Retinal ganglion cell degeneration correlates with hippocampal spine loss in experimental Alzheimer\u2019s disease

Ryan J Bevan,Mark A Good,James E Morgan,Tim R Hughes,Pete A Williams,B Paul Morgan

doi:10.1186/s40478-020-01094-2

Abstract

Neuronal dendritic and synaptic pruning are early features of neurodegenerative diseases, including Alzheimer’s disease. In addition to brain pathology, amyloid plaque deposition, microglial activation, and cell loss occur in the retinas of human patients and animal models of Alzheimer’s disease. Retinal ganglion cells, the output neurons of the retina, are vulnerable to damage in neurodegenerative diseases and are a potential opportunity for non-invasive clinical diagnosis and monitoring of Alzheimer’s progression. However, the extent of retinal involvement in Alzheimer’s models and how well this reflects brain pathology is unclear. Here we have quantified changes in retinal ganglion cells dendritic structure and hippocampal dendritic spines in three well-studied Alzheimer’s mouse models, Tg2576, 3xTg-AD and APPNL-G-F. Dendritic complexity of DiOlistically labelled retinal ganglion cells from retinal explants was reduced in all three models in an age-, gender-, and receptive field-dependent manner. DiOlistically labelled hippocampal slices showed spine loss in CA1 apical dendrites in all three Alzheimer’s models, mirroring the early stages of neurodegeneration as seen in the retina. Morphological classification showed that loss of thin spines predominated in all. The demonstration that retinal ganglion cells dendritic field reduction occurs in parallel with hippocampal dendritic spine loss in all three Alzheimer’s models provide compelling support for the use of retinal neurodegeneration. As retinal dendritic changes are within the optical range of current clinical imaging systems (for example optical coherence tomography), our study makes a case for imaging the retina as a non-invasive way to diagnose disease and monitor progression in Alzheimer’s disease.

Highlights

Alzheimer’s disease (AD) is the underlying cause of up to 70% of all dementias and estimated to afflict 40 million people worldwide by 2050 [32, 36]
Retinal ganglion cell degeneration is a common feature of the Tg2576, 3xTg‐AD and A PPNL‐G‐F AD mouse models We first sought to determine whether retinal ganglion cells (RGCs) dendritic degeneration occurred in Tg2576, 3xTg-AD and APPNL-G-F AD mouse models at 12 months, a time point when these models have been demonstrated to have hippocampal and behavioural degenerative changes that are indicative of AD-like pathology
AD-relevant changes in the retina in AD models and human disease offer the prospect of noninvasive monitoring through in vivo imaging of retinal pathology as a tool to diagnose disease, monitor progression and test the efficacy of AD treatments; to date, reports of retinal pathology in humans and animal models have been few and inconsistent [5]

Summary

Introduction

Alzheimer’s disease (AD) is the underlying cause of up to 70% of all dementias and estimated to afflict 40 million people worldwide by 2050 [32, 36]. AD pathology is characterised by extracellular amyloid plaques, neurofibrillary tangles, neuroinflammation and synaptic loss that result in severe brain atrophy [14, 37, 42, 49]. Visual deficits can include reduced acuity, visual field defects, changes in contrast sensitivity, impaired object recognition, and delayed visual processing [30]. While of interest, these observations have not pinpointed specific deficits in the visual pathway that consistently account for a reduction. AD retinal pathology resembles that found in the brain, including neuronal cell loss, of retinal ganglion cells (RGCs) [8]. Loss of RGCs, the output neuron of the retina, and resulting thinning of the retinal nerve fibre layer (RGC axons) suggests that these could be a meaningful index of cognitive decline and a feature in AD [31, 45]

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Results

Conclusion