Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease
Abstract Background Tau 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 affec...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-08-01
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| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13024-017-0199-3 |
| _version_ | 1819079445566193664 |
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| author | Marius Chiasseu Luis Alarcon-Martinez Nicolas Belforte Heberto Quintero Florence Dotigny Laurie Destroismaisons Christine Vande Velde Fany Panayi Caroline Louis Adriana Di Polo |
| author_facet | Marius Chiasseu Luis Alarcon-Martinez Nicolas Belforte Heberto Quintero Florence Dotigny Laurie Destroismaisons Christine Vande Velde Fany Panayi Caroline Louis Adriana Di Polo |
| author_sort | Marius Chiasseu |
| collection | DOAJ |
| description | Abstract Background Tau 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. Methods Alterations 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. Results Our 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. Conclusions Our 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. |
| first_indexed | 2024-12-21T19:29:06Z |
| format | Article |
| id | doaj.art-ba4cd4b957d247038e5bb2d2f25f57cd |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-12-21T19:29:06Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-ba4cd4b957d247038e5bb2d2f25f57cd2022-12-21T18:52:45ZengBMCMolecular Neurodegeneration1750-13262017-08-0112112010.1186/s13024-017-0199-3Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s diseaseMarius Chiasseu0Luis Alarcon-Martinez1Nicolas Belforte2Heberto Quintero3Florence Dotigny4Laurie Destroismaisons5Christine Vande Velde6Fany Panayi7Caroline Louis8Adriana Di Polo9Department of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalInstitut de Recherches ServierInstitut de Recherches ServierDepartment of Neuroscience and Centre de recherche du centre hospitalier de l’Université de Montréal (CRCHUM), Université de MontréalAbstract Background Tau 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. Methods Alterations 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. Results Our 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. Conclusions Our 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.http://link.springer.com/article/10.1186/s13024-017-0199-3Alzheimer’s diseaseRetinal ganglion cellTauAxonal transportNeurodegeneration |
| spellingShingle | Marius Chiasseu Luis Alarcon-Martinez Nicolas Belforte Heberto Quintero Florence Dotigny Laurie Destroismaisons Christine Vande Velde Fany Panayi Caroline Louis Adriana Di Polo Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease Molecular Neurodegeneration Alzheimer’s disease Retinal ganglion cell Tau Axonal transport Neurodegeneration |
| title | Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease |
| title_full | Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease |
| title_fullStr | Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease |
| title_full_unstemmed | Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease |
| title_short | Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease |
| title_sort | tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of alzheimer s disease |
| topic | Alzheimer’s disease Retinal ganglion cell Tau Axonal transport Neurodegeneration |
| url | http://link.springer.com/article/10.1186/s13024-017-0199-3 |
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