MicroRNAs in Extracellular Vesicles of Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disease with dysfunction of memory, language and thinking. More than 55 million people were diagnosed with AD or other dementia around the world in 2020. The pathology of AD is still unclear and there are no applicable therapies for AD. MicroRNAs (miRNAs) play key roles in AD pathology and have great potential for the diagnosis and treatment of AD. Extracellular vesicles (EVs) widely exist in body fluids such as blood and cerebrospinal fluid (CSF) and contain miRNAs that are involved in cell-to-cell communication. We summarized the dysregulated miRNAs in EVs derived from the different body fluids of AD patients, as well as their potential function and application in AD. We also compared these dysregulated miRNAs in EVs to those in the brain tissues of AD patients aiming to provide a comprehensive view of miRNAs in AD. After careful comparisons, we found that miR-125b-5p and miR-132-3p were upregulated and downregulated in several different brain tissues of AD and EVs of AD, respectively, suggesting their value in AD diagnosis based on EV miRNAs. Furthermore, miR-9-5p was dysregulated in EVs and different brain tissues of AD patients and had also been tested as a potential therapy for AD in mice and human cell models, suggesting that miR-9-5p could be used to design new therapies for AD.

Keywords: Alzheimer’s disease; blood; brain; cerebrospinal fluid; extracellular vesicles; microRNA.

Figure 1

Dysregulated miRNAs in different brain regions of AD patients. The detailed legend is given on the next page. (A) Dysregulated miRNAs in different brain regions of AD patients. A line between a miRNA and a brain region means the miRNA is dysregulated in the brain region. These miRNAs were reported by at least 2 studies. 8 miRNAs in orange ellipses of the left column were upregulated in AD patients compared to HC. 16 miRNAs in blue ellipses of the right column were downregulated in AD patients compared to HC. Abbreviations of the different brain regions in the central column: ATC: anterior temporal cortex; CB: cerebellum; CSF: cerebrospinal fluid; EC: entorhinal cortex; EVs: extracellular vesicles; FC: frontal cortex; HP: hippocampus; MFG: medial frontal gyrus; MTG: middle temporal gyrus; PC: prefrontal cortex; PL: parietal lobe; PLC: parietal lobe cortex; STG: superior temporal gyrus; STLN: superior temporal lobe neocortex; TC: temporal cortex; TL: temporal lobe; TLN: temporal lobe neocortex; and Unknown: unknown brain region. (B) Upregulated miRNAs of EVs derived from plasma, serum, whole blood and cerebrospinal fluid (CSF). There is no upregulated miRNA in exosomes derived from whole blood. Among the upregulated miRNAs from serum EVs, only miR-22-3p is common in serum EVs and plasma EVs and 3 miRNAs (miR-125b-5p, miR-135a-5p, miR-193b) are common in serum EVs and CSF EVs. (C) Downregulated miRNAs of EVs derived from plasma, serum, whole blood and CSF. There is no common miRNA in plasma EVs, serum EVs and whole-blood EVs. Among the upregulated miRNAs from serum EVs, 3 miRNAs (miR-21-5p, miR-342-3p, miR-375) are shared with plasma EVs and 2 miRNAs (miR-124-3p, miR-193b) are shared with CSF EVs. There are 3 (miR-132-3p, miR-139-5p, miR-451a) downregulated miRNAs in both plasma EVs and CSF EVs. (D) Dysregulated miRNAs in EVs of different body fluids of AD patients. These miRNAs are dysreguated in EVs from 2 different body fluids. 4 miRNAs in orange ellipse of the left column were upregulated in AD patients compared to HC. 8 miRNAs in blue ellipse of the right column were downregulated in AD patients compared to HC. (E) EVs and brain tissue have 8 upregulated miRNAs in common. (F) EVs and brain tissue have 17 downregulated miRNAs in common. (G) MiRNAs as AD biomarkers and all of the dysregulated miRNAs from EVs and brain tissue. Among all 17 miRNAs in EVs that could be an AD biomarker, only miR-125b-5p and miR-132-3p are dysregulated in EVs and brain tissue. Moreover, another 31 common miRNAs are dysregulated in EVs and brain tissue. (H) MiRNAs as AD therapeutic targets and all of the dysregulated miRNAs from EVs and brain tissue. For the 5 therapeutic miRNAs, miR-16-5p is dysregulated in EVs only. miR-29b and miR-124 are dysregulated in brain only. Only miR-9-5p was dysregulated in EVs and brain of AD patients and was tested as a therapeutic target of AD. miR-206-3p was not found to be dysregulated in either EVs or brain tissue.