Hypoxia Facilitates Alzheimer's Disease Pathogenesis by Up-Regulating BACE1 Gene Expression

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 49; pp. 18727 - 18732
• Main Authors: Sun, Xiulian, He, Guiqiong, Qing, Hong, Zhou, Weihui, Dobie, Frederick, Cai, Fang, Staufenbiel, Matthias, Huang, L. Eric, Song, Weihong
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 05.12.2006; National Acad Sciences
• Subjects: Alzheimer Disease - genetics; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid plaque; Amyloid Precursor Protein Secretases - biosynthesis; Amyloid Precursor Protein Secretases - genetics; Animals; Aspartic Acid Endopeptidases - biosynthesis; Aspartic Acid Endopeptidases - genetics; Biological Sciences; Brain hypoxia; Cell Line; Cell Line, Tumor; Gene expression; Genes; HEK293 cells; Humans; Hypoxia; Hypoxia - genetics; Hypoxia - metabolism; Mice; Mice, Transgenic; Pathogenesis; Pathology; Plasmids; Transfection; Up-Regulation - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0606298103

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 β-site β-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 hypoxiaresponsive element in the BACE1 gene promoter. Hypoxia up-regulated β-secretase cleavage of APP and amyloid-β protein (AP) production by increasing BACE1 gene transcription and expression both in vitro and in vivo. Hypoxia treatment markedly increased Aβ 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.