Increased BACE1 maturation contributes to the pathogenesis of Alzheimer's disease in Down syndrome.
Almost all Down syndrome (DS) patients develop characteristic Alzheimer's disease (AD) neuropathology, including neuritic plaques and neurofibrillary tangles, after middle age. The mechanism underlying AD neuropathology in DS has been unknown. Abeta is the central component of neuritic plaques and is generated from APP by cleavage by the beta- and gamma-secretases. Here we show that beta-secretase activity is markedly elevated in DS. The ratio of mature to immature forms of BACE1 is altered in DS. DS has significantly higher levels of mature BACE1 proteins in Golgi than normal controls. Time-lapse live image analysis showed that BACE1 proteins were predominantly immobile in Golgi in DS cells, while they underwent normal trafficking in controls. Thus, overproduction of Abeta in DS is caused by abnormal BACE1 protein trafficking and maturation. Our results provide a novel molecular mechanism by which AD develops in DS and support the therapeutic potential of inhibiting BACE1 in AD and DS.
Sun
Xiulian
X
Department of Psychiatry, Brain Research Center, The University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC V6T 1Z3, Canada.
Tong
Yigang
Y
Qing
Hong
H
Chen
Chia-Hsiung
CH
Song
Weihong
W
D000544:Alzheimer Disease / Q000517:prevention & control*; D053829:Amyloid Precursor Protein Secretases; D016229:Amyloid beta-Peptides / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases; D002478:Cells, Cultured; D004314:Down Syndrome / Q000201:enzymology*; D010450:Endopeptidases / Q000235:genetics* / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D005333:Fetus; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology / Q000502:physiology; D006056:Golgi Apparatus / Q000201:enzymology; D006801:Humans; D010446:Peptide Fragments / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction
D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human