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 factors 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 keratinocyte proliferation, In human skin APP was detectable predominantly in the basal cell layer of the epidermis whereas the immunocytochemical signal in the underlying mesenchymal tissue was very low Cultured normal human keratinocytes expressed the three APP isoforms 695, 751 and 770 with highest values for the isoforms 751 and 770, HaCaT cells, a spontaneously immortalized human keratinocyte cell line, exhibited almost identical patterns in the expression of the APP isoforms and in the release of endogenous sAPP, In HaCaT cells, recombinant sAPP (sAPPrec) was found to compete,vith endogenous sAPP 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 growth. 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 sAPP was inhibited by similar to 50% when antisense oligonucleotides directed against the APP mRNA were applied. The predominant expression of APP in basal cells, the growth-promoting effect of sAPP on keratinocytes, the physiologically relevant concentrations of sAPP secreted by keratinocytes, and the antisense-induced inhibition of proliferation point to a function in the autocrine regulation of epidermal growth by sAPP.