β-Amyloid Deposition and Functional Impairment in the Retina of the APPswe/PS1ΔE9 Transgenic Mouse Model of Alzheimer’s Disease

Abstract

Purpose To determine whether β-amyloid (Aβ) deposition affects the structure and function of the retina of the APPswe/PS1ΔE9 transgenic (tg) mouse model of Alzheimer’s disease. Methods Retinas from 12–19 month-old APPswe/PS1ΔE9 tg and age-matched non-transgenic (ntg) littermates were single or double stained with thioflavine-S and antibodies against Aβ, glial fibrilar acidic protein (GFAP), microglial marker F4/80, choline acetyltransferase (ChAT) and syntaxin 1. Quantification of thioflavine-S positive plaques and retinal layer thickness was analyzed semi-quantitatively, whereas microglial cell size and levels of F4/80 immunoreactivity were evaluated using a densitometry program. Scotopic electroretinogram (ERG) recording was used to investigate retinal physiology in these mice. Results Thioflavine-S positive plaques appeared at 12 months in the retinas of APPswe/PS1ΔE9 tg mice with the majority of plaques in the outer and inner plexiform (IPL) layers. Plaques were embedded in the IPL strata displaying syntaxin 1 and ChAT. The number and size of the plaques in the retina increased with age. Plaques appeared earlier and in greater numbers in females than in male tg littermate mice. Microglial activity was significantly increased in the retinas of APPswe/PS1ΔE9 tg mice. Although we did not detect neuronal degeneration in the retina, ERG recordings revealed a significant reduction in the amplitudes of a and b waves in aged APPswe/PS1ΔE9 tg compared to ntg littermates. Conclusions The present findings suggest that Aβ deposition disrupts retinal structure and may contribute to the visual deficits seen in aged APPswe/PS1ΔE9 tg mice. Whether Aβ is involved in other forms of age-related retinal dysfunction is unclear.

How strong is the relationship between glaucoma, the retinal nerve fibre layer, and neurodegenerative diseases such as Alzheimer’s disease and multiple sclerosis?

“…68 Furthermore, AB plaques, hyperphosphorylated tau, and retinal microvascular neuro-inflammation have been identified in the retinas of AD transgenic mice. 69,70 The main ocular biomarker investigated for AD has been thinning of the RNFL, as this may reflect both generalised neurodegeneration and local involvement, and this is reviewed below. Other ocular biomarkers investigated in AD include pupillary abnormalities: hypersensitivity to pupillary dilatation with cholinergic antagonist eye drops, [71][72][73] supersensitive pupillary response to cholinergic agonists, 74 and altered pupil flash responses.…”

“…101 Other studies of human tau transgenic mice 79 have reported accumulations of hyperphosphorylated transgenic tau in the RNFL and RGCs. Other transgenic mice models have suggested that the inner plexiform layer may be a more sensitive biomarker for detecting AD-related changes compared with RGCs, 70,80 making it difficult to draw firm conclusions. 102 However, both human and mouse studies suggest that AD-related pathology is seen in the retina.…”

Ocular Biomarkers for Early Detection of Alzheimer's Disease

“…Plaques and tangles have not been found in the human retina although Aβ has been isolated in aged human retinas [132]. Research on the retinas of AD transgenic mice has demonstrated Aβ plaques, hyperphosphorylated tau, increased microvascular deposition of Aβ and neuroinflammation [133][134]. Aβ immunotherapy in such transgenic mice has resulted in the clearance of retinal plaques but an increase in retinal amyloid angiopathy, identifying non-invasive retinal imaging as an alternative method for monitoring disease response to immunotherapy in these mice.…”

Ocular and Visual Manifestation of the Alzheimer’s Disease: A Literature Review, Part I: Animal Models and Human Pathology

“…Perez et al (5) found retinal Aβ plaques in the APPswe/PS1∆E9 transgenic mouse at the age of 12 -13 months associated with a significant increase in microglial activity. In the brain of these mice, Aβ plaques were found at the age of 2 -6 months.…”