Oxygen Sensing and Signaling in Alzheimer's Disease: A Breathtaking Story!

Oxygen sensing and homeostasis is indispensable for the maintenance of brain structural and functional integrity. Under low-oxygen tension, the non-diseased brain has the ability to cope with hypoxia by triggering a homeostatic response governed by the highly conserved hypoxia-inducible family (HIF) of transcription factors. With the advent of advanced neuroimaging tools, it is now recognized that cerebral hypoperfusion, and consequently hypoxia, is a consistent feature along the Alzheimer's disease (AD) continuum. Of note, the reduction in cerebral blood flow and tissue oxygenation detected during the prodromal phases of AD, drastically aggravates as disease progresses. Within this scenario a fundamental question arises: How HIF-driven homeostatic brain response to hypoxia "behaves" during the AD continuum? In this sense, the present review is aimed to critically discuss and summarize the current knowledge regarding the involvement of hypoxia and HIF signaling in the onset and progression of AD pathology. Importantly, the promises and challenges of non-pharmacological and pharmacological strategies aimed to target hypoxia will be discussed as a new "hope" to prevent and/or postpone the neurodegenerative events that occur in the AD brain.