Work

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

Year: 2024

Type: article

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.

Source: Alzheimer s & Dementia

DOI: 10.1002/alz.14086