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

YoneJung Yoon1,2, Georgios Voloudakis1,3, Nathan Doran1

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|June 17, 2020
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Summary
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Familial Alzheimer disease (AD) mutations impair brain blood vessel repair by disrupting endothelial cell (EC) sprouting and neovascularization, leading to neuronal death and cognitive decline after ischemia.

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Area of Science:

  • Neuroscience
  • Vascular Biology
  • Molecular Biology

Background:

  • Microvascular pathology and ischemic lesions are key contributors to neuronal dysfunction and loss in Alzheimer disease (AD).
  • The brain initiates neovascularization through sprouting angiogenesis, regulated by endothelial cells (ECs) and the EphB4/ephrinB2 system, to repair damaged tissue.
  • Understanding the molecular mechanisms underlying impaired angiogenesis in AD is crucial for developing therapeutic strategies.

Purpose of the Study:

  • To investigate the impact of Presenilin 1 (PS1) familial AD (FAD) mutations on EC angiogenic functions and brain neovascularization following ischemia.
  • To elucidate the role of the EphB4/ephrinB2 signaling pathway in PS1 FAD mutant-mediated impairment of angiogenesis.
  • To explore the therapeutic potential of targeting the ephrinB2 C-terminal peptide in mitigating FAD mutant-induced neurodegeneration.

Main Methods:

  • Utilized primary brain endothelial cell (EC) cultures expressing PS1 FAD mutants.
  • Assessed EphB4-stimulated γ-secretase cleavage of ephrinB2 and production of the angiogenic peptide ephrinB2/CTF2.
  • Evaluated EC sprouting, tube formation, VE-cadherin complex formation, and neoangiogenesis markers in PS1 FAD mutant mouse models after induced ischemia.
  • Administered a C-terminal ephrinB2 peptide to rescue angiogenic functions.

Main Results:

  • PS1 FAD mutants reduced EphB4-stimulated ephrinB2 cleavage and production of the angiogenic peptide ephrinB2/CTF2.
  • ECs expressing PS1 FAD mutants exhibited impaired sprouting, tube formation, and VE-cadherin complex assembly.
  • PS1 FAD mutant mice showed decreased ischemia-induced angiogenesis, vascular density, cerebral blood flow recovery, increased neuronal death, and cognitive deficits.
  • Treatment with an ephrinB2/CTF2 peptide restored angiogenic functions in PS1 FAD mutant ECs.

Conclusions:

  • PS1 FAD mutations disrupt the EphB4/ephrinB2-mediated angiogenic pathway, impairing brain neovascularization and recovery after ischemia.
  • These mutations lead to neuronal survival deficits and cognitive impairment independent of classical AD neuropathology.
  • Targeting the ephrinB2 C-terminal peptide represents a novel therapeutic strategy for ischemia-induced neurodegeneration in the context of FAD.