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.
Highlights
Tau is a member of the microtubule-associated proteins family, which is mainly expressed by neurons, especially in their axons where it controls the polymerization and stabilization of the microtubules and regulates axonal transport
Since many transgenic mice used to study tauopathy or Alzheimer’s disease (AD) pathology are on a mixed background potentially bearing inherited retinal degeneration mutations [11], tail snips from founder mouse lines (P301S, Cx3cr1GFP/+ and P301L) were sent to GenoTyping Center of America (Waterville, ME) to perform single nucleotide polymorphism (SNP) before using them to set up colonies to produce mice used for the experiments
As aggregated tau protein in particular the soluble tau oligomers is toxic and tau immunotherapy has been shown to be beneficial in various animal models [2, 23, 27], we investigated the effects of tau oligomer monoclonal antibody (TOMA) on retinal neurovascular unit (NVU) in P301L mice previously used to evaluated the therapeutic effects of TOMA on neurodegenerative phenotypes in the brain, which allowed us to follow the treatment procedure of previous studies and compare retinal changes to those changes reported in the brain [9, 10, 22]
Summary
Tau is a member of the microtubule-associated proteins family, which is mainly expressed by neurons, especially in their axons where it controls the polymerization and stabilization of the microtubules and regulates axonal transport. The retina comprises several cell types including retinal neurons, vascular cells, microglia and glial cells. It is an extension of the neural network of the brain and shares many similar pathophysiological changes and underlying mechanisms with the brain during neurodegenerative diseases including AD [8, 12, 17, 18, 20, 25, 33,34,35, 47, 57, 64]. Due to the anatomical and functional characters, the pathological changes in the retina may precede those in the brain These features make the retina an appealing source of noninvasive biomarkers as well as an alternative platform to study neurovascular coupling in tauopathy [64]. Previous studies have some exploration of retinal abnormality in different AD-related models [8, 12, 18, 20, 25, 33, 47, 58, 61], retinal vascular changes in this process are largely unknown; and quantitative and temporal analyses for the alterations of different retinal cell types are missing
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