Exercise reverses age-related vulnerability of the retina to injury by preventing complement-mediated synapse elimination via a BDNF-dependent pathway.

Vicki Chrysostomou,Ian A Trounce,Sandra Galic,Gregory R Steinberg,Peter Wijngaarden,Jonathan G Crowston

doi:10.1111/acel.12512

Abstract

SummaryRetinal ganglion cells (RGCs) become increasingly vulnerable to injury with advancing age. We recently showed that this vulnerability can be strongly modified in mice by exercise. However, the characteristics and underlying mechanisms of retinal protection with exercise remain unknown. Hence, the aim of this study was to investigate cellular changes associated with exercise‐induced protection of aging retinal cells and the role of local and peripheral trophic signalling in mediating these effects. We focussed on two molecules that are thought to play key roles in mediating beneficial effects of exercise: brain‐derived neurotrophic factor (BDNF) and AMP‐activated protein kinase (AMPK). In middle‐aged (12 months old) C57BL/6J mice, we found that exercise protected RGCs against dysfunction and cell loss after an acute injury induced by elevation of intra‐ocular pressure. This was associated with preservation of inner retinal synapses and reduced synaptic complement deposition. Retinal expression of BDNF was not upregulated in response to exercise alone. Rather, exercise maintained BDNF levels in the retina, which were decreased postinjury in nonexercised animals. Confirming a critical role for BDNF, we found that blocking BDNF signalling during exercise by pharmacological means or genetic knock‐down suppressed the functional protection of RGCs afforded by exercise. Protection of RGCs with exercise was independent of activation of AMPK in either retina or skeletal muscle. Our data support a previously unidentified mechanism in which exercise prevents loss of BDNF in the retina after injury and preserves neuronal function and survival by preventing complement‐mediated elimination of synapses.

Highlights

The prevalence and incidence of glaucoma, a neurodegenerative disease characterized by the selective loss of retinal ganglion cells (RGCs), increases almost exponentially with age across all major populations (Quigley & Broman, 2006)
We recently discovered that exercise in middle-aged mice, in the form of daily swimming, robustly protected RGCs against age-related functional loss and signs of stress after an acute injury (Chrysostomou et al, 2014)
Neurotrophins and growth factors such as brainderived neurotrophic factor (BDNF) and insulin-like growth factor-1 are thought to act as broad signalling molecules to mediate beneficial effects of exercise in other regions of the CNS (Carro et al, 2001; Vaynman et al, 2004; Gomez-Pinilla et al, 2008; Lawson et al, 2014), but it is not clear whether similar factors are involved in protecting cells within the retina or if/how they are altered with age

Summary

Introduction

The prevalence and incidence of glaucoma, a neurodegenerative disease characterized by the selective loss of retinal ganglion cells (RGCs), increases almost exponentially with age across all major populations (Quigley & Broman, 2006). The effect was so potent that exercised 12-month-old mice responded to injury in a similar manner to young nonexercised 3-month-old mice. These data provide compelling evidence that exercise can reverse negative impacts of aging in RGCs and modify their response to injury. Neurotrophins and growth factors such as brainderived neurotrophic factor (BDNF) and insulin-like growth factor-1 are thought to act as broad signalling molecules to mediate beneficial effects of exercise in other regions of the CNS (Carro et al, 2001; Vaynman et al, 2004; Gomez-Pinilla et al, 2008; Lawson et al, 2014), but it is not clear whether similar factors are involved in protecting cells within the retina or if/how they are altered with age

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