Journal Article

DZNE-2025-00752

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Role of Compensatory miRNA Networks in Cognitive Recovery from Heart Failure.

Gisa, V. (First author)DZNE* ; Islam, M. R.DZNE* ; Lbik, D. ; Hofmann, R. M. ; Pena, T.DZNE* ; Krüger, D. M.DZNE* ; Burkhardt, S.DZNE* ; Schütz, A.-L.DZNE* ; Sananbenesi, F.DZNE* ; Toischer, K. ; Fischer, A. (Last author)DZNE*

2025
MDPI Basel

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Please use a persistent id in citations: doi:10.3390/ncrna11030045

Abstract: Background: Heart failure (HF) is associated with an increased risk of cognitive impairment and hippocampal dysfunction, yet the underlying molecular mechanisms remain poorly understood. This study aims to investigate the role of microRNA (miRNA) networks in hippocampus-dependent memory recovery in a mouse model of HF. Methods: CaMKIIδC transgenic (TG) mice, a model for HF, were used to assess hippocampal function at 3 and 6 months of age. Memory performance was evaluated using hippocampus-dependent behavioral tasks. Small RNA sequencing was performed to analyze hippocampal miRNA expression profiles across both time points. Bioinformatic analyses identified miRNAs that potentially regulate genes previously implicated in HF-induced cognitive impairment. Results: We have previously shown that at 3 months of age, CaMKIIδC TG mice exhibited significant memory deficits associated with dysregulated hippocampal gene expression. In this study, we showed that these impairments, memory impairment and hippocampal gene expression, were no longer detectable at 6 months, despite persistent cardiac dysfunction. However, small RNA sequencing revealed a dynamic shift in hippocampal miRNA expression, identifying 27 miRNAs as 'compensatory miRs' that targeted 73% of the transcripts dysregulated at 3 months but reinstated by 6 months. Notably, miR-181a-5p emerged as a central regulatory hub, with its downregulation coinciding with restored memory function. Conclusions: These findings suggest that miRNA networks contribute to the restoration of hippocampal function in HF despite continued cardiac pathology and provide an important compensatory mechanism towards memory impairment. A better understanding of these compensatory miRNA mechanisms may provide novel therapeutic targets for managing HF-related cognitive dysfunction.

Keyword(s): Alzheimer ; MicroRNA ; cognitive impairment ; heart failure ; hippocampal function ; memory recovery ; transcriptional homeostasis

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Contributing Institute(s):

1. Epigenetics and Systems Medicine in Neurodegenerative Diseases (AG Fischer)
2. Bioinformatics and Genome Dynamics Core (Göttingen) (Bioinformatics Unit (Göttingen))
3. Genome Dynamics in Neurodegenerative Diseases (AG Sananbenesi)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)
2. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2025

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