Memory Decline and Its Reversal in Aging and Neurodegeneration Involve miR-183/96/182 Biogenesis

Mol Neurobiol. 2019 May;56(5):3451-3462. doi: 10.1007/s12035-018-1314-3. Epub 2018 Aug 20.


Aging is characterized by progressive memory decline that can lead to dementia when associated with neurodegeneration. Here, we show in mice that aging-related memory decline involves defective biogenesis of microRNAs (miRNAs), in particular miR-183/96/182 cluster, resulting from increased protein phosphatase 1 (PP1) and altered receptor SMAD (R-SMAD) signaling. Correction of the defect by miR-183/96/182 overexpression in hippocampus or by environmental enrichment that normalizes PP1 activity restores memory in aged animals. Regulation of miR-183/96/182 biogenesis is shown to involve the neurodegeneration-related RNA-binding proteins TDP-43 and FUS. Similar alterations in miR-183/96/182, PP1, and R-SMADs are observed in the brains of patients with amyotrophic lateral sclerosis (ALS) or frontotemporal lobar degeneration (FTLD), two neurodegenerative diseases with pathological aggregation of TDP-43. Overall, these results identify new mechanistic links between miR-183/96/182, PP1, TDP-43, and FUS in age-related memory deficits and their reversal.

Keywords: Dementia; FUS; Memory; Protein phosphatase 1; TDP-43; microRNA.

MeSH terms

  • Aging / pathology*
  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / pathology
  • Animals
  • Cell Line, Tumor
  • Cell Nucleus / metabolism
  • Cognition Disorders / genetics
  • Cognition Disorders / pathology
  • Frontotemporal Lobar Degeneration / genetics
  • Frontotemporal Lobar Degeneration / pathology
  • Hippocampus / metabolism
  • Hippocampus / pathology
  • Humans
  • Memory Disorders / complications*
  • Memory Disorders / genetics*
  • Mice, Inbred C57BL
  • MicroRNAs / biosynthesis*
  • MicroRNAs / genetics
  • Nerve Degeneration / complications*
  • Nerve Degeneration / genetics*
  • Protein Phosphatase 1 / metabolism
  • RNA-Binding Protein FUS / metabolism
  • Smad Proteins / metabolism


  • MicroRNAs
  • RNA-Binding Protein FUS
  • Smad Proteins
  • Protein Phosphatase 1