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The App^NL-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 App^NL-G-F mouse. We demonstrate that soluble A? accumulation is present in the retina of these mice early in life and progresses to A? plaque formation by midlife. This rising A? 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 App^NL-G-F mouse. Furthermore, we show that hyperspectral imaging can be used to quantify retinal A?, underscoring its potential as a biomarker for AD diagnosis and monitoring. These findings suggest that the App^NL-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.

SUBMITTER: Vandenabeele M

PROVIDER: S-EPMC7788955 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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The App<sup>NL-G-F</sup> mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

Vandenabeele Marjan M Veys Lien L Lemmens Sophie S Hadoux Xavier X Gelders Géraldine G Masin Luca L Serneels Lutgarde L Theunis Jan J Saito Takashi T Saido Takaomi C TC Jayapala Murali M De Boever Patrick P De Strooper Bart B Stalmans Ingeborg I van Wijngaarden Peter P Moons Lieve L De Groef Lies L

Acta neuropathologica communications 20210106 1

In this study, we report the results of a comprehensive phenotyping of the retina of the App<sup>NL-G-F</sup> 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 obser ...[more]

PMID: 33407903

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Project description:BackgroundIn spite of many years of research, our understanding of the molecular bases of Alzheimer's disease (AD) is still incomplete, and the medical treatments available mainly target the disease symptoms and are hardly effective. Indeed, the modulation of a single target (e.g., β-secretase) has proven to be insufficient to significantly alter the physiopathology of the disease, and we should therefore move from gene-centric to systemic therapeutic strategies, where AD-related changes are modulated globally.MethodsHere we present the complete characterization of three murine models of AD at different stages of the disease (i.e., onset, progression and advanced). We combined the cognitive assessment of these mice with histological analyses and full transcriptional and protein quantification profiling of the hippocampus. Additionally, we derived specific Aβ-related molecular AD signatures and looked for drugs able to globally revert them.ResultsWe found that AD models show accelerated aging and that factors specifically associated with Aβ pathology are involved. We discovered a few proteins whose abundance increases with AD progression, while the corresponding transcript levels remain stable, and showed that at least two of them (i.e., lfit3 and Syt11) co-localize with Aβ plaques in the brain. Finally, we found two NSAIDs (dexketoprofen and etodolac) and two anti-hypertensives (penbutolol and bendroflumethiazide) that overturn the cognitive impairment in AD mice while reducing Aβ plaques in the hippocampus and partially restoring the physiological levels of AD signature genes to wild-type levels.ConclusionsThe characterization of three AD mouse models at different disease stages provides an unprecedented view of AD pathology and how this differs from physiological aging. Moreover, our computational strategy to chemically revert AD signatures has shown that NSAID and anti-hypertensive drugs may still have an opportunity as anti-AD agents, challenging previous reports.

Project description:Background: Alzheimer's disease (AD) may present retinal changes before brain pathology, suggesting the retina as an accessible biomarker of AD. The present work is a diachronic study using spectral domain optical coherence tomography (SD-OCT) to determine the total retinal thickness and retinal nerve fiber layer (RNFL) thickness in an APPNL-F/NL-F mouse model of AD at 6, 9, 12, 15, 17, and 20 months old compared to wild type (WT) animals. Methods: Total retinal thickness and RNFL thickness were determined. The mean total retinal thickness was analyzed following the Early Treatment Diabetic Retinopathy Study sectors. RNFL was measured in six sectors of axonal ring scans around the optic nerve. Results: In the APPNL-F/NL-F group compared to WT animals, the total retinal thickness changes observed were the following: (i) At 6-months-old, a significant thinning in the outer temporal sector was observed; (ii) at 15-months-old a significant thinning in the inner temporal and in the inner and outer inferior retinal sectors was noticed; (iii) at 17-months-old, a significant thickening in the inferior and nasal sectors was found in both inner and outer rings; and (iv) at 20-months-old, a significant thinning in the inner ring of nasal, temporal, and inferior retina and in the outer ring of superior and temporal retina was seen. In RNFL thickness, there was significant thinning in the global analysis and in nasal and inner-temporal sectors at 6 months old. Thinning was also found in the supero-temporal and nasal sectors and global value at 20 months old. Conclusions: In the APPNL-F/NL-F AD model, the retinal thickness showed thinning, possibly produced by neurodegeneration alternating with thickening caused by deposits and neuroinflammation in some areas of the retina. These changes over time are similar to those observed in the human retina and could be a biomarker for AD. The APPNL-F/NL-F AD model may help us better understand the different retinal changes during the progression of AD.

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

Publications

The App<sup>NL-G-F</sup> mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.

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The App^NL-G-F mouse retina is a site for preclinical Alzheimer's disease diagnosis and research.