Acute and Chronic Sustained Hypoxia Do Not Substantially Regulate Amyloid-β 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-β peptide accumulation through various molecular mechanisms including the up-regulation of the amyloid-β precursor protein, the β-secretase Bace1, or the γγ-secretase complex components, as well as the down-regulation of Aβ-degrading enzymes.

OBJECTIVES:

To investigate the effects of acute and chronic sustained hypoxia in Aβ 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 Aβ-related genes were measured by quantitative real-time PCR, whereas levels of Bace1 protein, full length AβPP, 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 Aβ40, Aβ42, full length AβPP, and soluble AβPPα (sAβPPα) were measured by ELISA or WB.

RESULTS:

Hypoxia (either acute or chronic sustained) did not impact the transcription of any of the Aβ-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 AβPP or a decreased C99/C83 ratio. Chronic sustained hypoxia did not significantly alter the levels of Bace1, full length AβPP or the C99/C83 ratio. Last, chronic sustained hypoxia did not significantly change the levels of Aβ40, Aβ42, full length AβPP, or sAβPPα in either young or aged APP/PS1 mice.

DISCUSSION:

Our results argue against a hypoxia-induced shift of AβPP proteolysis from the non-amyloidogenic to the amyloidogenic pathways. We discuss the possible methodological caveats of previous in vivo studies.

• Authors: Alberto Serrano-Pozo, Manuel A Sánchez-García, Antonio Heras-Garvín, Rosana March-Díaz, Victoria Navarro, Marisa Vizuete, José López-Barneo, Javier Vitorica, Alberto Pascual
• Journal: PloS one (PLoS One) Vol. 12 Issue 1 Pg. e0170345 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28099462 (Publication Type: Journal Article)

Chemical References

• Amyloid beta-Peptides
• Hif1a protein, mouse
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• Amyloid Precursor Protein Secretases
• Aspartic Acid Endopeptidases
• Bace1 protein, mouse

Topics

• Alzheimer Disease (pathology)
• Amyloid Precursor Protein Secretases (metabolism)
• Amyloid beta-Peptides (biosynthesis, genetics)
• Animals
• Aspartic Acid Endopeptidases (metabolism)
• Brain (metabolism)
• Enzyme-Linked Immunosorbent Assay
• Hypoxia (pathology)
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• RNA, Messenger (genetics)
• Real-Time Polymerase Chain Reaction
• Transcription, Genetic (genetics)