Cerebral microvasculature abnormalities, such as degeneration of the capillary endothelium, are implicated in the genesis of Alzheimer's disease (AD) neuropathology. In addition, ischemic lesions that cause neuronal damage are often found in AD brains. The brain responds to ischemia by stimulating tissue neovascularization via sprouting angiogenesis; impairment of this function renders the brain vulnerable to the insult. It has been hypothesized that decreased angiogenesis in AD leads to insufficient blood flow and neuronal dysfunction in affected areas. The EphB4/ephrinB2 (efnB2) ligand-receptor system is known to regulate brain angiogenesis in response to ischemia. We present evidence that Presnilin1 (PS1), an important factor in familial AD (FAD), regulates angiogenic functions of EphB4/efnB2 such as stimulation of VE-cadherin angiogenic complexes in brain endothelial cells (ECs). We also found that this function is impaired by PS1 FAD mutants. In addition, we found that ischemia stimulates formation of the same angiogenic complexes in the brain and that this function is attenuated by PS1 FAD mutants together with ischemia-induced neovascularization and cerebral blood flow while neuronal death is increased. We also found that PS1 FAD mutants decrease the ?-secretase processing of efnB2 and production of the angiogenic peptide efnB2/CTF2 thus impairing the response of brain ECs to angiogenic factors. Together, our data support the hypothesis that PS1 FAD mutants inhibit ischemia-induced angiogenic functions of ECs by decreasing the ?-secretase processing of efnB2 and impairing the EphB4/efnB2 signaling, thus decreasing neovascularization in the adult brain and leading to increased vulnerability to this toxic insult and neuronal death. In this application we examine the roles of PS1 FAD mutants and ?-secretase on ischemia-induced angiogenic complexes, blood flow, angiogenesis and neuronal death. In addition, we propose to test a small peptide, which derives from the proteolytic processing of efnB2 by ?-secretase and which we found to rescue angiogenic functions of PS1 FAD ECs, for its pro-angiogenic and neuroprotective functions in brains expressing FAD mutants. In addition we aim to search for novel ischemia-induced angiogenic pathways that are impaired by PS1 FAD mutants and examine whether VE-cadherin angiogenic complexes and angiogenic protein expression are impaired in brains of human PS1 FAD and AD patients.
Alzheimer Disease (AD) brains show severe defects in the vascular system, causing ischemia, a condition known to induce reparative angiogenesis, and neuronal dysfunction. There is also evidence that reparative angiogenesis is impaired in AD brains. We discovered that a mouse model expressing Presenilin1 Familial AD (FAD) mutant shows decreased ischemia-induced angiogenesis and angiogenic protein complexes and increased neuronal death in the brain. Furthermore, endothelial cells (ECs) of these mutant brains have decreased response to angiogenic factor EphB4. Successful completion of this project will identify novel molecular mechanisms of toxicity-induced brain angiogenesis and will test whether these mechanisms are impaired in AD. In addition, the project will test whether a novel pro-angiogenic peptide that rescues angiogenic functions of FAD ECs, promotes brain neovascularization and increases neuronal survival against toxic insults.
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