Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles
Alzheimer's disease (AD) is the most common type of dementia.  Extracellular amyloid ß (Aß) plaques and intracellular Tau-containing neurofibrillary tangles are major AD lesions that identify Alzheimer's pathology and to neuronal loss.  However, given that these structures are also seen in cognitively normal persons (healthy controls, HC) and in persons who have mild cognitive impairment (MCI), extensive efforts have been undertaken to identify other diagnostic or prognostic indicators.  Here, we characterized the RNA contents of extracellular vesicles (EVs) in the plasma of age-matched individuals who are healthy or have MCI or AD.  Using RNA sequencing analysis, we found that mitochondrial (mt)RNAs, including MT-ND1 through MT-ND6 and other protein-coding and noncoding mtRNAs, were strikingly elevated in MCI- and AD-associated plasma EVs compared with healthy control EVs.  In cultured cells derived from astrocytes, microglia, and neurons, exposure to the toxic conditions in the AD environment (Aß fibers and H2O2), EVs contained mitochondrial structures (as detected by electron microscopy) as well as mitochondrial RNAs.  We propose that in the MCI and AD brain environment, toxicity causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs, and further propose that mitochondrial RNAs in plasma EVs are robust diagnostic and prognostic markers in AD. Overall design: We used 4ml of plasma from 5 Healthy donors, 5 patients with mild cognitive impairment, 5 patient with Alzheimer's disease.