VEGF Mediates ApoE4-Induced Neovascularization and Synaptic Pathology in the Choroid and Retina

Abstract

Apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD), is associated with neuronal and vascular impairments. Recent findings suggest that retina of apoE4 mice have synaptic and functional impairments. We presently investigated the effects of apoE4 on retinal and choroidal vasculature and the possible role of VEGF in these effects. There were no histological differences between the retinal and choroidal vasculatures of naïve apoE3 and apoE4 mice. In contrast, laserdriven choroidal injury induced higher levels of choroidal neovascularization (CNV) in apoE4 than in apoE3 mice. These effects were associated with an inflammatory response and with activation of the Muller cells and asrocytic markers gluthatione synthetase and GFAP, all of which were more pronounced in the apoE4 mice. CNV also induced a transient increase in the levels of the synaptic markers synaptophysin and PSD95 which were however similar in the apoE4 and apoE3 naive mice. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury. Retinal and choroidal VEGF and apoE levels were lower in naïve apoE4 than in corresponding apoE3 mice. In contrast, VEGF and apoE levels rose more pronouncedly following laser injury in the apoE4 than in apoE3 mice. Taken together, these findings suggest that the apoE4-induced retinal impairments, under basal conditions, may be related to reduced VEGF levels in the eyes of these mice. The hyper-neovascularization in the apoE4 mice might be driven by increased inflammation and the associated surge in VEGF following injury.

Ocular indicators of Alzheimer’s: exploring disease in the retina

“…Many of these findings mirror those recorded in AD patients (Table 3) [5, 6, 30, 39, 48, 52, 56, 72, 117, 123, 139, 148, 152, 154, 178, 184]. …”

“…Double nuclei and hypertrophy in RPE; increased ATP q release; Mitochondrial swelling, crista fragmentation and reduced complexity[75, 151, 152, 178, 184]RatTgF344-ADMouseApoE4Choroid. Increased neovascularization post-LDI r , decreased VEGF s , damage to neonatal vascular branching[6, 123] a Drosophila expressing amyloid β-protein precursor b Drosophila expressing β-secretase 1 c Model expressing drosophila presenilin-1 protein d Glass multiple reporter drosophila model expressing Aβ 42 e Drosophila expressing AβPP-like protein f Drosophila model expressing human Aβ 42 g Mouse overexpressing APP isoform 695 bearing Swedish double mutations K670 M/N671L h Mouse overexpressing APP SWE /PS1 ΔE9 or APP SWE /PS1 M146L i Mouse overexpressing APP SWE/FL/LON /PS1 M146L/L286V j Drosophila model expressing human AβPP k Mouse overexpressing APP SWE /PS1/TAU P301L l Apoliprotein E mouse model m Monocyte chemoattractant protein-1 n Astrocytes positive for glial fibrillary acidic protein o APP SWE /PS1 ΔE9 rat model p Octodon degus , WT rodent native to Chile showing symptoms of sporadic AD q Adenosine triphosphate, in APP SWE /PS1 ΔE9 model overexpressing ATP r Laser-driven injury s Vascular endothelial growth factor …”

“…In 2008, Ning and colleagues were the first to show that the accumulation of Aβ in the retina of Tg mice was associated with neurodegeneration and inflammation [139]. Since then, several reports of ocular inflammation in rodent models of AD have indicated increases in microgliosis, GFAP +  astrogliosis, retinal infiltration of lymphocytes and monocytes, and upregulation of MCP-1, among other markers in many layers of the retina and choroid [6, 48, 61, 117, 139, 152, 154, 178, 187]. …”

“…Structural changes in the retinas of AD animal models have included tight junction attenuation, variations in vascular branching and budding, and decreases in complexity, field area, and length of RGC dendrites (Table 3) [5, 6, 123, 148, 184]. While synaptic density in the Tg2576 mouse has shown no change in either pre- or post-synaptic markers [184], synaptic loss and impairment, typically related to cognitive deficits when observed in the brain, have been reported in the ApoE4 mouse retina [5, 6].…”

“…While synaptic density in the Tg2576 mouse has shown no change in either pre- or post-synaptic markers [184], synaptic loss and impairment, typically related to cognitive deficits when observed in the brain, have been reported in the ApoE4 mouse retina [5, 6]. Changes observed outside of ocular CNS tissues in rodent and fly eyes have included thinning of the choroid [178], as well as cellular swelling, organelle disorganization, and opacity in the lens [39, 56].…”