THE UPSTREAM STIMULATORY FACTOR FUNCTIONALLY INTERACTS WITH THE ALZHEIMER AMYLOID BETA-PROTEIN PRECURSOR GENE

The amyloid beta-protein precursor (APP) gives rise to the A beta pept ide, which is deposited in the brains of patients with Alzheimer's dis ease and Down's syndrome. Overexpression of APP due to a third copy of the gene appears to correlate with very early onset of Alzheimer's di sease neuropathology in the brains of Down's syndrome patients. Thus, the identification of the factors involved with transcriptional regula tion of the APP gene could provide critical clues regarding the events leading to the formation of amyloid deposits. An overlapping AP-1/AP- 4 site in the proximal promoter region (-39 to -49) of the human APP g ene has previously been shown to increase transcription 4-fold. Here w e identify the factor binding specifically to this element as the upst ream stimulatory factor USF, unrelated to the c-fos/c-jun complex or t he AP-4 factor. In vitro transcription and co-transfection studies sho w that USF activates transcription from the APP promoter and that the AP-1/AP-4 element participates in this activation. Modulation of APP e xpression via regulation of USF could potentially ameliorate the produ ction of Alzheimer-augmented beta-amyloid.