Alpha7 nicotinic acetylcholine receptor-specific agonist DMXBA (GTS-21) attenuates Aβ accumulation through suppression of neuronal γ-secretase activity and promotion of microglial amyloid-β phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer's disease

Neurobiol Aging. 2018 Feb;62:197-209. doi: 10.1016/j.neurobiolaging.2017.10.021. Epub 2017 Nov 22.

Abstract

We previously demonstrated that stimulation of nicotinic acetylcholine receptors (nAChRs) increases amyloid-β (Aβ) phagocytosis in rat microglia and is closely associated with the decrease of brain Aβ and amelioration of memory dysfunction in a transgenic mouse model of Alzheimer's disease (AD). Here, we examined the subtypes of nAChRs involved in these beneficial effects. In primary cultures of rat microglia, the α7 nAChR selective agonist 3-[(2,4-dimethoxy)benzylidene]-anabaseine dihydrochloride (DMXBA) promoted Aβ and fluorescent latex bead phagocytosis, whereas selective α7 nAChR antagonists suppressed the enhanced Aβ phagocytosis. In a transgenic mouse model of AD, administration of DMXBA attenuated brain Aβ burden and memory dysfunction. Moreover, DMXBA suppressed γ-secretase activity in solubilized fractions of human neuroblastoma cells and transgenic mouse brain. These results suggested that selective activation of α7 nAChRs promoted microglial Aβ phagocytosis and suppressed neuronal γ-secretase activity to contribute to the attenuation of the brain Aβ burden and cognitive impairment. Thus, we propose neuronal and microglial α7 nAChRs as new therapeutic targets in the treatment of AD.

Keywords: Amyloid-β; Microglia; Neuron; Phagocytosis; α7 Nicotinic acetylcholine receptor; γ-Secretase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / complications
  • Alzheimer Disease / drug therapy*
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Peptides / immunology*
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Benzylidene Compounds / pharmacology*
  • Benzylidene Compounds / therapeutic use*
  • Brain / metabolism*
  • Cells, Cultured
  • Cognitive Dysfunction / drug therapy*
  • Cognitive Dysfunction / etiology
  • Disease Models, Animal
  • Humans
  • Mice, Transgenic
  • Microglia / immunology*
  • Neuroblastoma / metabolism
  • Phagocytosis / drug effects*
  • Phagocytosis / immunology*
  • Pyridines / pharmacology*
  • Pyridines / therapeutic use*
  • Rats
  • Tumor Cells, Cultured
  • alpha7 Nicotinic Acetylcholine Receptor / agonists*

Substances

  • Amyloid beta-Peptides
  • Benzylidene Compounds
  • Pyridines
  • alpha7 Nicotinic Acetylcholine Receptor
  • 3-(2,4-dimethoxybenzylidene)anabaseine
  • Amyloid Precursor Protein Secretases