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P4–104: Hypoxia facilitates Alzheimer's disease pathogenesis
Author(s) -
Song Weihong,
Sun Xiulian,
Zhou Weihui,
Qing Hong,
He Guiqiong,
Staufenbiel Matthias
Publication year - 2006
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2006.05.1843
Subject(s) - pathogenesis , hypoxia (environmental) , morris water navigation task , cerebral hypoperfusion , vascular dementia , ischemia , signal transduction , neurodegeneration , biology , cerebral hypoxia , medicine , pathology , neuroscience , microbiology and biotechnology , dementia , hippocampus , disease , perfusion , chemistry , organic chemistry , oxygen
Background: The pathogenesis of sporadic Alzheimer’s disease (AD) is largely unknown. Patients with stroke or cerebral infarction showed poorer cognitive performance and greater severity of clinical dementia. Vascular risk factors have been suggested to be associated with development of AD. A reduced cerebral perfusion is a common vascular component among AD risk factors. Hypoxia is a direct consequence of hypoperfusion. The hypoxia signal transduction pathway plays a major role in vascular development and ischemia, as well as neurodegeneration. Hypoxia inducible transcription factor (HIF1) is a central mediator of hypoxia signal transduction pathway through which cells in the brain respond to reduced oxygen tension. Objectives: To study if hypoxia is involved in AD pathogenesis. Methods: GSA assay was performed to identify the HRE in human and mouse BACE1 promoter. Immunohistochemical staining was used to check the plaques in the brains of mutant APP mice. The Morris water-maze test was used to test the hippocampus dependent spatial memory of APP23 mice after hypoxia treatment. Results: Hypoxia increased APP CTF production by increasing BACE1 expression and transcription in cells. BACE1 promoter contains a functional hypoxia responsive element (HRE). BACE1 expression was significantly upregulated in mice under hypoxia treatment. Furthermore, hypoxia condition deteriorated the memory impairment in mutant APP transgenic mice. Conclusion: Our results suggested that hypoxia facilitated AD pathogenesis and interventions that improve cerebral perfusion might benefit AD patients.