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

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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.

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Acknowledgements

This work was supported by Grants R01 5R01AG31517-2 and 5R01AG045058-01A1 from the National Institute on Aging at the National Institutes of Health (NIH) to Obisesan TO and in part by Grant # UL1TR000101 from the National Center for Advancing Translational Sciences/NIH through the Clinical and Translational Science Award Program (CTSA). The funders had no role in the design, data collection, and interpretation of this study.

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  1. Geriatrics Division, Department of Medicine, Howard University Hospital, 2041 Georgia Ave NW, Washington, DC, 20060, USA

    Osigbemhe Iyalomhe, Ngozi Enwerem, Yuanxiu Chen, Monica O. Adedeji, Joanne Allard, Oyonumo Ntekim, Sheree Johnson, Philip Kurian & Thomas O. Obisesan

  2. Department of Hematology/BMT, University of Utah School of Medicine, 30 N Medical Dr, Salt Lake City, UT, 84132, USA

    Sabina Swierczek

  3. Division of Endovascular Surgery, Howard University Hospital, 2041 Georgia Ave NW, Washington, DC, 20060, USA

    Kakra Hughes

  4. Human Genome Center, Howard University, 2041 Georgia Ave NW, Washington, DC, 20060, USA

    Philip Kurian

  5. Howard University Clinical Research Unit (GHUCCTS CTSA), 2041 Georgia Ave, NW, Washington, DC, 20060, USA

    Thomas O. Obisesan

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Iyalomhe, O., Swierczek, S., Enwerem, N. et al. The Role of Hypoxia-Inducible Factor 1 in Mild Cognitive Impairment. Cell Mol Neurobiol 37, 969–977 (2017). https://doi.org/10.1007/s10571-016-0440-6

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