miR-124 regulates cerebromicrovascular function in APP/PS1 transgenic mice via C1ql3

Brain Res Bull. 2019 Nov;153:214-222. doi: 10.1016/j.brainresbull.2019.09.002. Epub 2019 Sep 6.

Abstract

Many neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease, are associated with microvascular dysfunction, but the cellular and molecular mechanisms are poorly understood. Recently, microRNAs (miRNAs) have been suggested to be involved in the microvascular dysfunction and subsequent memory impairment. MicroRNA-124 (miR-124) is one of the most abundant miRNAs in the brain that is dysregulated in the hippocampus of AD animals. To explore the role of miR-124 in AD pathology, we employed the APP/PS1 transgenic mice and found downregulation of miR-124 and upregulation of complement C1q-like protein 3 (C1ql3) in the hippocampus and cerebral cortex. Downregulation of miR-124 expression resulted in Aβ deposition and a variety of cerebromicrovascular impairments, including the decline in microvascular density, reduced angiogenesis, accompanied by C1ql3 alteration. Treatment with lentivirus-mediated overexpression of miR-124 or the C1q inhibitor C1INH rescued breakdown of blood-brain barrier, promoted angiogenesis and reduced Aβ deposition, and finally alleviated learning and memory deficit in APP/PS1 mice. Moreover, we found that C1ql3, a component of the classical complement, might be a potential target of miR-124. These results suggested that miR-124 was involved in the angiogenesis and vascular integrity in the hippocampus and the cerebral cortex of the AD mice by regulating the classical complement C1ql3.

Keywords: Alzheimer’s disease; C1ql3; Cerebromicrovasculature; microRNA-124.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / genetics*
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Brain / metabolism
  • Cerebral Cortex / metabolism
  • Complement C1q / genetics
  • Complement C1q / metabolism*
  • Disease Models, Animal
  • Hippocampus / metabolism
  • Male
  • Memory Disorders / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Microvessels / physiology*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Presenilin-1 / genetics
  • Presenilin-1 / metabolism

Substances

  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • MIRN124 microRNA, human
  • MicroRNAs
  • Nerve Tissue Proteins
  • Presenilin-1
  • complement C1q-like protein 3, mouse
  • Complement C1q