Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-ß Peptide Generation In Vivo.

ABSTRACT

BACKGROUND: Recent epidemiological evidence has linked hypoxia with the development of Alzheimer disease (AD). A number of in vitro and in vivo studies have reported that hypoxia can induce amyloid-ß peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-ß precursor protein, the ß-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aß-degrading enzymes. OBJECTIVES: To investigate the effects of acute and chronic sustained hypoxia in Aß generation in vivo. METHODS: 2-3 month-old C57/Bl6J wild-type mice were exposed to either normoxia (21% O2) or hypoxia (9% O2) for either 4 to 72 h (acute) or 21-30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of Aß-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AßPP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 transgenic mice were subjected to 9% O2 for 21 days and levels of Aß40, Aß42, full length AßPP, and soluble AßPPα (sAßPPα) were measured by ELISA or WB. RESULTS: Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aß-related genes in young wild-type mice. A significant reduction of Bace1 protein level was noted with acute hypoxia for 16 h but did not correlate with an increased level of full length AßPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AßPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aß40, Aß42, full length AßPP, or sAßPPα in either young or aged APP/PS1 mice. DISCUSSION: Our results argue against a hypoxia-induced shift of AßPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies.