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.
Highlights
Alzheimer’s disease (AD) is the number one neurodegenerative disorder and cause of dementia
Amyloid accumulates in the retinas of AppNL‐G‐F mice, with Aβ plaque formation at old age Retinal amyloid burden was studied in AppNL-G-F mice of various ages via ELISA
In the amyloid precursor protein (APP)/PS1 overexpression mouse model, at 18 months of age, we detected the accumulation of soluble Aβ42, soluble Aβ40, and insoluble Aβ42 (Fig. 1c)
Summary
Alzheimer’s disease (AD) is the number one neurodegenerative disorder and cause of dementia. Accumulation of amyloid-beta (Aβ) plaques and hyperphosphorylated Tau in tangles are two hallmarks of AD, and are believed to lead to neurotoxic inflammation, neuronal dysfunction, and eventually neurodegeneration. The AD field is still struggling with finding techniques for adequate diagnosis and disease monitoring, rational treatment strategies and valid research models. AD is supposed to start 20 years before the first cognitive symptoms appear [20, 39, 51], and it is nowadays believed that one should focus on this time window for diagnosis and future treatment [19, 47]. In the search for new biomarkers and animal models that allow evaluation of this preclinical phase of AD, increasing attention has gone to the retina. State-of-the-art technologies for ocular imaging (e.g. optical coherence tomography and confocal scanning laser ophthalmoscopy) allow these processes to be visualised at a resolution of at least an order of a magnitude higher than conventional brain imaging techniques, Vandenabeele et al acta neuropathol commun (2021) 9:6 without the need for invasive, costly procedures or tracers, and in a reproducible and quantifiable manner [11]
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