Alpha7 nicotinic acetylcholine receptor specific agonist DMXBA (GTS 21) attenuates Ab accumulation through suppression of neuronal g secretase activity and promotion of microglial amyloid b phagocytosis and ameliorates cognitive impairment in a mouse model of Alzheimer's disease
We previously demonstrated that stimulation of nicotinic acetylcholine receptors (nAChRs) increases amyloid b (Ab) phagocytosis in rat microglia and is closely associated with the decrease of brain Ab 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 a7 nAChR selective agonist 3 (2,4 dimethoxy)benzylidene] anabaseine dihydrochloride (DMXBA) promoted Ab and fluorescent latex bead phagocytosis, whereas selective a7 nAChR antagonists suppressed the enhanced Ab phagocytosis. In a transgenic mouse model of AD, administration of DMXBA attenuated brain Ab burden and memory dysfunction. Moreover, DMXBA suppressed g secretase activity in solubilized fractions of human neuroblastoma cells and transgenic mouse brain. These results suggested that selective activation of a7 nAChRs promoted microglial Ab phagocytosis and suppressed neuronal g secretase activity to contribute to the attenuation of the brain Ab burden and cognitive impairment. Thus, we propose neuronal and microglial a7 nAChRs as new therapeutic targets in the treatment of AD.
Neurobiology of Aging