title: Reversal of ApoE4-Driven Brain Pathology by Vascular Endothelial Growth Factor Treatment.
abstract: Apolipoprotein E4 (ApoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with increased neurodegeneration and vascular impairments. Vascular endothelial growth factor (VEGF), originally described as a key angiogenic factor, has recently been shown to play a crucial role in the nervous system. The objective of this research is to examine the role of VEGF in mediating the apoE4-driven pathologies. We show that hippocampal VEGF levels are lower in apoE4 targeted replacement mice compared to the corresponding apoE3 mice. This effect was accompanied by a specific decrease in both VEGF receptor-2 and HIF1-α. We next set to examine whether upregulation of VEGF can reverse apoE4-driven pathologies, namely the accumulation of hyperphosphorylated tau (AT8) and Aβ42, and reduced levels of the pre-synaptic marker, VGluT1, and of the ApoE receptor, ApoER2. This was first performed utilizing intra-hippocampal injection of VEGF-expressing-lentivirus (LV-VEGF). This revealed that LV-VEGF treatment reversed the apoE4-driven cognitive deficits and synaptic pathologies. The levels of Aβ42 and AT8, however, were increased in apoE3 mice, masking any potential effects of this treatment on the apoE4 mice. Follow-up experiments utilizing VEGF-expressing adeno-associated-virus (AAV-VEGF), which expresses VEGF specifically under the GFAP astrocytic promoter, prevented this effects on apoE3 mice, and reversed the apoE4-related increase in Aβ42 and AT8. Taken together, these results suggest that apoE4-driven pathologies are mediated by a VEGF-dependent pathway, resulting in cognitive impairments and brain pathology. These animal model findings suggest that the VEGF system is a promising target for the treatment of apoE4 carriers in AD.
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Salomon-Zimri
authors.affiliation: Sackler School of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Micaela Johanna
authors.initials: MJ
authors.lastname: Glat
authors.affiliation: Sackler School of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Barhum
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ishai
authors.initials: I
authors.lastname: Luz
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Anat
authors.initials: A
authors.lastname: Boehm-Cagan
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Liraz
authors.affiliation: Sackler School of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Tali
authors.initials: T
authors.lastname: Ben-Zur
authors.affiliation: Sackler School of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Daniel
authors.initials: D
authors.lastname: Offen
authors.affiliation: Department of Neurobiology, The George S. Wise Faculty of Life Sciences, The Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Michaelson
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D005822:Genetic Vectors; D006624:Hippocampus / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D008297:Male; D008569:Memory Disorders / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D016875:tau Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D026502:LDL-Receptor Related Proteins; C558298:Mapt protein, mouse; D010446:Peptide Fragments; C493465:Slc17a7 protein, mouse; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D050598:Vesicular Glutamate Transport Protein 1; C075222:amyloid beta-protein (1-42); C098773:low density lipoprotein receptor-related protein 8; D016875:tau Proteins; C467480:vascular endothelial growth factor A, mouse; C000592875:Kdr protein, mouse; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: Alzheimer’s disease; Morris water maze; apolipoprotein E4; behavior; hippocampus; lentivirus; object recognition; targeted replacement mice; vascular endothelial growth factor