Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: effects on axonal viability.
Tau inclusions play a key role in the pathogenesis of tauopathies. Altered tau levels have been detected in retina and optic nerve of patients with glaucoma, suggesting the possibility of shared pathogenic mechanisms with tauopathies. Here we report that hyperphosphorylated transgenic tau accumulates in the nerve fibre layer and, from 2 months of age, aggregates into filamentous inclusions in retinal ganglion cells of human P301S tau transgenic mice. Axonopathy and accumulation of hyperphosphorylated tau in the nerve fibre layer preceded inclusion formation. Hyperphosphorylated tau and tau inclusions were also detected in cultured retinal explants from 5-month-old transgenic mice. Axonal outgrowth was similar in transgenic and wild-type retinal explants under basal conditions. However, when exposed to growth-promoting stimuli, axon elongation was enhanced in explants from wild-type but not transgenic mice, indicating that the presence of abnormal tau can impair stimulated axonal outgrowth. These findings suggest that the retina is a good model system for investigating tau-driven neurodegeneration and for assessing potential pharmacological modifiers for tauopathies.
Gasparini
Laura
L
Cambridge Centre for Brain Repair, The University of Cambridge, Robinson Way, Forvie site, Cambridge CB2 0PY, UK. laura.gasparini@iit.it
Crowther
R Anthony
RA
Martin
Keith R
KR
Berg
Nicola
N
Coleman
Michael
M
Goedert
Michel
M
Spillantini
Maria Grazia
MG
D000704:Analysis of Variance; D000818:Animals; D001369:Axons / Q000473:pathology*; D001426:Bacterial Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology* / Q000648:ultrastructure; D036341:Intercellular Signaling Peptides and Proteins / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission / Q000379:methods; D009154:Mutation / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009887:Ophthalmoscopy / Q000379:methods; D009924:Organ Culture Techniques; D010766:Phosphorylation / Q000235:genetics; D011392:Proline / Q000235:genetics; D012165:Retinal Ganglion Cells / Q000473:pathology* / Q000648:ultrastructure; D012694:Serine / Q000235:genetics; D024801:Tauopathies / Q000473:pathology*; D016875:tau Proteins / Q000235:genetics*
D001426:Bacterial Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008164:Luminescent Proteins; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D016875:tau Proteins; C054562:yellow fluorescent protein, Bacteria; D012694:Serine; D011392:Proline