Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator.

Autor:	Vanherle L; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Lidington D; Department of Physiology, University of Toronto, Toronto, Canada., Uhl FE; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Steiner S; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Vassallo S; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Skoug C; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Duarte JMN; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden., Ramu S; Department of Experimental Medical Science, Lund University, Lund, Sweden., Uller L; Department of Experimental Medical Science, Lund University, Lund, Sweden., Desjardins JF; Keenan Research Centre for Biomedical Science, St. Michael's Hospital; Toronto, Ontario, Canada., Connelly KA; Keenan Research Centre for Biomedical Science, St. Michael's Hospital; Toronto, Ontario, Canada., Bolz SS; Department of Physiology, University of Toronto, Toronto, Canada., Meissner A; Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden; Department of Physiology, Institute of Theoretical Medicine, Medical Faculty, University of Augsburg, Augsburg, Germany; German Centre for Neurodegenerative Diseases, Bonn, Germany. Electronic address: anja.meissner@med.lu.se.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2022 Dec; Vol. 86, pp. 104384. Date of Electronic Publication: 2022 Nov 30.
DOI:	10.1016/j.ebiom.2022.104384
Abstrakt:	Background: Cognitive impairment is a serious comorbidity in heart failure patients, but effective therapies are lacking. We investigated the mechanisms that alter hippocampal neurons following myocardial infarction (MI). Methods: MI was induced in male C57Bl/6 mice by left anterior descending coronary artery ligation. We utilised standard procedures to measure cystic fibrosis transmembrane regulator (CFTR) protein levels, inflammatory mediator expression, neuronal structure, and hippocampal memory. Using in vitro and in vivo approaches, we assessed the role of neuroinflammation in hippocampal neuron degradation and the therapeutic potential of CFTR correction as an intervention. Findings: Hippocampal dendrite length and spine density are reduced after MI, effects that associate with decreased neuronal CFTR expression and concomitant microglia activation and inflammatory cytokine expression. Conditioned medium from lipopolysaccharide-stimulated microglia (LCM) reduces neuronal cell CFTR protein expression and the mRNA expression of the synaptic regulator post-synaptic density protein 95 (PSD-95) in vitro. Blocking CFTR activity also down-regulates PSD-95 in neurons, indicating a relationship between CFTR expression and neuronal health. Pharmacologically correcting CFTR expression in vitro rescues the LCM-mediated down-regulation of PSD-95. In vivo, pharmacologically increasing hippocampal neuron CFTR expression improves MI-associated alterations in neuronal arborisation, spine density, and memory function, with a wide therapeutic time window. Interpretation: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI. Funding: Knut and Alice Wallenberg Foundation [F 2015/2112]; Swedish Research Council [VR; 2017-01243]; the German Research Foundation [DFG; ME 4667/2-1]; Hjärnfonden [FO2021-0112]; The Crafoord Foundation; Åke Wibergs Stiftelse [M19-0380], NMMP 2021 [V2021-2102]; the Albert Påhlsson Research Foundation; STINT [MG19-8469], Lund University; Canadian Institutes of Health Research [PJT-153269] and a Heart and Stroke Foundation of Ontario Mid-Career Investigator Award. Competing Interests: Declaration of interests D.L. is a consultant for Qanatpharma AG and Aphaia Pharma AG. S.-S.B. is an executive board member of Qanatpharma and Aphaia Pharma. Neither Qanatpharma nor Aphaia Pharma had any financial or intellectual involvement in this article. All other authors declare no competing interests. (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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