Mitochondrial dysfunction in lymphocytes – a potential biomarker for Alzheimer's disease

Alzheimer's disease (AD) is a most common progressive neurodegenerative disease. The AD brain is marked by severe neurodegeneration like the loss of synapses and neurons, atrophy and depletion of neurotransmitter systems in the hippocampus and cerebral cortex. Recent findings suggest that these pathological changes are causally induced by mitochondrial dysfunction, increased oxidative and elevated apoptosis. Until now, AD cannot be diagnosed by a valid clinical method or a biomarker before the disease has progressed so far that dementia is present. Furthermore, no valid method is available to determine which patient with mild cognitive impairment (MCI) will progress to AD. Therefore, we investigated if mitochondrial dysfunction in lymphocytes could be a valid and easy detectable biomarker for AD. Lymphocytes from Alzheimer patients (n=23; MMSE 19.57±6.577), MCI's (n=17; MMSE 28.69±1.58) and aged controls (n=15; MMSE 29.83±0.40) were isolated and reactive oxygen species (ROS), the mitochondrial membrane potential (MMP), ATP levels, and the MMP after additional mitochondrial stress using complex inhibitors of the respiratory chain were measured. ROS levels were significantly decreased in AD patients in CD4+ lymphocytes. No changes were observed in MCIs. Furthermore, the MMP was significantly decreased in CD4+ lymphocytes from AD patients and in MCIs. In contrast, no differences in ATP levels could be detected between the different groups. After additional mitochondrial stress using the complex I inhibitor rotenone (25µM) or the complex III inhibitor antimycine (10µM) the MMP of CD4+ lymphocytes of MCIs and AD patients was strongly reduced compared to aged controls. Furthermore, we found a graduation of susceptibility between CD4+ lymphocytes of AD patients and MCIs using the complex IV inhibitor sodiumazide and the complex V inhibitor oligomycine. Taken together, lymphocytes are a promising cell model for biomarker in AD, further studies need to be conducted to evaluate the most adequate biomarker.