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

Abstract

Purpose : 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 and evaluated the therapeutic effects of a tau oligomer monoclonal antibody (TOMA).

Methods : Studies were performed in P301S and P301L transgenic mice which overexpress the human tau mutated gene. Optical coherence tomography, scanning laser ophthalmoscopy and electroretinography were applied to non-invasively analyze retinal structural and functional changes. Vascular leakage was determined by analyzing FITC-BSA extravasation into the retina. Leukocyte adhesion was assessed by Concanavalin A labeling. Alterations of adhesion junction, microglia, leukocytes and RGCs were assessed by immunostaining in retinal flatmounts. TOMA was utilized to treat tauopathy.

Results : 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.

Conclusions : Our data provide compelling evidence that abnormal tau accumulation can lead to pathology in the retinal neurovascular unit, 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. 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.

This is a 2021 ARVO Annual Meeting abstract.