Senolytic therapy preserves blood-brain barrier integrity and promotes microglia homeostasis in a tauopathy model.

Autor: Yao M; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Wei Z; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Nielsen JS; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Ouyang Y; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Kakazu A; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Wang H; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Du L; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Li R; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA., Chu T; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Scafidi S; Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Lu H; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Aggarwal M; The Russell H. Morgan Department of Radiology and Radiological Science, Johns Hopkins University School of Medicine, Baltimore, MD, USA., Duan W; Division of Neurobiology, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of medicine, Baltimore, MD, USA; Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA. Electronic address: wduan2@jhmi.edu.
Jazyk: angličtina
Zdroj: Neurobiology of disease [Neurobiol Dis] 2024 Nov; Vol. 202, pp. 106711. Date of Electronic Publication: 2024 Oct 21.
DOI: 10.1016/j.nbd.2024.106711
Abstrakt: Cellular senescence, characterized by expressing the cell cycle inhibitory proteins, is evident in driving age-related diseases. Senescent cells play a crucial role in the initiation and progression of tau-mediated pathology, suggesting that targeting cell senescence offers a therapeutic potential for treating tauopathy associated diseases. This study focuses on identifying non-invasive biomarkers and validating their responses to a well-characterized senolytic therapy combining dasatinib and quercetin (D + Q), in a widely used tauopathy mouse model, PS19. We employed human-translatable MRI measures, including water extraction with phase-contrast arterial spin tagging (WEPCAST) MRI, T2 relaxation under spin tagging (TRUST), longitudinally assessed brain physiology and high-resolution structural MRI evaluated the brain regional volumes in PS19 mice. Our data reveal increased BBB permeability, decreased oxygen extraction fraction, and brain atrophy in 9-month-old PS19 mice compared to their littermate controls. (D + Q) treatment effectively preserves BBB integrity, rescues cerebral oxygen hypometabolism, attenuates brain atrophy, and alleviates tau hyperphosphorylation in PS19 mice. Mechanistically, D + Q treatment induces a shift of microglia from a disease-associated to a homeostatic state, reducing a senescence-like microglial phenotype marked by increased p16/Ink4a. D + Q-treated PS19 mice exhibit enhanced cue-associated cognitive performance in the tracing fear conditioning test compared to the vehicle-treated littermates, implying improved cognitive function by D + Q treatment. Our results pave the way for application of senolytic treatment as well as these noninvasive MRI biomarkers in clinical trials in tauopathy associated neurological disorders.
Competing Interests: Declaration of competing interest The authors declare no other competing financial interests.
(Copyright © 2024. Published by Elsevier Inc.)
Databáze: MEDLINE
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