Thus, I envision AD as being susceptible to experimental acceleration by phorbol esters. When applied repeatedly at nontoxic doses to brain tissue in situ, phorbol esters would stimulate coordinated changes in gene expression within neurons, astrocytes, microglia and vasculature. Other tumor promoting agents which affect gene expression in neural tissue, such as okadaic acid and TGF-beta, may be expected to have similar accelerating effects as phorbol esters. Some AD researchers currently pursue initiator-promoter protocols, but these are conceptually and practically different from the one advocated here. For example, Frautschy et al.
Promoters are effective only when applied after initiation.
Give repeated doses of promoters, chronically and at doses which are relatively nontoxic in normal animals. Employ phorbol esters or okadaic acid, perhaps the two best studied tumor promoters. These guidelines could be readily applied to currently available animal models of AD, such as those bearing mutations in beta-APP and those which overproduce amyloid peptide, to test whether an acceleration of pathological lesions occurs.