Title:Defective HIF Signaling Pathway and Brain Response to Hypoxia in Neurodegenerative Diseases: Not an “Iffy” Question!
Volume: 19
Issue: 38
Author(s): Sónia C. Correia, Cristina Carvalho, Susana Cardoso, Renato X. Santos, Ana I. Plácido, Emanuel Candeias, Ana I. Duarte and Paula I. Moreira
Affiliation:
Keywords:
Alzheimer’s disease, Amyotrophic lateral sclerosis, hypoxia, hypoxia-inducible factor, neurodegeneration, neuroprotection, Parkinson’s
disease
Abstract: Brain structural and functional integrity exquisitely relies on a regular supply of oxygen. In order to circumvent the potential
deleterious consequences of deficient oxygen availability, brain triggers endogenous adaptive and pro-survival mechanisms - a phenomenon
known as brain hypoxic tolerance. The highly conserved hypoxia-inducible family (HIF) of transcription factors is the “headquarter”
of the homeostatic response of the brain to hypoxia. HIF acts as a cellular oxygen sensor and regulates the expression of proteins involved
in a broad range of biological processes, including neurogenesis, angiogenesis, erythropoiesis, and glucose metabolism, and thus,
enables brain cells to survive in low-oxygen conditions. Hypoxia, as well as hypoxia-reoxygenation, is intimately implicated in the clinical
and pathological course of several neurodegenerative diseases. Thus, two major questions can arise: Is HIF signaling and brain response
to hypoxia compromised in neurodegenerative diseases? If so, are HIF stabilizers a possible therapeutic strategy to halt or prevent
the progression of neurodegenerative diseases? This review highlights the current knowledge pertaining the role of HIF on brain response
to hypoxia and its close association with the development of Alzheimer’s, and Parkinson’s disease and amyotrophic lateral sclerosis. Finally,
the potential therapeutic effects of HIF stabilizers (deferoxamine, clioquinol, M30, HLA20, DHB, FG0041, and VK-28) against the
symptomatic and neuropathological features of the abovementioned neurodegenerative diseases will be discussed.
