The AppNL-G-F mouse retina is a site for preclinical Alzheimer’s disease diagnosis and research

Abstract

In this study, we report the results of a comprehensive phenotyping of the retina of the AppNL-G-F mouse. We demonstrate that soluble Aβ accumulation is present in the retina of these mice early in life and progresses to Aβ plaque formation by midlife. This rising Aβ burden coincides with local microglia reactivity, astrogliosis, and abnormalities in retinal vein morphology. Electrophysiological recordings revealed signs of neuronal dysfunction yet no overt neurodegeneration was observed and visual performance outcomes were unaffected in the AppNL-G-F mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal Aβ, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the AppNL-G-F retina mimics the early, preclinical stages of AD, and, together with retinal imaging techniques, offers unique opportunities for drug discovery and fundamental research into preclinical AD.

Retinal and Brain Microglia in Multiple Sclerosis and Neurodegeneration

“…These activated microglia were also found to co-localise with Aß aggregates, and as Aß accumulated, microglial cell death was observed [103]. Similarly, Aß plaques were found surrounded by retinal microglia with a large cell body and fewer and thicker ramifications, suggesting activated microglia observations could be seen in the AD modelled retina [100][101][102]. Some sources have found activated retinal microglia in 3× transgenic AD mice as young as 5 postnatal weeks old, suggesting an initial microglial response in AD pathology [102].…”

“…AD is the most common cause of dementia. It is characterised by the progressive loss of neurons as a result of the build-up of extracellular amyloid-beta (Aß) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins [99][100][101]. By the time the first cognitive symptoms start to appear, roughly 20 years of irreversible neurodegeneration would already have occurred [100].…”

“…It is characterised by the progressive loss of neurons as a result of the build-up of extracellular amyloid-beta (Aß) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau proteins [99][100][101]. By the time the first cognitive symptoms start to appear, roughly 20 years of irreversible neurodegeneration would already have occurred [100]. Although the exact pathogenesis is still unknown, microglial activation in the brain and retina has been associated with AD pathology [4,13,21,[99][100][101][102][103].…”

“…By the time the first cognitive symptoms start to appear, roughly 20 years of irreversible neurodegeneration would already have occurred [100]. Although the exact pathogenesis is still unknown, microglial activation in the brain and retina has been associated with AD pathology [4,13,21,[99][100][101][102][103]. This highlights the unmet need for earlier detection of AD pathogenesis and that characterisation of microglia may be a potential answer to this dilemma.…”

Changes in Retinal Multilayer Thickness and Vascular Network of Patients With Alzheimer’s Disease

“…These vascular changes may be caused by the deposition of Aβ protein [29]. Local microglia reactivity around Aβ plaques could affect retinal vein morphology and lead to the decrease of vascular density [30]. The retinal vascular and even capillary network can also provide a valuable insight on AD brain [31,32].…”