Abstract
BackgroundTau is an axon-enriched protein that binds to and stabilizes microtubules, and 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 in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. At present, however, the mechanisms that underlie vision changes in these patients are poorly understood. Here, we asked whether tau plays a role in early retinal pathology and neuronal dysfunction in AD.MethodsAlterations in tau protein and gene expression, phosphorylation, and localization were investigated by western blots, qPCR, and immunohistochemistry in the retina and visual pathways of triple transgenic mice (3xTg) harboring mutations in the genes encoding presenilin 1 (PS1M146 V), amyloid precursor protein (APPSwe), and tau (MAPTP301L). Anterograde axonal transport was assessed by intraocular injection of the cholera toxin beta subunit followed by quantification of tracer accumulation in the contralateral superior colliculus. RGC survival was analyzed on whole-mounted retinas using cell-specific markers. Reduction of tau expression was achieved following intravitreal injection of targeted siRNA.ResultsOur data demonstrate an age-related increase in endogenous retinal tau characterized by epitope-specific hypo- and hyper-phosphorylation in 3xTg mice. Retinal tau accumulation was observed as early as three months of age, prior to the reported onset of behavioral deficits, and preceded tau aggregation in the brain. Intriguingly, tau build up occurred in RGC soma and dendrites, while tau in RGC axons in the optic nerve was depleted. Tau phosphorylation changes and missorting correlated with substantial defects in anterograde axonal transport that preceded RGC death. Importantly, targeted siRNA-mediated knockdown of endogenous tau improved anterograde transport along RGC axons.ConclusionsOur study reveals profound tau pathology in the visual system leading to early retinal neuron damage in a mouse model of AD. Importantly, we show that tau accumulation promotes anterograde axonal transport impairment in vivo, and identify this response as an early feature of neuronal dysfunction that precedes cell death in the AD retina. These findings provide the first proof-of-concept that a global strategy to reduce tau accumulation is beneficial to improve axonal transport and mitigate functional deficits in AD and tauopathies.
Highlights
Tau is an axon-enriched protein that binds to and stabilizes microtubules, and plays a crucial role in neuronal function
We recently reported key pathological changes of endogenous tau in glaucoma, an optic neuropathy characterized by selective retinal ganglion cell (RGC) death and the leading cause of irreversible blindness worldwide [4]
Experimental animals The 3xTg mice bearing the human mutations in the genes encoding presenilin 1 (PS1M146V), amyloid precursor protein (APPSwe), and tau (MAPTP301L) [51], tau knockout mice, and age-matched littermate wild-type controls were purchased from Jackson Laboratories (Bar Harbor, ME) and maintained in our animal facility
Summary
Tau is an axon-enriched protein that binds to and stabilizes microtubules, and plays a crucial role in neuronal function. Substantial visual deficits are found in individuals affected by AD including a preferential loss of retinal ganglion cells (RGCs), the neurons that convey visual information from the retina to the brain. A member of the microtubule-associated protein family, plays a crucial role in many neurodegenerative diseases including Alzheimer’s disease (AD), corticobasal dementia, frontotemporal lobar degeneration, progressive supranuclear palsy, and glaucoma [1,2,3,4]. Morphological and additional functional impairments have been described in the retina of AD individuals suffering from AD including preferential RGC loss and thinning of the retinal nerve fiber layer [35,36,37,38], abnormal electroretinogram response [39], and reduced blood flow [40, 41]
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