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PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival

Molecular Psychiatry volume 26, pages 1996–2012 (2021)Cite this article

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Abstract

Microvascular pathology and ischemic lesions contribute substantially to neuronal dysfunction and loss that lead to Alzheimer disease (AD). To facilitate recovery, the brain stimulates neovascularization of damaged tissue via sprouting angiogenesis, a process regulated by endothelial cell (EC) sprouting and the EphB4/ephrinB2 system. Here, we show that in cultures of brain ECs, EphB4 stimulates the VE-cadherin/Rok-α angiogenic complexes known to mediate sprouting angiogenesis. Importantly, brain EC cultures expressing PS1 FAD mutants decrease the EphB4-stimulated γ-secretase cleavage of ephrinB2 and reduce production of the angiogenic peptide ephrinB2/CTF2, the VE-cadherin angiogenic complexes and EC sprouting and tube formation. These data suggest that FAD mutants may attenuate ischemia-induced brain angiogenesis. Supporting this hypothesis, ischemia-induced VE-cadherin angiogenic complexes, levels of neoangiogenesis marker Endoglin, vascular density, and cerebral blood flow recovery, are all decreased in brains of mouse models expressing PS1 FAD mutants. Ischemia-induced brain neuronal death and cognitive deficits also increase in these mice. Furthermore, a small peptide comprising the C-terminal sequence of peptide ephrinB2/CTF2 rescues angiogenic functions of brain ECs expressing PS1 FAD mutants. Together, our data show that PS1 FAD mutations impede the EphB4/ephrinB2-mediated angiogenic functions of ECs and impair brain neovascularization, neuronal survival and cognitive recovery following ischemia. Furthermore, our data reveal a novel brain angiogenic mechanism targeted by PS1 FAD mutants and a potential therapeutic target for ischemia-induced neurodegeneration. Importantly, FAD mutant effects occur in absence of neuropathological hallmarks of AD, supporting that such hallmarks may form downstream of mutant effects on neoangiogenesis and neuronal survival.

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Fig. 1: PS1 FAD mutants M146V and I213T inhibit the EphB4-Fc-induced, sprouting, tube formation and angiogenic complexes of pCECs.
Fig. 2: PS1 FAD mutants M146V and I213T inhibit the EphB4-Fc-induced processing of efnB2 by PS1/γ-secretase.
Fig. 3: PS1 M146V increases duration of brain edema following MCAO.
Fig. 4: PS1 M146V decreases MCAO-induced angiogenesis, CBF restoration and NeuN-positive neurons and increases MCAO-induced behavioral deficits.
Fig. 5: PS1 FAD mutants inhibit ischemia-induced angiogenic complexes in brain.

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Acknowledgements

We thank Ms. Bridget Wicinski for help with stereologic design and microscopy analyses. We also thank Dr. Elodie Drapeau from department of Psychiatry at the Icahn School of Medicine at Mount Sinai for her assistance in behavioral tests. This work was supported by NIH Grants 2R01-NS047229, P50AG05138, and AG-008200.

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  1. These authors contributed equally: YoneJung Yoon, Georgios Voloudakis

Authors and Affiliations

  1. Center for Molecular Biology and Genetics of Neurodegeneration, Departments of Psychiatry and Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    YoneJung Yoon, Georgios Voloudakis, Nathan Doran, Emily Zhang, Christina Dimovasili, Nikolaos K. Robakis & Anastasios Georgakopoulos

  2. Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    YoneJung Yoon

  3. Pamela Sklar Division of Psychiatric Genomics, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Georgios Voloudakis & Zhiping Shao

  4. Department of Physiology, Spinal Cord and Brain Injury Research Center, University of Kentucky, Lexington, KY, 40536, USA

    Lei Chen

  5. Departments of Bioengineering and Applied Physics, Stanford University and Chan Zuckerberg Biohub, Stanford, CA, 94305, USA

    Spyros Darmanis

  6. Department of Radiology, Neuroscience and Psychiatry Translational and Molecular Imaging Institute at Mount Sinai, New York, NY, USA

    Cheuk Tang & Jun Tang

  7. Department of Radiology, Translational and Molecular Imaging Institute at Mount Sinai, New York, NY, USA

    Victoria X. Wang

  8. Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Patrick R. Hof

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  1. YoneJung Yoon
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Yoon, Y., Voloudakis, G., Doran, N. et al. PS1 FAD mutants decrease ephrinB2-regulated angiogenic functions, ischemia-induced brain neovascularization and neuronal survival. Mol Psychiatry 26, 1996–2012 (2021). https://doi.org/10.1038/s41380-020-0812-7

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  • DOI: https://doi.org/10.1038/s41380-020-0812-7

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