Neurobiology of Aging 32 (2011) 419–433 Tau inclusions in retinal ganglion cells of human P301S tau transgenic mice: Effects on axonal viability Laura Gasparini a,∗ , R. Anthony Crowther b , Keith R. Martin a , Nicola Berg a , Michael Coleman c , Michel Goedert b , Maria Grazia Spillantini a,∗∗ a Cambridge Centre for Brain Repair, The University of Cambridge, Robinson Way, Forvie site, Cambridge CB2 0PY, UK b Medical Research Council Laboratory of Molecular Biology, Cambridge CB2 0QH, UK c The Babraham Institute, Cambridge CB2 4AT, UK Received 6 November 2008; received in revised form 9 February 2009; accepted 3 March 2009 Abstract 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. © 2009 Elsevier Inc. All rights reserved. Keywords: Tau; Retinal ganglion cells; Axonopathy; Tauopathy; Alzheimer disease; Frontotemporal dementia 1. Introduction Intracellular deposits of microtubule-associated tau protein are major pathological hallmarks of several neu- rodegenerative diseases termed “tauopathies”, including frontotemporal dementia with parkinsonism linked to chro- mosome 17 (FTDP-17) and Alzheimer disease (AD) (Gasparini et al., 2007). The identification of mutations in the tau gene in cases with FTDP-17 (Goedert and Spillantini, 2006) has led to the development of animal models of tauopa- thy (Allen et al., 2002; Lewis et al., 2000). The human P301S ∗ Corresponding author. Present address: Dept of Neurosciences and Brain Technologies, The Italian Institute of Technology, Via Morego 30, 16163 Genova, Italy. Tel.: +39 010 71781; fax: +39 010 720321. ∗∗ Corresponding author. E-mail addresses: laura.gasparini@iit.it (L. Gasparini), mgs11@cam.ac.uk (M.G. Spillantini). tau transgenic mouse line (Allen et al., 2002) is one such model and develops extensive tau pathology throughout the nervous system with abundant accumulation of tau filaments resembling those of human tauopathies. In the spinal cord, the development of tau pathology leads to a loss of about 50% of motor neurons, which is paralleled by progressive motor impairment and culminates in a severe paraparesis at 5–6 months of age in homozygous mice. Clinical and pathological studies indicate that some patients with AD suffer visual function impairment, optic neuropathy and retinal ganglion cell (RGC) loss (Blanks et al., 1989; Iseri et al., 2006; Jackson and Owsley, 2003; Parisi, 2003; Sadun and Bassi, 1990). Indeed, Alzheimer-type patho- logical mechanisms occur in retinal degeneration and ocular diseases such as glaucoma, diabetic neuropathy and mac- ular degeneration. It has been shown that -amyloid (A) deposits lead to retinal degeneration and dysfunction in AD transgenic mouse models overexpressing mutant human A 0197-4580/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.neurobiolaging.2009.03.002