Using synaptosomes purified from the brains of two transgenic mouse models overexpressing mutated human tau (TgP301S and Tg4510) and brains of patients with sporadic Alzheimer's disease, we showed that aggregated and hyperphosphorylated tau was both present in purified synaptosomes and released in a calcium- and synaptosome-associated protein of 25 kDa (SNAP25)-dependent manner. In all mouse and human synaptosomal preparations, tau release was inhibited by the selective metabotropic glutamate receptor 2/3 (mGluR2/3) agonist LY379268, an effect prevented by the selective mGlu2/3 antagonist LY341495. LY379268 was also able to block pathologic tau propagation between primary neurons in an in vitro microfluidic cellular model. These novel results are transformational for our understanding of the molecular mechanisms mediating tau release and propagation at synaptic terminals in Alzheimer's disease and suggest that these processes could be inhibited therapeutically by the selective activation of presynaptic G protein-coupled receptors. SIGNIFICANCE STATEMENT: Pathological tau release and propagation are key neuropathological events underlying cognitive decline in Alzheimer's disease patients. This paper describes the role of regulated exocytosis, and the soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) protein SNAP25, in mediating tau release from rodent and human synaptosomes. This paper also shows that a selective mGluR2/3 agonist is highly effective in blocking tau release from synaptosomes and tau propagation between neurons, opening the way to the discovery of novel therapeutic approaches to this devastating disease.
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http://dx.doi.org/10.1124/jpet.122.001307 | DOI Listing |
Alzheimers Dement
December 2024
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.
Introduction: Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.
Methods: We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).
Psychiatry Res
December 2024
Department of Clinical Psychology and Psychotherapy, University of Bern, Bern, Switzerland.
The feasibility and the preliminary effectiveness of an internet-based emotion regulation intervention added to acute psychiatric inpatient care were assessed with a randomized controlled pilot trial. Sixty patients were allocated in a 1:1 ratio to the intervention group or treatment as usual (TAU). Feasibility was evaluated via patient satisfaction, system usability, and program usage.
View Article and Find Full Text PDFActa Biomater
December 2024
Department of Sport and Motion Science, University of Stuttgart, Stuttgart, Germany; Stuttgart Center for Simulation Science, University of Stuttgart, Stuttgart, Germany.
The urinary bladder is a hollow organ that undergoes significant deformation as it receives, stores, and releases urine. To understand the organ mechanics, it is necessary to obtain information about the material properties of the tissues involved. In displacement-controlled tensile tests, tissue samples are mounted on a device that applies stretches to the tissue in one or more directions, resulting in a specific stress response.
View Article and Find Full Text PDFMedicine (Baltimore)
December 2024
Department of Neurology, Hebei General Hospital, Shijiazhuang, China.
Rationale: Cerebral amyloid angiopathy-related inflammation (CAA-ri) is a treatable condition characterized by an acute or subacute onset, with its primary pathological hallmark being the deposition of amyloid, predominantly β-amyloid (Aβ), within intracranial microvessels. Despite its potential for treatment, CAA-ri is a rare disorder that is frequently underrecognized by clinicians in practice. This article provides a comprehensive overview of the clinical manifestations and therapeutic approaches associated with CAA-ri, aiming to enhance awareness among healthcare professionals.
View Article and Find Full Text PDFTrials
December 2024
Osakidetza Basque Health Service, Araba Mental Health Network, Psychiatric Hospital of Alava, Vitoria-Gasteiz, Spain.
Background: Around 40% of people with major depressive disorder (MDD) experience moderate remission, with the remainder meeting the criteria for resistant major depression (RMD). It has been shown that exercise has a low-to-moderate effect on MDD, but there is a lack of evidence on exercise interventions in RMD patients. The primary purpose of the proposed study will be to investigate the effect of a 12-week supervised combined exercise program on depressive symptoms in people with RMD compared to a treatment-as-usual (TAU) group.
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