Mitochondrial RNA in Alzheimer's Disease Circulating Extracellular Vesicles.

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

doi:10.3389/fcell.2020.581882

Abstract

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 MT-ND1-6 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 H2O2), 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.

Highlights

Alzheimer’s disease (AD) is the leading age-associated neurodegenerative disease
The mitochondrial RNA reads in extracellular vesicles (EVs) from HC individuals were lower than the mitochondrial RNA reads from mild cognitive impairment (MCI) or AD
This finding suggests that the levels of mt-RNAs in circulating EVs could be developed into a novel diagnostic biomarker for early AD

Summary

Introduction

The disease is associated with numerous structural and functional alterations involving neurons and all other brain cells (Weller and Budson, 2018). Extensive efforts are underway to identify robust, specific, sensitive, and accessible indicators of AD, at its mild cognitive impairment (MCI) prodromal stage or even preclinically (Sperling et al, 2011; Dubois et al, 2016). In addition to their importance for clinical practice, such biomarkers might inform us about the molecular neuropathology of AD and provide us with novel therapeutic targets

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