Targeting MicroRNA-485-3p Blocks Alzheimer's Disease Progression

Int J Mol Sci. 2021 Dec 4;22(23):13136. doi: 10.3390/ijms222313136.


Alzheimer's disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.

Keywords: Alzheimer’s disease; IL-1β; TNF-α; antisense oligonucleotide; cognitive function; miR-485-3p; microRNA; neuroinflammation; tau; β-amyloid.

MeSH terms

  • Alzheimer Disease / diagnostic imaging
  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / etiology
  • Alzheimer Disease / genetics*
  • Animals
  • Case-Control Studies
  • Cognitive Dysfunction / drug therapy
  • Cognitive Dysfunction / genetics*
  • Cytokines / metabolism
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Humans
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • MicroRNAs / cerebrospinal fluid*
  • MicroRNAs / metabolism
  • Molecular Targeted Therapy / methods
  • Motor Neurons / metabolism
  • Motor Neurons / pathology
  • Oligonucleotides, Antisense / pharmacology
  • Phagocytosis / drug effects
  • Phagocytosis / genetics
  • Positron-Emission Tomography
  • tau Proteins / metabolism


  • Cytokines
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • MIRN485 microRNA, human
  • MicroRNAs
  • Oligonucleotides, Antisense
  • tau Proteins