The hibernation-derived compound SUL-138 shifts the mitochondrial proteome towards fatty acid metabolism and prevents cognitive decline and amyloid plaque formation in an Alzheimer’s disease mouse model

Abstract

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide and remains without effective cure. Increasing evidence is supporting the mitochondrial cascade hypothesis, proposing that loss of mitochondrial fitness and subsequent ROS and ATP imbalance are important contributors to AD pathophysiology. Here, we tested the effects of SUL-138, a small hibernation-derived molecule that supports mitochondrial bioenergetics via complex I/IV activation, on molecular, physiological, behavioral, and pathological outcomes in APP/PS1 and wildtype mice. SUL-138 treatment rescued long-term potentiation and hippocampal memory impairments and decreased beta-amyloid plaque load in APP/PS1 mice. This was paralleled by a partial rescue of dysregulated protein expression in APP/PS1 mice as assessed by mass spectrometry-based proteomics. In-depth analysis of protein expression revealed a prominent effect of SUL-138 in APP/PS1 mice on mitochondrial protein expression. SUL-138 increased the levels of proteins involved in fatty acid metabolism in both wildtype and APP/PS1 mice. Additionally, in APP/PS1 mice only, SUL-138 increased the levels of proteins involved in glycolysis and amino acid metabolism pathways, indicating that SUL-138 rescues mitochondrial impairments that are typically observed in AD. Our study demonstrates a SUL-138-induced shift in metabolic input towards the electron transport chain in synaptic mitochondria, coinciding with increased synaptic plasticity and memory. In conclusion, targeting mitochondrial bioenergetics might provide a promising new way to treat cognitive impairments in AD and reduce disease progression.