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

Vanherle, Lotte LU ; Lidington, Darcy ; Uhl, Franziska E LU ; Steiner, Saskia LU ; Vassallo, Stefania LU ; Skoug, Cecilia LU ; Duarte, Joao M N LU orcid ; Ramu, Sangeetha LU ; Uller, Lena LU and Desjardins, Jean-François , et al. (2022) In EBioMedicine 86.
Abstract

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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Mice, Animals, Male, Cystic Fibrosis, Cystic Fibrosis Transmembrane Conductance Regulator/genetics, Myocardial Infarction/complications, Mice, Inbred C57BL, Lipopolysaccharides, Memory, Long-Term, Ontario
in
EBioMedicine
volume
86
article number
104384
publisher
Elsevier
external identifiers
  • scopus:85144588894
  • pmid:36462404
ISSN
2352-3964
DOI
10.1016/j.ebiom.2022.104384
language
English
LU publication?
yes
id
0d825b4a-16f3-4759-9414-e86bbabfcd71
date added to LUP
2022-12-30 14:12:05
date last changed
2024-09-05 22:26:20
@article{0d825b4a-16f3-4759-9414-e86bbabfcd71,
  abstract     = {{<p>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).</p><p>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.</p><p>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.</p><p>INTERPRETATION: Our results indicate that CFTR therapeutics improve inflammation-induced alterations in hippocampal neuronal structure and attenuate memory dysfunction following MI.</p>}},
  author       = {{Vanherle, Lotte and Lidington, Darcy and Uhl, Franziska E and Steiner, Saskia and Vassallo, Stefania and Skoug, Cecilia and Duarte, Joao M N and Ramu, Sangeetha and Uller, Lena and Desjardins, Jean-François and Connelly, Kim A and Bolz, Steffen-Sebastian and Meissner, Anja}},
  issn         = {{2352-3964}},
  keywords     = {{Mice; Animals; Male; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator/genetics; Myocardial Infarction/complications; Mice, Inbred C57BL; Lipopolysaccharides; Memory, Long-Term; Ontario}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{EBioMedicine}},
  title        = {{Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane regulator}},
  url          = {{http://dx.doi.org/10.1016/j.ebiom.2022.104384}},
  doi          = {{10.1016/j.ebiom.2022.104384}},
  volume       = {{86}},
  year         = {{2022}},
}