Effect of protein kinase A inhibitors on the production of Aβ40 and Aβ42 by human cells expressing normal and Alzheimer's disease‐linked mutated βAPP and presenilin 1

We previously established that the formation of both α‐ and β/γ‐secretase‐derived products generated by human embryonic kidney 293 cells (HEK293) expressing either wild type or mutant βAPP could be stimulated by agonists of the cyclic AMP/protein kinase A pathways. This cyclic AMP‐dependent effect modulates post‐translational events since it is not prevented by actinomycin D or cycloheximide. We show here that two protein kinase A inhibitors, H89 and PKI, both trigger dose‐dependent inhibition of the basal constitutive production of Aβ40 and Aβ42 by HEK293 cells expressing wild type βAPP751. H89 also potently inhibits the total Aβ produced by the neocortical neuronal cell line TSM1. These two inhibitors also drastically reduce the recovery of Aβ40 and Aβ42 produced by HEK293 cells expressing the Swedish (Sw) βAPP and M146V‐presenilin 1 (PS1) mutations responsible for cases of the early‐onset forms of Familial Alzheimer's disease (FAD). By contrast, H89 and PKI do not significantly affect the recovery of the physiological α‐secretase‐derived fragment APPα. Our study indicates that protein kinase A inhibitors selectively lower the formation of Aβ40 and Aβ42 in human cells expressing normal and mutant βAPP and PS1 without affecting the physiological α‐secretase pathway in these cells. Selective inhibitors of protein kinase A may be of therapeutic value in both sporadic and Familial Alzheimer's disease, since they may decrease the production of Aβ that is thought to be responsible for the neurodegenerative process.British Journal of Pharmacology (1999) 126 , 1186–1190; doi: 10.1038/sj.bjp.0702406