The small molecular CCR3 antagonist YM344031 attenuates neurodegenerative pathologies and improves learning and memory performance in a mouse model of Alzheimer's disease

Abstract

The chemokine C-C receptor 3 (CCR3) plays a role in the pathogenesis of Alzheimer's disease (AD). Based on our previous observations that deletion of CCR3 prevented neurodegenerative pathologies in amyloid precursor protein/presenilin 1 (APP/PS1) double-transgenic mice, we hypothesize that CCR3 antagonists may provide therapeutic benefits to AD. To this end, we examined the effect of the brain-penetrable CCR3 antagonist, YM344031, on AD-related pathologies in APP/PS1 double transgenic mice. Treatment of 10-month-old APP/PS1 double-transgenic mice with YM344031 (50 mg/kg, b.i.d.) for two months resulted in dramatic decreases in β-amyloid deposition, tau hyperphosphorylation and synaptic loss in the forebrain, significant attenuation of microgliosis and astrogliosis, and marked improvement of spatial learning and memory performance compared with the vehicle-treated mice. These results support CCR3 antagonism as a potential therapeutic strategy for AD.

Keywords: Alzheimer’s disease; CCR3; Chemokine; Cognitive dysfunction; Tau; β amyloid.