Optic nerve thinning and neurosensory retinal degeneration in the rTg4510 mouse model of frontotemporal dementia

Abstract

Visual impairments, such as difficulties in reading and finding objects, perceiving depth and structure from motion, and impaired stereopsis, have been reported in tauopathy disorders, such as frontotemporal dementia (FTD). These impairments however have been previously attributed to cortical pathologies rather than changes in the neurosensory retina or the optic nerve. Here, we examined tau pathology in the neurosensory retina of the rTg(tauP301L)4510 mouse model of FTD. Optic nerve pathology in mice was also assessed using MRI, and corresponding measurements taken in a cohort of five FTD sufferers and five healthy controls. rTg(tauP301L)4510 mice were imaged (T2-weighted MRI) prior to being terminally anesthetized and eyes and brains removed for immunohistochemical and histological analysis. Central and peripheral retinal labelling of tau and phosphorylated tau (pTau) was quantified and retinal layer thicknesses and cell numbers assessed. MR volumetric changes of specific brain regions and the optic nerve were compared to tau accumulation and cell loss in the visual pathway. In addition, the optic nerves of a cohort of healthy controls and behavioural variant FTD patients, were segmented from T1- and T2-weighted images for volumetric study. Accumulation of tau and pTau were observed in both the central and peripheral retinal ganglion cell (RGC), inner plexiform and inner nuclear layers of the neurosensory retina of rTg(tauP301L)4510 mice. This pathology was associated with reduced nuclear density (− 24.9 ± 3.4%) of the central RGC layer, and a reduced volume (− 19.3 ± 4.6%) and elevated T2 signal (+ 27.1 ± 1.8%) in the optic nerve of the transgenic mice. Significant atrophy of the cortex (containing the visual cortex) was observed but not in other area associated with visual processing, e.g. the lateral geniculate nucleus or superior colliculus. Atrophic changes in optic nerve volume were similarly observed in FTD patients (− 36.6 ± 2.6%). The association between tau-induced changes in the neurosensory retina and reduced optic nerve volume in mice, combined with the observation of optic nerve atrophy in clinical FTD suggests that ophthalmic tau pathology may also exist in the eyes of FTD patients. If tau pathology and neurodegeneration in the retina were to reflect the degree of cortical tau burden, then cost-effective and non-invasive imaging of the neurosensory retina could provide valuable biomarkers in tauopathy. Further work should aim to validate whether these observations are fully translatable to a clinical scenario, which would recommend follow-up retinal and optic nerve examination in FTD.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0654-6) contains supplementary material, which is available to authorized users.

Disrupted visual cortical plasticity in early neurodegeneration

“…We note that retinal and optic nerve atrophy has been reported in late-stages (ca. 7.5 months) of rTg4510 neurodegeneration (Harrison et al, 2019). These changes in retinal structure may be expected to reduce the visual cortical response as measured by the VEP.…”

Alzheimer’s Retinopathy: Seeing Disease in the Eyes

“…Accumulation of pTau, NFT Liu et al, 2009;Schön et al, 2012;Yang et al, 2013;Zhao et al, 2013;Chiasseu et al, 2017;Grimaldi et al, 2018;Harrison et al, 2019 O. degus Spontaneous Accumulation of pTau Du et al, 2015;Chang et al, 2020 APP, amyloid precursor protein; Aβ, amyloid-beta; pTau, phosphorylated Tau; NFT, neurofibrillary tangle; O. degus, Octodon Degus.…”

“…In the rTg(tauP301L)4510 tauopathy mouse model of frontotemporal dementia (FTD), accumulation of both tau and pTau have been observed in RGCs as well as the IPL and INL (Harrison et al, 2019). These areas are associated with reduced neuronal density and optic nerve degeneration in these mice (Harrison et al, 2019).…”

“…In the rTg(tauP301L)4510 tauopathy mouse model of frontotemporal dementia (FTD), accumulation of both tau and pTau have been observed in RGCs as well as the IPL and INL ( Harrison et al, 2019 ). These areas are associated with reduced neuronal density and optic nerve degeneration in these mice ( Harrison et al, 2019 ). In an experimental rat model of optic nerve crush, injury-induced impaired autophagy was followed by an increase in hyperphosphorylated tau (pSer396), which co-localized with apoptotic markers in dying RGCs ( Oku et al, 2019 ).…”

Novel alterations in corneal neuroimmune phenotypes in mice with central nervous system tauopathy

“…The accumulation of hyperphosphorylated tau, concomitant with the progressive formation of neurofibrillary tangles (NFTs), further drives impairment of cellular trafficking [1], synaptic dysfunction [2,3], cognitive deficits [4], and neuronal loss [5,6]. The effect of CNS degeneration on ocular health [7], such as retinal nerve fiber thinning and retinal neuronal loss, has been described both in patients [8][9][10] and mouse models of tauopathy [11][12][13]. As one of the most highly innervated tissues of the body, the cornea has recently been used in clinical studies to non-invasively examine peripheral nervous system pathology secondary to CNS neurodegeneration in vivo [14][15][16][17][18][19][20].…”