ApoE4 Induces Synaptic and ERG Impairments in the Retina of Young Targeted Replacement ApoE4 Mice

Abstract

The vertebrate retina, which is part of the central nervous system, is a window into the brain. The present study investigated the extent to which the retina can be used as a model for studying the pathological effects of apolipoprotein E4 (apoE4), the most prevalent genetic risk factor for Alzheimer's disease (AD). Immunohistochemical studies of retinas from young (4 months old) apoE4-targeted replacement mice and from corresponding mice which express the AD benign apoE3 allele, revealed that the density of the perikarya of the different classes of retinal neurons was not affected by apoE4. In contrast, the synaptic density of the retinal synaptic layers, which was assessed immunohistochemically and by immunoblot experiments, was significantly lower in the apoE4 than in the apoE3 mice. This was associated with reduced levels of the presynaptic vesicular glutamatergic transporter, VGluT1, but not of either the GABAergic vesicular transporter, VGaT, or the cholinergic vesicular transporter, VAChT, suggesting that the glutamatergic nerve terminals are preferentially affected by apoE4. In contrast, the post synaptic scaffold proteins PSD-95 and Gephyrin, which reside in excitatory and inhibitory synapses, respectively, were both elevated, and their ratio was not affected by apoE4. Electroretinogram (ERG) recordings revealed significant attenuation of mixed rod-cone responses in dark-adapted eyes of apoE4 mice. These findings suggest that the reduced ERG response in the apoE4 mice may be related to the observed decrease in the retinal nerve terminals and that the retina could be used as a novel model for non-invasive monitoring of the effects of apoE4 on the CNS.

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]. …”

“…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].…”

Glia-Mediated Retinal Neuroinflammation as a Biomarker in Alzheimer's Disease

“…Furthermore, assessment of the retinal function by electroretinography of a transgenic mouse model of AD revealed significant alterations in the response of photoreceptors [63]. However, this issue is controversial because it is claimed that these alterations are not specific of AD and are often related with normal aging or even with AD-associated changes in the visual cortex (reviewed by Tzekov and Mullan [64] and Chang et al [65]).…”

Apolipoprotein E2 and E3, but Not E4, Promote Retinal Pathologic Neovascularization

“…Apolipoprotein E (ApoE) is a 34-kDa glycoprotein and exists in three common isoforms: ApoE2, ApoE3, and ApoE4. 16 The ApoEs are produced mainly in the liver and serve as ligands for the LDL receptor and its family members. The ApoEs are involved in lipid metabolism.…”