Effect of protein kinase A inhibitors on the production of A beta 40 and Abeta 42 by human cells expressing normal and Alzheimer's disease-linked mutated beta APP and presenilin 1

1 We previously established that the formation of both alpha- and beta/gamm a-secretase-derived products generated by human embryonic kidney 293 cells (HEK293) expressing either wild type or mutant beta APP could be stimulated by agonists of the cyclic AMP/protein kinase A pathways. This cyclic AMP-d ependent effect modulates post-translational events since it is not prevent ed by actinomycin D or cycloheximide. 2 We show here that two protein kinase A inhibitors, H89 and PKI, both trig ger dose-dependent inhibition of the basal constitutive production of A bet a 40 and A beta 42 by HEK293 cells expressing wild type beta APP751. 3 H89 also potently inhibits the total A beta produced by the neocortical n euronal cell line TSM1. 4 These two inhibitors also drastically reduce the recovery of A beta 40 an d A beta 42 produced by HEK293 cells expressing the Swedish (Sw) beta APP a nd M146V-presenilin 1 (PS1) mutations responsible for cases of the early-on set forms of Familial Alzheimer's disease (FAD). 5 By contrast, H89 and PKI do not significantly affect the recovery of the physiological alpha-secretase-derived fragment APP alpha. 6 Our study indicates that protein kinase A. inhibitors selectively lower t he formation of A beta 40 and A beta 42 in human cells expressing normal an d mutant beta APP and PS1 without affecting the physiological alpha-secreta se pathway in these cells. Selective inhibitors of protein kinase A may be of therapeutic value in both sporadic and Familial Alzheimer's disease, sin ce they may decrease the production of A beta that is thought to be respons ible for the neurodegenerative process.