Modulation of mitochondrial functions contributes to the protection of lamotrigine against Alzheimer's disease

Abstract

Background

Our previous studies have established that the broad-spectrum anti-epileptic drug lamotrigine (LTG) confers protection against cognitive impairments, synapse and nerve cell damage, as well as characteristic neuropathologies in APP/PS1 mice, a mouse model of Alzheimer's disease (AD). However, the precise molecular mechanisms responsible for this protective effect induced by LTG remain largely elusive.

Objective

In this study, we aimed to investigate the mechanisms underlying the beneficial effects of LTG against AD.

Methods

Five-month-old APP/PS1 mice were treated with 30 mg/kg of LTG daily for three consecutive months. Subsequently, high-throughput ribosome profiling sequencing was conducted to identify differentially translated genes (DTGs) rescued by LTG in the brains of these mice. To gain further insights into the potential functions and pathways of these LTG-rescued DTGs, gene ontology enrichment analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis were performed. RNA expression, protein levels, and translational efficiency were assessed to explore how LTG regulated gene expression processes in AD-related DTGs. Additionally, Aβ₄₂ peptide-stimulated primary neurons were used to uncover the potential mechanisms and signaling pathway by which LTG mitigated oxidative stress under AD context.

Results

For the first time, we reveal that LTG inactivates mitochondrial complexes in the brains of APP/PS1 mice by suppressing the translational efficiency of mitochondrial complexes-related genes. More importantly, we demonstrate that LTG mitigates mitochondrial-mediated oxidative stress in neurons within the context of AD by activation of SIRT6/PGC-1α pathway.

Conclusions

These findings provide further insights into the mechanisms underlying the protective effects of LTG against AD.