantitative platform to elucidate the processing of extracellular tau within human induced pluripotent stem cell (iPSC)-derived microglia. We show that iPSC-derived microglia internalize monomeric and fibrillar tau through different cellular mechanisms and with different clearance kinetics. Acute inflammatory activation of microglia alters tau endocytosis, but surprisingly does not impact tau clearance. These results highlight the importance of the microglial endo-lysosome system as a regulator of tau pathology that is decoupled from acute microglial activation.
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http://dx.doi.org/10.1016/j.nbd.2025.107058 | DOI Listing |
Curr Alzheimer Res
September 2025
Department of Biochemistry, General Medicine Practice Program, Batterjee Medical College, Jeddah, Saudi Arabia.
A serine/threonine kinase with a wide variety of substrates, Glycogen Synthase Kinase-3 (GSK-3) is widely expressed. GSK-3 is a key player in cell metabolism and signaling, modulating numerous cellular functions and playing significant roles in both healthy and diseased states. The two histopathological features of Alzheimer's disease, the intracellular neurofibrillary tangles composed of hyperphosphorylated tau, and the extracellular senile plaques composed of beta-amyloid, have been linked to GSK-3.
View Article and Find Full Text PDFActa Neuropathol Commun
September 2025
Ann Romney Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, 60 Fenwood Rd, Boston, MA, 02115, USA.
Optineurin (OPTN) is an autophagy adaptor protein involved in selective autophagy, including aggrephagy and mitophagy. Pathogenic mutations in OPTN have also been linked to amyotrophic lateral sclerosis, frontotemporal dementia, and glaucoma, supporting its role in the etiology of neurodegenerative diseases. Despite its established biological roles, knowledge about its potential contribution to Alzheimer's disease (AD) pathology and neuronal functioning is lacking.
View Article and Find Full Text PDFFEBS J
September 2025
Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
TDP-linked proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD) and limbic-predominant age-related TDP-43 encephalopathy (LATE), are characterised by pathogenic deposits containing transactive response DNA-binding protein 43 (TDP-43) in the brain and spinal cord of patients. These hallmark pathological features are associated with widespread neuronal dysfunction and progressive neurodegeneration. TDP-43's role as an essential RNA/DNA-binding protein in RNA metabolism and gene expression regulation is clear, but deciphering the intricate pathophysiological mechanisms underpinning TDP-43-mediated neurodegeneration is paramount for developing effective therapies and novel diagnostic tools for early detection before frank neuronal loss occurs.
View Article and Find Full Text PDFSci Rep
September 2025
Paul Flechsig Institute - Centre of Neuropathology and Brain Research, Liebigstr. 19, 04103, Leipzig, Germany.
Perineuronal nets (PNNs) are a specialized form of neuronal extracellular matrix that often ensheath highly active cells, such as parvalbumin-positive (PV+) interneurons. Net-bearing neurons have been shown to be devoid of pathological aggregates of hyperphosphorylated tau protein (p-tau), suggesting they may serve neuroprotective functions. P-tau is a major hallmark of tauopathies like Alzheimer's disease (AD) but is also naturally present in the brains of hibernating mammals during the torpor phase.
View Article and Find Full Text PDFToxicology
August 2025
State Key Laboratory of Trauma and Chemical Poisoning, National Institute for Occupational Health and Poison Control, Chinese Center for Disease Control and Prevention, Beijing, China. Electronic address:
Acrylamide (ACR) is a pervasive environmental and workplace contaminant with established neurotoxic effects but unclear pathogenic mechanisms. In this study, we screened for potential ACR binding targets associated with neurotoxicity and identified the astrocytic glutamate transporter EAAT2. Molecular docking and dynamics simulations revealed that ACR interacts stably with the glutamate-binding pocket of EAAT2, potentially impairing transport function.
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