A possible role for the Alzheimer amyloid precursor protein in the regulation of epidermal basal cell proliferation

The regulation of epidermal growth involves a number of ions, growth factor s and cytokines and possibly additional but as yet unknown factors. Here we report on the potential role of the secretory N-terminal domain (sAPP) of the Alzheimer amyloid precursor protein (APP) in the regulation of keratino cyte proliferation, In human skin APP was detectable predominantly in the b asal cell layer of the epidermis whereas the immunocytochemical signal in t he underlying mesenchymal tissue was very low Cultured normal human keratin ocytes expressed the three APP isoforms 695, 751 and 770 with highest value s for the isoforms 751 and 770, HaCaT cells, a spontaneously immortalized h uman keratinocyte cell line, exhibited almost identical patterns in the exp ression of the APP isoforms and in the release of endogenous sAPP, In HaCaT cells, recombinant sAPP (sAPPrec) was found to compete,vith endogenous sAP P for the same binding sites. Binding of sAPPrec was specific and occurred in microdomains of similar to0.1 to similar to0.3 mum in diameter. At 10 nM , sAPPrec binding induced a 2- to 1-fold increase in the rate of cell growt h. sAPP concentrations in the conditioned media were found to reach 5-20 nM which is in the mitogenic range of sAPPrec, The proliferative effect of sA PP was inhibited by similar to 50% when antisense oligonucleotides directed against the APP mRNA were applied. The predominant expression of APP in ba sal cells, the growth-promoting effect of sAPP on keratinocytes, the physio logically relevant concentrations of sAPP secreted by keratinocytes, and th e antisense-induced inhibition of proliferation point to a function in the autocrine regulation of epidermal growth by sAPP.