Proteomic Analysis of Brain Tissue from Patients with Alzheimer’s disease and Healthy Controls Reveals Differential Expression of Proteins Involved in Mitochondrial Dysfunction between Brain Domains

Alzheimer’s disease (AD) is the major contributor to cognitive decline and dementia worldwide. Considering the expanding numbers of elderly in our society, studies of health and disease in the aging population is increasingly important. The brain’s high energy demand, high consumption of oxygen and dependence on components for the ATP production renders it highly reliant on mitochondria. AD patients have increased mutations in their mitochondrial DNA and impaired oxidative phosphorylation. The various domains of the brain serve diverse functions and the molecular composition is expected to vary between brain parts, however, little is known on how similar or divergent these brain domains are. The objective of this study was to characterize the proteome of brain tissue in the frontal cortex (FC) and cerebellum (CB) from AD patients compared to healthy controls (HC). We have monitored the expression of proteins in post-mortem brain tissue from AD patients and HC by mass spectrometry. A total of 4513 proteins were identified and the analysis of the differentially abundant proteins by functional pathways provided an overview of the protein profile. The amount of differentially abundant proteins and levels of fold change were greater between brain regions than between AD and HC. Notably, this indicates that there is a more pronounced difference between FC and CB than between AD and HC. The most enriched pathways when comparing the CB and FC in both AD and HC were mitochondrial dysfunction, oxidative phosphorylation, calcium signaling pathway and dsDNA break repair. These pathways are highly interconnected and many of the differentially abundant proteins are represented in multiple pathways, with the mitochondria as the common denominator. These results suggest that the differences are greater between brain parts than between health/disease conditions, demonstrating the importance of assessing brain parts separately when providing new keys to understanding ageing and AD.