Abstract
It was recently discovered that brain cells release extracellular vesicles (EV) which can pass from brain into blood. These findings raise the possibility that brain-derived EV’s present in blood can be used to monitor disease processes occurring in the cerebrum. Since the levels of certain micro-RNAs (miRNAs) have been reported to be altered in Alzheimer’s disease (AD) brain, we sought to assess miRNA dysregulation in AD brain tissue and to determine if these changes were reflected in neural EVs isolated from blood of subjects with AD. To this end, we employed high-content miRNA arrays to search for differences in miRNAs in RNA pools from brain tissue of AD (n = 5), high pathological control (HPC) (n = 5), or cognitively intact pathology-free controls (n = 5). Twelve miRNAs were altered by >1.5-fold in AD compared to controls, and six of these were also changed compared to HPCs. Analysis of hits in brain extracts from 11 AD, 7 HPCs and 9 controls revealed a similar fold difference in these six miRNAs, with three showing statistically significant group differences and one with a strong trend toward group differences. Thereafter, we focused on the four miRNAs that showed group differences and measured their content in neurally derived blood EVs isolated from 63 subjects: 16 patients with early stage dementia and a CSF Aβ42+ tau profile consistent with AD, 16 individuals with mild cognitive impairment (MCI) and an AD CSF profile, and 31 cognitively intact controls with normal CSF Aβ42+ tau levels. ROC analysis indicated that measurement of miR-132-3p in neurally-derived plasma EVs showed good sensitivity and specificity to diagnose AD, but did not effectively separate individuals with AD-MCI from controls. Moreover, when we measured the levels of a related miRNA, miR-212, we found that this miRNA was also decreased in neural EVs from AD patients compared to controls. Our results suggest that measurement of miR-132 and miR-212 in neural EVs should be further investigated as a diagnostic aid for AD and as a potential theragnostic.
Highlights
Alzheimer’s disease is a devastating disorder for which there is no cure or effective treatment
To determine whether miRNAs are dysregulated in AD brain, we pooled RNA isolated from the brains of five individuals who died with AD, five individuals who had AD pathology but were without cognitive impairment at the time of death, and miR-212/miR-132 Are Downregulated in AD
RNA was extracted from cortical gray matter, pooled, reverse transcribed into cDNA, and cDNA was used for miRNA assays (Figure 1A)
Summary
Alzheimer’s disease is a devastating disorder for which there is no cure or effective treatment. Advances in brain imaging and the development of robust immunoassays to measure tau and amyloid β-protein (Aβ) in cerebrospinal fluid (CSF) have greatly aided diagnosis (Blennow et al, 2012). Measurement of tau and Aβ in CSF, or quantitation of amyloid or tangle pathology by PET imaging, can be used to identify mild cognitive impairment (MCI), a frequent precursor of AD (Jack et al, 2013; Bao et al, 2017), and use of these markers is common in clinical research (Blennow et al, 2012; Jack et al, 2013). There is a pressing need for less costly and intrusive, and more widely available biomarkers that can replace or supplement current CSF and PET markers (Bateman et al, 2019). Measurement of a blood-based analyte would be ideal since blood collection is widely accepted by patients and can be done almost anywhere
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