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Restoring myocardial infarction-induced long-term memory impairment by targeting the cystic fibrosis transmembrane
Lotte Vanherle1, Darcy Lidington2, Franziska E Uhl1
1Department of Experimental Medical Science, Lund University, Lund, Sweden; Wallenberg Centre for Molecular Medicine, Lund University, Lund, Sweden.
Insights
Myocardial infarction (MI) impairs memory by reducing hippocampal neuron health and cystic fibrosis transmembrane regulator (CFTR) expression. CFTR therapeutics can restore neuronal structure and improve memory after MI.
Area of Science:
- Neuroscience
- Cardiology
- Cell Biology
Background:
- Cognitive impairment is a significant issue in heart failure patients, lacking effective treatments.
- Myocardial infarction (MI) negatively impacts hippocampal neurons, the brain region critical for memory.
Purpose of the Study:
- To investigate the mechanisms by which MI alters hippocampal neurons.
- To assess the therapeutic potential of correcting cystic fibrosis transmembrane regulator (CFTR) expression in MI-induced cognitive dysfunction.
Main Methods:
- Myocardial infarction (MI) was induced in mice.
- Measurements included CFTR protein levels, neuroinflammation markers, neuronal structure, and memory function.
- In vitro and in vivo models were used to evaluate neuroinflammation's role and CFTR-based interventions.
Main Results:
- MI reduced hippocampal dendrite length and spine density, correlating with decreased CFTR expression and increased neuroinflammation.
- Microglia-conditioned medium reduced neuronal CFTR and synaptic protein PSD-95 expression.
- Pharmacological correction of CFTR in vitro and in vivo improved neuronal structure and memory function in MI models.
Conclusions:
- Decreased CFTR expression and neuroinflammation contribute to MI-induced cognitive deficits.
- CFTR therapeutics show promise for treating inflammation-related neuronal and memory dysfunction after MI.
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.
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