Effects of γ‐secretase modulator BPN‐15606 in amyloidogenic responses to air pollution in mouse cortex
Year: 2023
Type: article
Abstract: Background Epidemiological studies show chronic exposure to air pollution accelerates cognitive decline and increase AD risk. In mouse models, brain accumulation of amyloid beta (Aβ) is enhanced by air pollution. Pharmacological approaches show benefit of γ‐secretase modulation (GSM; BPN‐15606), decreasing Aβ42 and amyloid plaques in mouse brain. We hypothesize that GSM will limit Aβ42 production during air pollution exposure in the diesel exhaust particle (DEP) model. Method C57BL/6 mice were exposed to DEP for 8 weeks. DEP from National Institute of Science and Technology (NIST 2975) was suspended in water and re‐aerosolized for 5 hr/day at concentration of 100 µg/m3. GSM was mixed into chow (10mg/day dose). Experimental groups were filtered air (FA), DEP, FA+GSM, and DEP+GSM; proteins from soluble fraction of cerebral cortex were analyzed by immunoblots. Result GSM alone increased amyloid precursor protein (APP) and the Aβ38 peptide. Air pollution (DEP) increased APP, with no further change in DEP+GSM. PSEN1, key enzyme for γ‐secretase function, decreased with DEP+GSM, along with the Aβ42 peptide and the Aβ42/40 ratio. Conclusion During exposure to DEP, GSM decreased Aβ42 and the ratio of Aβ42/40. These results suggest that γ‐secretase modulation is beneficial during air pollution, preventing Aβ42 increases.
Source: Alzheimer s & Dementia
DOI: 10.1002/alz.075224
Institution: University of Southern California
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4390195647