miR-212 and miR-132 Are Downregulated in Neurally Derived Plasma Exosomes of Alzheimer’s Patients

Frontiers in Neuroscience

Dominic M. Walsh¹  Douglas Galasko³  David Mengel⁴  Diana J. Cha⁵  Wen Liu⁵  Dennis J. Selkoe⁵  Dimitrios Kapogiannis⁶  Maja Mustapic⁶  David A. Bennett⁷  Robert A. Rissman⁸ 

[1] Alzheimer’s Disease and Dementia Research Unit, Biogen Inc., Cambridge, MA, United States;Department of Neurodegenerative Diseases, Hertie-Institute for Clinical Brain Research and Center of Neurology, University of Tübingen, Tübingen, Germany;Department of Neurosciences, University of California, San Diego, La Jolla, CA, United States;German Center for Neurodegenerative Diseases, University of Tübingen, Tübingen, Germany;Laboratory for Neurodegenerative Disease Research, Ann Romney Center for Neurologic Diseases, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States;Laboratory of Neurosciences, National Institute on Aging, National Institutes of Health, Baltimore, MD, United States;Rush Alzheimer‘s Disease Center, Rush Medical College, Chicago, IL, United States;VA San Diego Healthcare System, La Jolla, CA, United States;

关键词: blood biomarker;    extracellular vesicles;    L1CAM;    micro-RNA;    mild cognitive impairment;    qRT-PCR;   

DOI  :  10.3389/fnins.2019.01208

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown