The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment

Abstract

Neuroinflammation and reactive oxygen species are thought to mediate the pathogenesis of Alzheimer's disease (AD), suggesting that mild cognitive impairment (MCI), a prodromal stage of AD, may be driven by similar insults. Several studies document that hypoxia-inducible factor 1 (HIF-1) is neuroprotective in the setting of neuronal insults, since this transcription factor drives the expression of critical genes that diminish neuronal cell death. HIF-1 facilitates glycolysis and glucose metabolism, thus helping to generate reductive equivalents of NADH/NADPH that counter oxidative stress. HIF-1 also improves cerebral blood flow which opposes the toxicity of hypoxia. Increased HIF-1 activity and/or expression of HIF-1 target genes, such as those involved in glycolysis or vascular flow, may be an early adaptation to the oxidative stressors that characterize MCI pathology. The molecular events that constitute this early adaptation are likely neuroprotective, and might mitigate cognitive decline or the onset of full-blown AD. On the other hand, prolonged or overwhelming stressors can convert HIF-1 into an activator of cell death through agents such as Bnip3, an event that is more likely to occur in late MCI or advanced Alzheimer's dementia.

Keywords: Alzheimer’s disease; Glucose; Glycolysis; Hypoxia-inducible factor 1; Inflammation; Mild cognitive impairment; Reactive oxygen species.

Fig. 1

Criteria for subject selection have been previously described (Iyalomhe et al. 2015). Platelets were obtained from 17 MCI subjects (mean of 69.1 years, standard deviation of 7.4 years) and 10 age-matched controls (mean 69.6 years, standard deviation of 4.1 years). Blood was collected using sterile techniques and stored in heparinized tubes. Samples were centrifuged at 500×g after which the top two-thirds of the top-most layer with platelet-rich plasma was gently pipetted into a separate tube, and the buffy coat layer containing the leukocyte population was removed and stored in aliquots at −80 °C. Approximately 50 ng of platelet RNA, isolated by Tri-Reagent (Molecular Research Center, Cincinnati, OH), was reverse transcribed using superscipt^® VILO™ Master Mix for qRT-PCR (Invitrogen, Carlsbad, CA), followed by qRT-PCR using TaqMan expression assay. Gene expression was normalized to HPRT1 (hypoxanthine phosphoribosyl transferase 1, 4333768F, Applied Biosystems). Relative gene expression was evaluated using Biogazelle QBasePLUS (Zwijanaarde, Belgium). Gene expression in MCI cases was expressed relative to cognitively normal, non-MCI controls. Errors are standard error measurements. A two-tailed t test was used to determine statistical significance for each gene. HK1 hexokinase 1, GLUT1 glucose transporter, isoform 1, VEGF-A vascular endothelial growth factor A, PDK1 pyruvate dehydrogenase kinase 1, BNIP3 BCL2/adenovirus E1B 19 kDa protein-interacting protein 3, BNIP3L BCL2/adenovirus E1B 19 kDa protein-interacting protein 3-like. ***p < 0.001, **p < 0.01, *p < 0.05

Fig. 2

Model of neuroprotective pathways in early MCI and cell death (in late AD) mediated by HIF-1