Microglial Activation in the Retina of a Triple-Transgenic Alzheimer’s Disease Mouse Model (3xTg-AD)

Abstract

Alzheimer’s disease (AD) is the most common type of dementia in the world. The main biomarkers associated with AD are protein amyloid-β (Aβ) plaques and protein tau neurofibrillary tangles, which are responsible for brain neuroinflammation mediated by microglial cells. Increasing evidence has shown that the retina can also be affected in AD, presenting some molecular and cellular changes in the brain, such as microglia activation. However, there are only a few studies assessing such changes in the retinal microglia in animal models of AD. These studies use retinal sections, which have some limitations. In this study, we performed, for the first time in a triple-transgenic AD mouse model (3xTg-AD), a quantitative morphometric analysis of microglia activation (using the anti-Iba-1 antibody) in retinal whole-mounts, allowing visualization of the entire microglial cell, as well as its localization along the extension of the retina in different layers. Compared to age-matched animals, the retina of 3xTg-AD mice presents a higher number of microglial cells and a thicker microglial cell body area. Moreover, the microglia migrate, reorient, and retract their processes, changing their localization from a parallel to a perpendicular position relative to the retinal surface. These findings demonstrate clear microglia remodeling in the retina of 3xTg-AD mice.

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

“…Analysis of 18-month-old App NL - G - F x CX 3 CR - 1 GFP/ + mice retinas, with GFP-labeled microglia, confirmed these findings (data not shown). However, a detailed investigation of these retinas, co-labeled for 6E10, revealed local microglia reactivity around Aβ plaques, as was previously shown in the brains of these mice [ 40 ] and in the retinas of other AD mouse models (3xTgAD, APP/PS1) [ 10 , 36 , 41 ]. Indeed, microglia clustered around Aβ plaques, and these cells showed less ramified, thicker processes and larger somas ( p = 0.0112) compared to microglia in regions without plaques (Fig.…”

TheAppNL-G-Fmouse retina is a site for preclinical Alzheimer’s disease diagnosis and research

“…Analysis of 18month-old App NL-G-F x CX3CR-1 GFP/+ mice retinas, with GFP-labeled microglia, confirmed these findings (data not shown). However, a detailed investigation of these retinas, co-labeled for 6E10, revealed local microglia reactivity around Aβ plaques, as was previously shown in the brains of these mice 21 and in the retinas of other AD mouse models (3xTgAD, APP/PS1) 19,29,30 . Indeed, microglia clustered around Aβ plaques, and these cells showed less ramified, thicker processes and larger somas (p=0.0112) compared to microglia in regions without plaques ( Fig.…”

Retinal Thickness Changes Over Time in a Murine AD Model APPNL-F/NL-F

“…Retinal areas with an increased thickness were found in AD patients, specifically in the macular area (Jáñez-Escalada et al, 2019 ; Salobrar-García et al, 2019a ), revealing areas of possible gliosis prior to neurodegeneration. These changes could be correlated with those found in the retinas of AD transgenic models, where marked neurodegeneration and a loss of optic nerve axons were observed (Gupta et al, 2016 ; Chiquita et al, 2019 ; Georgevsky et al, 2019 ), alongside retinal thickening and increased microglial activation in the early stages of the disease (Perez et al, 2009 ; Yang et al, 2013 ; Gao et al, 2015 ; Salobrar-García et al, 2020 ). In addition to the retinal structural changes, several functional changes have been observed by means of electroretinogram (ERG) in the APP swe/PS1 transgenic mouse model of AD finding a significant reduction of the a and b wave amplitudes between 12 and 16 months of age (Perez et al, 2009 ).…”