Investigating degeneration of the retina in young and aged tau P301L mice

Ho, Wing Lau; Leung, Yen; Cheng, Sally Shuk Yee; Lok, Carmen Ka Ming; Ho, Yuen Shan; Baum, Larry; Yang, Xifei; Chiu, Kin; Chang, Raymond Chuen‐Chung

doi:10.1016/j.lfs.2014.12.019

Cited by 14 publications

(20 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The cellular distribution of tau in the retina was investigated by immunohistochemistry using the K9JA antibody against total tau. In agreement with previous reports [ 4 , 78 ], a low basal level of tau expression was found in all retinal layers except the outer nuclear layer (Fig. 4a , c ).…”

Section: Resultssupporting

confidence: 93%

“…Our data using the 3xTg mouse model, demonstrate early accumulation of tau in the retina prior to the onset of reported cognitive defects [ 50 ]. This finding is consistent with previous studies demonstrating increased retinal tau levels in murine models of tauopathies [ 45 , 46 , 48 , 78 ]. The increase in retinal tau reported here was considerably more pronounced in younger mice than in older individuals.…”

Section: Discussionsupporting

confidence: 93%

See 1 more Smart Citation

Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease

Chiasseu

Alarcón-Martínez

Belforte

et al. 2017

Mol Neurodegeneration

110

103

View full text Add to dashboard Cite

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.

show abstract

Section: Resultssupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease

Chiasseu

Alarcón-Martínez

Belforte

et al. 2017

Mol Neurodegeneration

110

103

View full text Add to dashboard Cite

show abstract

“…The diffuse signal of pTau observed in the current study was most apparent in the peripheral retina, as reported previously in tau transgenic mice [15]. This, might be of interest for in-vivo studies that currently mainly focus on imaging of the central retina.…”

Section: Discussionsupporting

confidence: 88%

Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s disease retinas

Haan

Morrema

Verbraak

et al. 2018

acta neuropathol commun

144

205

View full text Add to dashboard Cite

In-vivo labeling of retinal amyloid-beta(Aβ) and tau has potential as non-invasive biomarker for Alzheimer’s disease (AD). However, literature on the presence of Aβ and phosphorylated tau (pTau) in AD retinas is inconclusive. We therefore assessed the presence of Aβ and pTau in post-mortem retinas in 6 AD and 6 control cases who donated brains and eyes to the Netherlands Brain Bank. Neuropathological diagnosis of AD was made according to NIA-AA criteria. Formalin fixed retinas were dissected in quadrants and cross-sections of medial and superior retinas were made. Immuno-histochemical stainings were performed for Aβ, amyloid precursor protein (APP) and pTau. To assess translation to an in-vivo set up using curcumin as labelling fluorophore, co-stainings with curcumin were performed. No typical Aβ-plaques and neurofibrillary tangles, like in the cerebral cortex, were observed in AD retinas. A diffuse immunoreactive signal for pTau was increased in the inner and outer plexiform layers of the retina in AD cases compared to control cases with absence of cerebral amyloid pathology. Immunostaining with anti-Aβ and anti-APP antibodies yielded signal in ganglion cells, amacrine cells, horizontal cells and Müller cells in both control and AD cases. We observed small extracellular deposits positive for anti-Aβ antibodies 12F4 and 6E10 and negative for 4G8 and curcumin. A subset of these deposits could be characterized as corpora amylacea. In conclusion we found that retinal manifestations of AD pathology appear to be different compared to cerebral AD pathology. Using a qualitative cross-sectional approach, we did not find Aβ/APP related differences in the retina between AD and control subjects. In contrast, tau related changes were found to be present in cases with cerebral AD pathology, suggesting retinal tau as a potential biomarker for AD.

show abstract

“…Assessments of retinal changes in mice expressing the P301S mutated human MAPT gene driven by the mouse Thy1.2 promoter (mThy1.2) showed increased phosphorylation of tau in the RGCL and filamentous inclusions in the retina [14] without an effect on RGC number. In transgenic mice expressing the P301L mutation in the human MAPT gene however, driven by the mouse prion promoter ( PRNP ), total tau and phosphorylated tau levels were shown to be elevated in the RGCL, the IPL and also the INL, accompanied by a reduction in the thickness of the INL, an effect which was more pronounced in the peripheral compared to the central retina [18]. These changes were accompanied by an increase in the number but reduction in the average size of RGCs in the transgenic mice [18].…”

Section: Introductionmentioning

confidence: 99%

“…In transgenic mice expressing the P301L mutation in the human MAPT gene however, driven by the mouse prion promoter ( PRNP ), total tau and phosphorylated tau levels were shown to be elevated in the RGCL, the IPL and also the INL, accompanied by a reduction in the thickness of the INL, an effect which was more pronounced in the peripheral compared to the central retina [18]. These changes were accompanied by an increase in the number but reduction in the average size of RGCs in the transgenic mice [18]. Together these data highlight the susceptibility of the neurosensory retina to mutations associated with familial FTD, and hence highlights the possibility of retinal changes in the clinical scenario.…”

Section: Introductionmentioning

confidence: 99%

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

Harrison

Whitaker

Bertelli

et al. 2019

acta neuropathol commun

View full text Add to dashboard Cite

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.

show abstract

Investigating degeneration of the retina in young and aged tau P301L mice

Cited by 14 publications

References 33 publications

Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease

Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease

Amyloid-beta and phosphorylated tau in post-mortem Alzheimer’s disease retinas

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

Contact Info

Product

Resources

About