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Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs
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Inhibition of CDK4/6 regulates AD pathology, neuroinflammation and cognitive function through DYRK1A/STAT3 signaling

Hyun-Ju Lee1, Hyang-Sook Hoe2

  • 1Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), 61, Cheomdan-ro, Daegu, the Republic of Korea.

Pharmacological Research
|March 12, 2023
PubMed

Insights

The anticancer drug abemaciclib mesylate improved memory and reduced Alzheimer

Area of Science:

  • Neuroscience
  • Pharmacology
  • Drug Repurposing

Background:

  • Alzheimer's disease (AD) drug development seeks novel therapeutic strategies.
  • Repurposing FDA-approved drugs offers a promising avenue for AD treatment.
  • The CDK4/6 inhibitor abemaciclib mesylate, used for breast cancer, has unknown effects on AD pathologies.

Purpose of the Study:

  • To investigate the therapeutic potential of abemaciclib mesylate in Alzheimer's disease.
  • To determine abemaciclib mesylate's effects on Aβ/tau pathology, neuroinflammation, and cognitive impairment.

Main Methods:

  • Utilized 5xFAD mice (Aβ-overexpressing AD model) and PS19 mice (tau-overexpressing model).
  • Administered abemaciclib mesylate to assess cognitive function, dendritic spine density, and Aβ/tau levels.
  • Investigated abemaciclib mesylate's impact on neuroinflammation in vivo (WT mice with LPS) and in vitro (BV2 microglial cells, primary astrocytes).

Main Results:

  • Abemaciclib mesylate improved spatial and recognition memory in 5xFAD mice by regulating dendritic spine number and neuroinflammation.
  • It inhibited Aβ accumulation via enhanced neprilysin and ADAM17 activity and reduced PS-1 levels.
  • The drug suppressed tau phosphorylation by decreasing DYRK1A and/or p-GSK3β levels.
  • Abemaciclib mesylate rescued memory and dendritic spine density in LPS-treated WT mice, downregulating microglial/astrocytic activation and pro-inflammatory cytokines via AKT/STAT3 signaling.

Conclusions:

  • Abemaciclib mesylate demonstrates significant therapeutic potential for Alzheimer's disease.
  • The drug acts as a multitarget therapeutic, addressing Aβ/tau pathology and neuroinflammation.
  • Repurposing abemaciclib mesylate as an Alzheimer's disease treatment warrants further investigation.
Keywords:
Abemaciclib mesylateAβCognitive functionLPSNeuroinflammationTau

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