Amyloid Precursor Protein (APP) Gene Expression is Controlled by a NFkB/Rel Related Protein

Abstract

Mammalian cells can process the Amyloid Precursor Protein (APP) by two alternative physiological pathways: one that can be defined “amyloidogenic” since cleavage occurs in the endosomal-lysosomal compartment to generate the entire ßA4 peptide sequence; the second which is “non-amyloidogenic” and involves the secretory cleavage of APP at a site within the (3A4 sequence (for a review see Selkoe, D.J., 1993). Since APP metabolism may become disrupted in both the idiopatic and transmissible forms of the disease, in vitro studies on the processing of endogenous or transfected APP molecules have emerged as major experimental endeavours in the past few years. But ß amyloid formation may not only depend on APP mismetabolism. It is feasable that the pathogenetic mechanisms of amyloid formation may involve changes in APP gene expression as a required step. Several observations underscore the potential contribution of APP gene overexpression to Alzheimer’s disease neuropathology: 1) in trisomy 21 (Down Syndrome) there seems to be a deregulated expression of APP since the difference in APP mRNA levels between patients and controls is higher than the expected 3:2 ratio (Neve et al., 1988; Tanzi et al., 1987); 2) there are differences between AD patients and controls in the levels of APP mRNAs in certain brain areas (Higgins et al., 1988; Cohen et al., 1988; Johnson et al., 1990); and 3) post-mitotic neurons overexpressing full-length APP degenerate in vitro and contain large amounts of amyloidogenic C-terminal fragments (Yoshikawa et al.,1992). These observations demonstrate the importance of elucidating the molecular mechanisms of APP gene regulation, in other words of identifying in the 5’ regulatory region cis-elements and transcription factors relevant for gene expression. APP overexpression may indeed result from imbalance between regulatory pathways for APP expression (alterations in transcription factors expression/activation) or mutations in the APP regulatory region. The APP gene promoter has been cloned (Salbaum et al.,1988) and shown to display the characteristics of a “housekeeping gene” since it lacks a canonical TATA box, has a high GC content and transcription initiates at multiple sites. Furthermore it has been proved that this region promotes neuro-specific expression of a LacZ reporter gene in transgenic mice (Wirak et al., 1991). Several groups have proposed that the APP 5’ region contains consensus sequences for several known transcription factors. In particular binding sites for the following regulatory proteins have been described: AP1, AP4, SP1, Hox1.3, AP2, and Heat Shock Proteins (Lahiri et al. 1991; Goldgaber et al., 1989; Pollwein et al., 1991; Quitscke et al., 1992).