BACE2, as a novel APP theta-secretase, is not responsible for the pathogenesis of Alzheimer's disease in Down syndrome.
Amyloid beta protein (Abeta), the major component of neuritic plaques in Alzheimer's disease (AD), is derived from APP by sequential cleavages of beta- and gamma-secretases. Beta-site APP cleaving enzyme 1 (BACE1) is the major beta-secretase in vivo. Beta-site APP cleaving enzyme 2 (BACE2) is the homologue of BACE1. The majority of people with Down syndrome (DS), also called Trisomy 21 syndrome, will develop AD neuropathology after middle age. We and others have shown that APP C99, the major beta-secretase product, and Abeta are markedly increased in DS. Since BACE2 is located on chromosome 21, it is speculated that BACE2 may play a role in AD pathogenesis in DS. In this report we found that BACE2 cleaves APP at a novel theta site downstream of the alpha site, abolishing Abeta production. Overexpression of BACE2 by lentivirus markedly reduced Abeta production in primary neurons derived from Swedish mutant APP transgenic mice. Despite an extra copy of the BACE2 gene in DS and the increase of its transcription, BACE2 protein levels are unchanged. Our data clearly demonstrate that BACE2, as a novel theta-secretase to cleave APP within the Abeta domain, is not involved in the AD pathogenesis of DS patients; instead, therapeutic interventions that potentiate BACE2 may prevent AD pathogenesis.
Sun
Xiulian
X
Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
He
Guiqiong
G
Song
Weihong
W
D000544:Alzheimer Disease / Q000209:etiology*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D003001:Cloning, Molecular; D004314:Down Syndrome / Q000201:enzymology* / Q000235:genetics* / Q000503:physiopathology / Q000517:prevention & control; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005822:Genetic Vectors; D006801:Humans; D007668:Kidney; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D010957:Plasmids; D016133:Polymerase Chain Reaction; D011994:Recombinant Proteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic; D014162:Transfection
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases