Abstract
Mitochondria provide energy to neurons through oxidative phosphorylation and eliminate Reactive Oxygen Species (ROS) through Superoxide Dismutase 1 (SOD1). Dysfunctional mitochondria, manifesting decreased activity of electron transport chain (ETC) complexes and high ROS levels, are involved in Alzheimer’s disease (AD) pathogenesis. We hypothesized that neuronal mitochondrial dysfunction in AD is reflected in ETC and SOD1 levels and activity in plasma neuron-derived extracellular vesicles (NDEVs). We immunoprecipitated NDEVs targeting neuronal marker L1CAM from two cohorts: one including 22 individuals with early AD and 29 control subjects; and another including 14 individuals with early AD and 14 control subjects. In the first cohort, we measured levels of complexes I, III, IV, ATP synthase, and SOD1; in the second cohort, we measured levels and catalytic activity of complexes IV and ATP synthase. AD individuals had lower levels of complexes I (p < 0.0001), III (p < 0.0001), IV (p = 0.0061), and V (p < 0.0001), and SOD1 (p < 0.0001) compared to controls. AD individuals also had lower levels of catalytic activity of complex IV (p = 0.0214) and ATP synthase (p < 0.0001). NDEVs confirm quantitative and functional abnormalities in ECT complexes and SOD1 previously observed in AD models and during autopsy, opening the way for using them as biomarkers for mitochondrial dysfunction in AD.
Highlights
IntroductionA wide range of structural and functional mitochondrial abnormalities are found in Alzheimer’s disease (AD) (for a comprehensive review, see [1])
Published: 31 October 2021A wide range of structural and functional mitochondrial abnormalities are found in Alzheimer’s disease (AD)
The neuronal marker neuron-specific enolase measured in neuron-derived extracellular vesicles (NDEVs) extracts confirmed a high degree of neuronal cargo enrichment, with a mean ± S.E.M. of 5816 ± 142 pg/mL in controls and 6049 ± 153 pg/mL in AD individuals, more than ten-fold higher than levels previously observed in astrocyte-derived exosome extracts [19]
Summary
A wide range of structural and functional mitochondrial abnormalities are found in Alzheimer’s disease (AD) (for a comprehensive review, see [1]). The main function of mitochondria is to generate energy, mainly through oxidative phosphorylation coupled to electron transfer across the respiratory or electron transfer chain (ETC), which consists of complexes I through IV, and ATP synthase. Studies investigating the mechanisms of oxidative injury in the AD brain have largely focused on abnormalities of superoxide dismutase (SOD), a mitochondrial enzyme that eliminates ROS [3]. The number of SOD-positive neurons is decreased in the hippocampus and frontotemporal cortex of AD patients [4]. Brain areas with lower density of neurofibrillary tangles (the hallmark abnormal tau deposits in AD) and milder neuronal loss compared to more severely affected areas, show normal total SOD activity, sug-
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