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Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion

Abstract

Hypoxic-ischemic injury has been linked with increased risk for developing Alzheimer’s disease (AD). The underlying mechanism of this association is poorly understood. Here, we report distinct roles for hypoxia-inducible factor-1α (Hif-1α) in the regulation of BACE1 and γ-secretase activity, two proteases involved in the production of amyloid-beta (Aβ). We have demonstrated that Hif-1α upregulates both BACE1 and γ-secretase activity for Aβ production in brain hypoxia-induced either by cerebral hypoperfusion or breathing 10% O2. Hif-1α binds to γ-secretase, which elevates the amount of active γ-secretase complex without affecting the level of individual subunits in hypoxic-ischemic mouse brains. Additionally, the expression of full length Hif-1α increases BACE1 and γ-secretase activity in primary neuronal culture, whereas a transcriptionally incompetent Hif-1α variant only activates γ-secretase. These findings indicate that Hif-1α transcriptionally upregulates BACE1 and nontranscriptionally activates γ-secretase for Aβ production in hypoxic-ischemic conditions. Consequently, Hif-1α-mediated Aβ production may be an adaptive response to hypoxic-ischemic injury, subsequently leading to increased risk for AD. Preventing the interaction of Hif-1α with γ-secretase may therefore be a promising therapeutic strategy for AD treatment.

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Fig. 1: Ischemic condition leads to an accumulation of Hif-1a in neurons in BCAS mice.
Fig. 2: γ-Secretase activity is upregulated in the ischemia mouse model.
Fig. 3: Ischemia hypoxia does change the expression and activity of ADAM-10 and ADAM-17.
Fig. 4: Hypoxia increases γ-secretase activity and BACE1 expression in mice.
Fig. 5: Non-transcriptional Hif-1α increases γ-secretase activity in primary neurons.
Fig. 6: Dual roles of Hif-1α activate γ-secretase and increase BACE1 through distinct mechanisms.

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Acknowledgements

This work is supported by the National Institutes of Health R01AG061350(YML), R01NS096275 (YML), RF1AG057593 (YML), 1R01NS100447 (CI), R01NS/HL37853 (CI) and the JPB Foundation (YML), Bilateral Research Joint Projects of Japan Society for the Promotion of Science, 120209939 (YH). Authors also acknowledge the MSK Cancer Center Support Grant/Core Grant (Grant P30 CA008748), Mr. William H. Goodwin and Mrs. Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC, and the William Randolph Hearst Fund in Experimental Therapeutics.

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CA, TL, YH. DC, GRF, LJ, CL, CLA,EW and LP conducted experiments and analyzed data. CA, TL, CI, and Y.-M.L. conceived the project and wrote the paper.

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Correspondence to Yue-Ming Li.

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LYM is a co-inventor of intellectual property (assay for gamma secretase activity and screening method for gamma secretase inhibitors) owned by MSKCC and licensed to Jiangsu Continental Medical Development. CI serves on the Scientific Advisory Board of Broadview Ventures.

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Alexander, C., Li, T., Hattori, Y. et al. Hypoxia Inducible Factor-1α binds and activates γ-secretase for Aβ production under hypoxia and cerebral hypoperfusion. Mol Psychiatry (2022). https://doi.org/10.1038/s41380-022-01676-7

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  • DOI: https://doi.org/10.1038/s41380-022-01676-7

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