AUTHOR=Kim Kyoung Mi , Meng Qiong , Perez de Acha Olivia , Mustapic Maja , Cheng Aiwu , Eren Erden , Kundu Gautam , Piao Yulan , Munk Rachel , Wood William H. , De Supriyo , Noh Ji Heon , Delannoy Michael , Cheng Lesley , Abdelmohsen Kotb , Kapogiannis Dimitrios , Gorospe Myriam 

TITLE=Mitochondrial RNA in Alzheimer’s Disease Circulating Extracellular Vesicles

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=8

YEAR=2020

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2020.581882

DOI=10.3389/fcell.2020.581882

ISSN=2296-634X

ABSTRACT=<p>Alzheimer’s disease (AD) is the most common type of dementia. Amyloid β (Aβ) plaques, tau-containing neurofibrillary tangles, and neuronal loss leading to brain atrophy are pathologic hallmarks of AD. Given the importance of early diagnosis, extensive efforts have been undertaken to identify diagnostic and prognostic biomarkers for AD. Circulating extracellular vesicles (EVs) provide a platform for “liquid biopsy” biomarkers for AD. Here, we characterized the RNA contents of plasma EVs of age-matched individuals who were cognitively normal (healthy controls (HC)) or had mild cognitive impairment (MCI) due to AD or had mild AD dementia (AD). Using RNA sequencing analysis, we found that mitochondrial (mt)-RNAs, including <italic>MT-ND1-6</italic> mRNAs and other protein-coding and non-coding mt-RNAs, were strikingly elevated in plasma EVs of MCI and AD individuals compared with HC. EVs secreted from cultured astrocytes, microglia, and neurons after exposure to toxic conditions relevant to AD pathogenesis (Aβ aggregates and H<sub>2</sub>O<sub>2</sub>), contained mitochondrial structures (detected by electron microscopy) and mitochondrial RNA and protein. We propose that in the AD brain, toxicity-causing mitochondrial damage results in the packaging of mitochondrial components for export in EVs and further propose that mt-RNAs in plasma EVs can be diagnostic and prognostic biomarkers for MCI and AD.</p>