Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression.
The molecular mechanism underlying the pathogenesis of the majority of cases of sporadic Alzheimer's disease (AD) is unknown. A history of stroke was found to be associated with development of some AD cases, especially in the presence of vascular risk factors. Reduced cerebral perfusion is a common vascular component among AD risk factors, and hypoxia is a direct consequence of hypoperfusion. Previously we showed that expression of the beta-site beta-amyloid precursor protein (APP) cleavage enzyme 1 (BACE1) gene BACE1 is tightly controlled at both the transcriptional and translational levels and that increased BACE1 maturation contributes to the AD pathogenesis in Down's syndrome. Here we have identified a functional hypoxia-responsive element in the BACE1 gene promoter. Hypoxia up-regulated beta-secretase cleavage of APP and amyloid-beta protein (Abeta) production by increasing BACE1 gene transcription and expression both in vitro and in vivo. Hypoxia treatment markedly increased Abeta deposition and neuritic plaque formation and potentiated the memory deficit in Swedish mutant APP transgenic mice. Taken together, our results clearly demonstrate that hypoxia can facilitate AD pathogenesis, and they provide a molecular mechanism linking vascular factors to AD. Our study suggests that interventions to improve cerebral perfusion may benefit AD patients.
Sun
Xiulian
X
Department of Psychiatry, Brain Research Center, and Graduate Program in Neuroscience, University of British Columbia, 2255 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3.
He
Guiqiong
G
Qing
Hong
H
Zhou
Weihui
W
Dobie
Frederick
F
Cai
Fang
F
Staufenbiel
Matthias
M
Huang
L Eric
LE
Song
Weihong
W
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D053829:Amyloid Precursor Protein Secretases / Q000096:biosynthesis* / Q000235:genetics*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000096:biosynthesis* / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D015854:Up-Regulation / Q000502:physiology*
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse