Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease

• DOI: 10.1186/s13024-017-0199-3
• Publication Date: 2017-08-03T12:41:55Z
• Authors: Marius Chiasseu; Luis Alarcon-Mart...; Nicolas Belforte; Heberto Quintero; Florence Dotigny; Laurie Destroisma...; Christine Vande V...; Fany Panayi; Caroline Louis; Adriana Di Polo
• Keywords: Superior colliculus; Tauopathy; Tau protein

Tau is an axon-enriched protein that binds to and stabilizes microtubules, hence plays a crucial role in neuronal function. In Alzheimer's disease (AD), pathological tau accumulation correlates with cognitive decline. Substantial visual deficits are found individuals affected by AD including preferential loss of retinal ganglion cells (RGCs), the neurons convey information from retina brain. At present, however, mechanisms underlie vision changes these patients poorly understood. Here, we asked whether early pathology dysfunction AD.Alterations gene expression, phosphorylation, localization were investigated western blots, qPCR, immunohistochemistry pathways triple transgenic mice (3xTg) harboring mutations genes encoding presenilin 1 (PS1M146 V), amyloid precursor (APPSwe), (MAPTP301L). Anterograde axonal transport was assessed intraocular injection cholera toxin beta subunit followed quantification tracer contralateral superior colliculus. RGC survival analyzed on whole-mounted retinas using cell-specific markers. Reduction expression achieved following intravitreal targeted siRNA.Our data demonstrate age-related increase endogenous characterized epitope-specific hypo- hyper-phosphorylation 3xTg mice. Retinal observed as three months age, prior reported onset behavioral deficits, preceded aggregation Intriguingly, build up occurred soma dendrites, while axons optic nerve depleted. phosphorylation missorting correlated substantial defects anterograde death. Importantly, siRNA-mediated knockdown improved along axons.Our study reveals profound system leading neuron damage mouse model AD. show promotes impairment vivo, identify this response feature precedes cell death retina. These findings provide first proof-of-concept global strategy reduce beneficial improve mitigate functional tauopathies.