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

作者：Serrano Pozo Alberto^*; Sanchez Garcia Manuel A; Heras Garvin Antonio; March Diaz Rosana; Navarro Victoria; Vizuete Marisa; Lopez Barneo Jose; Vitorica Javier; Pascual Alberto

来源：PLos One, 2017, 12(1): e0170345.

DOI：10.1371/journal.pone.0170345

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-beta peptide accumulation through various molecular mechanisms including the up regulation of the amyloid-beta precursor protein, the beta-secretase Bace1, or the Upsilon-secretase complex components, as well as the down-regulation of A beta-degrading enzymes.
Objectives
To investigate the effects of acute and chronic sustained hypoxia in A beta generation in vivo.
Methods
2-3 month-old C57/BI6J wild-type mice were exposed to either normoxia (21% 02) or hypoxia (9% 02) for either 4 to 72 h (acute) or 21-30 days (chronic sustained) in a hermetic chamber. Brain mRNA levels of A beta-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length A beta PP, and its C-terminal fragments (C99/C88 ratio) were measured by Western blot. In addition, 8 and 14-month-old APP/PS1 trans genic mice were subjected to 9% 02 for 21 days and levels of A beta(40), A beta(42), full length A beta PP, and soluble A beta PP alpha (sA beta PP alpha) were measured by ELISA or WB.
Results
Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the A beta 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 A beta PP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length A beta PP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of A beta(40), A beta(42), full length ApPP, or sA beta PP alpha in either young or aged APP/PS1 mice.
Discussion
Our results argue against a hypoxia-induced shift of A beta PP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies.

• 出版日期2017-1-18