Histone deacetylase inhibition mitigates cognitive deficits and astrocyte dysfunction induced by amyloid-β (Aβ) oligomers

Br J Pharmacol. 2024 Oct;181(20):4028-4049. doi: 10.1111/bph.16439. Epub 2024 Jun 27.

Abstract

Background and purpose: Inhibitors of histone deacetylases (iHDACs) are promising drugs for neurodegenerative diseases. We have evaluated the therapeutic potential of the new iHDAC LASSBio-1911 in Aβ oligomer (AβO) toxicity models and astrocytes, key players in neuroinflammation and Alzheimer's disease (AD).

Experimental approach: Astrocyte phenotype and synapse density were evaluated by flow cytometry, Western blotting, immunofluorescence and qPCR, in vitro and in mice. Cognitive function was evaluated by behavioural assays using a mouse model of intracerebroventricular infusion of AβO.

Key results: LASSBio-1911 modulates reactivity and synaptogenic potential of cultured astrocytes and improves synaptic markers in cultured neurons and in mice. It prevents AβO-triggered astrocytic reactivity in mice and enhances the neuroprotective potential of astrocytes. LASSBio-1911 improves behavioural performance and rescues synaptic and memory function in AβO-infused mice.

Conclusion and implications: These results contribute to unveiling the mechanisms underlying astrocyte role in AD and provide the rationale for using astrocytes as targets to new drugs for AD.

Keywords: Alzheimer's disease; astrocyte; histone deacetylase inhibitor; multitarget drugs; neuroinflammation; reactivity.

MeSH terms

  • Amyloid beta-Peptides* / metabolism
  • Amyloid beta-Peptides* / toxicity
  • Animals
  • Astrocytes* / drug effects
  • Astrocytes* / metabolism
  • Cells, Cultured
  • Cognitive Dysfunction* / chemically induced
  • Cognitive Dysfunction* / drug therapy
  • Cognitive Dysfunction* / metabolism
  • Histone Deacetylase Inhibitors* / pharmacology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neuroprotective Agents / administration & dosage
  • Neuroprotective Agents / pharmacology
  • Synapses / drug effects
  • Synapses / metabolism

Substances

  • Amyloid beta-Peptides
  • Histone Deacetylase Inhibitors
  • Neuroprotective Agents