Air pollution amyloidogenesis is attenuated by the gamma‐secretase modulator GSM‐15606

Abstract INTRODUCTION Chronic air pollution (AirPoll) is associated with accelerated cognitive decline and risk of Alzheimer's disease (AD). Correspondingly, wild‐type and AD‐transgenic rodents exposed to AirPoll have increased amyloid peptides and behavioral impairments. METHODS We examined the γ‐secretase modulator GSM‐15606 for potential AirPoll protection by its attenuating of amyloid beta (Aβ)42 peptide production. Male and female wild‐type mice were fed GSM‐15606 during an 8‐week inhalation exposure to AirPoll subfractions, ambient nanoparticulate matter (nPM), and diesel exhaust particles (DEP). RESULTS GSM‐15606 decreased Aβ42 during nPM and DEP exposure without changing beta‐ or gamma‐secretase activity or BACE1 and PS1 protein levels. DEP increased lateral ventricle volume by 25%. DISCUSSION These enzyme responses are relevant to AD drug treatments, as well as to the physiological functions of the Aβ42 peptide. GSM‐15606 attenuation of Aβ42 may benefit human exposure to AirPoll. Highlights Gamma‐secretase modulator (GSM‐15606) attenuates the amyloidogenic amyloid beta (Aβ)42 peptide during exposure to air pollution, which may be a mechanism by which air pollution increases Alzheimer's disease (AD) risk. AD drug treatments may also consider Aβ homeostasis among the chronic effects of GSM‐15606 and other amyloid reduction treatments on secretase enzymes.