Prion protein expression alters APP cleavage without interaction with BACE-1.
The prion protein (PrP) and the beta-site amyloid precursor protein (APP) cleaving enzyme 1 (BACE-1) are both copper binding proteins, but are associated with two separate neurodegenerative diseases. The role of BACE-1 in the formation of beta-amyloid has made it a major target in attempts to reduce the formation of beta-amyloid in Alzheimer's diseases. However, the suggestion that PrP, normally associated with prion diseases, binds to BACE-1 and reduces its activity has led to the suggestion that the study of this interaction could be of considerable importance to Alzheimer's disease. We therefore undertook to investigate the possible interaction of these two proteins physically and at the level of transcription, translation and APP cleavage. Our findings suggest that mature PrP and BACE-1 do not physically interact, but that altered PrP expression results in altered BACE-1 protein expression and promoter activity. Additionally, overexpression of PrP results in increased cleavage of APP in contrast to previous datas suggesting a reduction. Our findings suggest that any relation between PrP and BACE-1 is indirect. Altered expression of PrP causes changes in the expression of many other proteins which may be as a result of altered copper metabolism.
Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK.
Patrick C
PC
McHugh
Josephine A
JA
Wright
Robert J
RJ
Williams
David R
DR
Brown
D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008822:Mice, Transgenic; D000072002:Prion Proteins; D011328:Prions / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000502:physiology; D051381:Rats
D016564:Amyloid beta-Protein Precursor; D000072002:Prion Proteins; D011328:Prions; C512657:Prnp protein, mouse; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human