All-trans Retinoic Acid Improved Impaired Proliferation of Neural Stem Cells and Suppressed Microglial Activation in the Hippocampus in an Alzheimer's Mouse Model

J Neurosci Res. 2017 Mar;95(3):897-906. doi: 10.1002/jnr.23843. Epub 2016 Jul 22.


Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by cognitive impairment with neuronal loss. The number of patients suffering from AD has increased, but none of the present therapies stops the progressive symptoms in patients with AD. It has been reported that the activation of microglial cells induces harmful chronic inflammation, leading to neuronal death. Furthermore, the impairment of adult neurogenesis in the hippocampus has been observed earlier than amyloid plaque formation. Inflammatory response may lead to impaired adult neurogenesis in patients with AD. This study examines the relationship between adult neurogenesis and neuroinflammation using APPswe/PS1M146V/tauP301L (3 × Tg) mice. We observed a decline in the proliferation of neural stem cells and the occurrence of severe inflammation in the hippocampus of 3 × Tg mouse brains at 12 months of age. Previously, our research had shown an anti-inflammatory effect of all-trans retinoic acid (ATRA) in the 3 × Tg mouse brain. We found that ATRA has effects on the recovery of proliferative cells along with suppression of activated microglia in the hippocampus. These results suggest that the inhibition of microglial activation by ATRA leads to recovery of adult neurogenesis in the hippocampus in an AD mouse model. © 2016 Wiley Periodicals, Inc.

Keywords: Alzheimer's disease; adult neurogenesis; model mouse; neuroinflammation; retinoic acid.

MeSH terms

  • Alzheimer Disease / genetics
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Calcium-Binding Proteins / metabolism
  • Cell Proliferation / drug effects*
  • Disease Models, Animal
  • Female
  • Gene Expression Regulation / drug effects
  • Gene Expression Regulation / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Hippocampus / pathology*
  • Humans
  • Male
  • Mice
  • Mice, Transgenic
  • Microfilament Proteins / metabolism
  • Microglia / drug effects*
  • Mutation / genetics
  • Neural Stem Cells / drug effects*
  • Tretinoin / pharmacology*
  • tau Proteins / genetics


  • Aif1 protein, mouse
  • Amyloid beta-Protein Precursor
  • Antineoplastic Agents
  • Calcium-Binding Proteins
  • Glial Fibrillary Acidic Protein
  • Microfilament Proteins
  • tau Proteins
  • Tretinoin