title: The effects of the apoE4 genotype on the developing mouse retina.
abstract: Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. The retina, which is as an extension of the central nervous system (CNS), is a particularly suitable model for studying developmental and functional aspects of the neuronal and vascular systems. This study investigates the apoE4-dependent developmental effects on the retinal vasculature and neuronal systems and on the levels of apoE and the vascular endothelial growth factor (VEGF) in the retina. This was performed utilizing retinas of 4, 7, 12, and of 120-day-old human-apoE4-targeted replacement mice and of corresponding mice that express the AD benign isoform, apoE3. The results obtained revealed retinal vascular pathology in the apoE4 mice, which started on the early post-natal days. This includes transient increase in vascular branching, and vascular buds which are round vascular elements representing sprouting or retracting vessels. These effects peaked and ended during the neonatal period. Examination of the synaptic system utilizing the pre-synaptic marker synaptophysin revealed a significant decrease of retinal synaptic density in the apoE4 mice, which was detectable by post-natal day 12 (P12). These morphological changes are associated with neonatal age-dependent elevation in the apoE levels in both apoE3 and apoE4 retinas which is more profound in the apoE4 mice and a corresponding increase in VEGF levels, which is less profound in the apoE4 mice. Additionally, we observed lower levels of retinal VEGF in the apoE4 mice compared to the apoE3 mice retinas on P12. These results show that apoE4 has a transient vascular effect during retinal development that ends in the neonatal period, which is accompanied by a synaptic effect that begins at the end of the neonatal period. These findings show that the apoE4 genotype can have distinct developmental effects on both the retinal vasculature and on neurons and suggest that the vascular effects of apoE4 may be related to reduced levels of VEGF.
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel; Department of Ophthalmology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Idit
authors.initials: I
authors.lastname: Maharshak
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Shiran
authors.initials: S
authors.lastname: Salomon-Zimri
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ran
authors.initials: R
authors.lastname: Antes
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Ori
authors.initials: O
authors.lastname: Liraz
authors.affiliation: Laboratory of Eye Research, Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Nisgav
authors.affiliation: Laboratory of Eye Research, Felsenstein Medical Research Center, Rabin Medical Center, Petach Tikva, Israel.
authors.forename: Tami
authors.initials: T
authors.lastname: Livnat
authors.affiliation: Department of Ophthalmology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Department of Ophthalmology, Rabin Medical Center, Petach Tikva, Israel.
authors.forename: Dov
authors.initials: D
authors.lastname: Weinberger
authors.affiliation: Division of Neurology, Duke University Medical Center, Department of Medicine, Durham, NC, USA.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Colton
authors.affiliation: Department of Ophthalmology, Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Goldschleger Eye Research Institute, Tel-Aviv University, Tel-Hashomer, Israel.
authors.forename: Arieh S
authors.initials: AS
authors.lastname: Solomon
authors.affiliation: Department of Neurobiology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel. Electronic address: dmichael@post.tau.ac.il.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Michaelson
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D053327:Apolipoprotein E4 / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D005838:Genotype; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018613:Microscopy, Confocal; D023421:Models, Animal; D012160:Retina / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism; D012171:Retinal Vessels / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism
chemical_list: D053327:Apolipoprotein E4
keywords: Apolipoprotein E4 (apoE4); Retina; Targeted replacement mice; Vascular endothelial growth factor (VEGF); Vasculature