Early alterations of neurovascular unit in the retina in mouse models of tauopathy

Abstract

The retina, as the only visually accessible tissue in the central nervous system, has attracted significant attention for evaluating it as a biomarker for neurodegenerative diseases. Yet, most of studies focus on characterizing the loss of retinal ganglion cells (RGCs) and degeneration of their axons. There is no integrated analysis addressing temporal alterations of different retinal cells in the neurovascular unit (NVU) in particular retinal vessels. Here we assessed NVU changes in two mouse models of tauopathy, P301S and P301L transgenic mice overexpressing the human tau mutated gene, and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA). We found that retinal edema and breakdown of blood–retina barrier were observed at the very early stage of tauopathy. Leukocyte adhesion/infiltration, and microglial recruitment/activation were constantly increased in the retinal ganglion cell layer of tau transgenic mice at different ages, while Müller cell gliosis was only detected in relatively older tau mice. Concomitantly, the number and function of RGCs progressively decreased during aging although they were not considerably altered in the very early stage of tauopathy. Moreover, intrinsically photosensitive RGCs appeared more sensitive to tauopathy. Remarkably, TOMA treatment in young tau transgenic mice significantly attenuated vascular leakage, inflammation and RGC loss. Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal NVU, and vascular alterations occur more manifest and earlier than neurodegeneration in the retina. Oligomeric tau-targeted immunotherapy has the potential to treat tau-induced retinopathies. These data suggest that retinal NVU may serve as a potential biomarker for diagnosis and staging of tauopathy as well as a platform to study the molecular mechanisms of neurodegeneration.

Characterizing the Retinal Phenotype of the Thy1-h[A30P]α-syn Mouse Model of Parkinson’s Disease

“…Previous studies demonstrated that α-syn triggers neuroinflammation, and that, in turn, inflammation increases α-syn phosphorylation and pathology in synucleinopathies ( Lee et al, 2010 ; Tansey and Goldberg, 2010 ; Ramirez et al, 2017 ; Ferreira and Romero-Ramos, 2018 ). Furthermore, retinal inflammation has been linked to both swelling of the outer retina and ERG deviations, and may therefore underlie -at least in part- the OCT and ERG abnormalities that we observed in the Thy1-h[A30P]α-syn mice ( Mirza and Jampol, 2013 ; Petzold, 2016 ; Pisa et al, 2021 ; Xia et al, 2021 ). Hence, we next investigated macroglia and microglia reactivity and water homeostasis in the retina.…”

Isolation of microglia from retinas of chronic ocular hypertensive rats

“…Moreover, from the viewpoint of researchers engaged in eye-related basic science, the lack of microglia-isolating protocol specialized for retina may appear to be the most notable inadequacy in this field, since retina is the unique observable tissue in the central nervous system, and this advantage makes adult rat modeling of retinal diseases an excellent reference for the study of the central nervous system in terms of both structure and function. Therefore, our research is devoted to remedy this inadequacy and try to develop a practical methodology as a research tool to facilitate associated scientific work, which focuses on potential mechanisms that microglia may be involved in the posterior segment of the eye, especially in the condition of glaucoma [ 34 , 35 ]. The density of isolated microglia obtained in different tissues is various.…”

Dysfunction of the glutamatergic photoreceptor synapse in the P301S mouse model of tauopathy

“…Studies on P301S mice aiming to distinguish more clearly between the impact of tau and amyloid have revealed the occurrence of an RGC axonopathy associated with reactive microgliosis and vasculopathy [ 18 , 65 ]. Xia et al [ 65 ] recently showed that p-tau was distributed throughout the retina in a mouse models of tauopathy in line with previously reported presence of p-tau in both retina and optic nerve soluble protein extracts coming from 5-months-old P301S mice [ 38 ]. Heavily burdened p-tau was also identified in the visual cortex of rTg4510 mouse model of tauopathy [ 23 ].…”