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Cerebrovascular miRNA expression profile during development of Alzheimer's disease
Author(s) -
Chum Phoebe,
Behringer Erik
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02206
Subject(s) - pathological , disease , etiology , medicine , microrna , cerebral blood flow , cognitive decline , downregulation and upregulation , angiogenesis , pathology , neuroscience , psychology , biology , dementia , genetics , gene
Alzheimer's disease (AD) is the fifth leading cause of death among Americans of age 65 years and older. Emerging evidence demonstrates the association of AD with impaired delivery of blood oxygen and nutrients to and throughout the brain. In particular, the cerebral circulation plays multiple roles underscoring optimal brain perfusion and cognition that entail moment‐to‐moment blood flow control, vascular permeability, and angiogenesis. With currently no effective treatment available while etiology remains obscure, discovery of novel diagnostic markers and corresponding therapeutic interventions for AD are desperately needed. Thus, to address a knowledge gap, our hypothesis was that cerebrovascular microRNA (miRNA) expression profiles corresponding to post‐transcriptional regulation can provide a diagnostic map of the development of AD pathology. We screened for 600 clinically relevant miRNAs in purified brain blood vessels throughout the adult healthspan of a mouse model of AD ( 3xTg‐AD ). Using Nanostring technology, we probed for the pathological contribution of age/disease stage [young, 1‐2 mo; cognitive impairment (CI), 4‐5 mo; extracellular amyloid‐β plaques (Aβ), 6‐8 mo; plaques + neurofibrillary tangles (AβT), 12‐15 mo] alongside biological sex as male vs. female (n=3 animals/group). Significant ( p <0.05) downregulation of various miRNAs indicated transitions from young to CI (let‐7g & let‐7i, males; miR‐133a & miR‐2140, females) and CI to Aβ (miR‐99a, males) but not from Aβ to AβT. In addition, transitions in miRNA expression from overall Pre‐AD (young + CI) to AD (Aβ + AβT) conditions were detected in both males (let‐7d, let‐7i, miR‐23a, miR‐34b‐3p, miR‐99a, miR‐132, miR‐150, miR‐181a) and females (miR‐150, miR‐539). These data demonstrate that cerebrovascular miRNAs pertaining to amyloid‐β/tau regulation, remodeled vascular permeability, and enhanced angiogenesis can track early (but not late) stage development of AD pathology in a sex‐based manner. Pairing such new found knowledge of vascular “signatures” of AD may yield novel theranostic approaches to maintain healthy cognition throughout adulthood.