Abstract

Background: Alzheimer's disease (AD) is characterised by progressive memory loss, with synaptic dysfunction emerging as a key early event. While deficits in synaptic mitochondrial bioenergetics have been proposed to be involved in AD pathophysiology, the precise underlying biochemical mechanisms remain largely unknown.

Methods: This study employed a range of biochemical approaches, including quantitative mass spectrometry-based proteomics, western blotting, and enzymatic activity analyses. It investigated synaptic-enriched fractions from the forebrain of 3-4 month-old wild-type (WT) mice and amyloid precursor protein transgenic (APPtg) mice, a model of AD-related amyloid deposition. Tissue from two behavioural groups of mice was analysed, one group under basal conditions (with no behavioural training) and the other group immediately following a memory retrieval probe trial in the Morris watermaze.

Results: Proteomics analysis suggested that memory retrieval triggered a robust synaptic proteome response in WT mice compared to the basal group. Pathway analysis using the String and Metascape databases suggested upregulation of proteins involved in oxidative phosphorylation, vesicle-mediated transport, and cellular homeostasis. In contrast, memory retrieval in APPtg mice was suggested to affect a smaller number of proteins, involved in pathways of inflammation, necroptosis, and protein degradation. Western blotting suggested changes in the synaptic levels of the glycolytic enzyme 6-phosphofructokinase (PFK) in the memory retrieval group compared to the basal group, specifically in the WT mice. In addition, differences in the levels of mitofilin, a protein involved in mitochondrial dynamics, were observed between the basal groups of APPtg and WT mice. The enzymatic activities of the mitochondrial enzyme malate dehydrogenase and PFK were assessed and remained unchanged across both memory states and genotypes.

Conclusion: These findings provide interesting insights into the biochemical mechanisms underlying memory retrieval, and how these can be affected in a mouse model of high beta-amyloid levels, with strong relevance to AD.