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One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina

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Abstract

Accumulation of amyloid β (Aβ) and its aggregates in the ageing central nervous system is regarded synonymous to Alzheimer’s disease (AD) pathology. Despite unquestionable advances in mechanistic and diagnostic aspects of the disease understanding, the primary cause of Aβ accumulation as well as its in vivo roles remains elusive; nonetheless, the majority of the efforts to address pathological mechanisms for therapeutic development are focused towards moderating Aβ accumulation in the brain. More recently, Aβ deposition has been identified in the eye and is linked with distinct age-related diseases including age-related macular degeneration, glaucoma as well as AD. Awareness of the Aβ accumulation in these markedly different degenerative disorders has led to an increasing body of work exploring overlapping mechanisms, a prospective biomarker role for Aβ and the potential to use retina as a model for brain related neurodegenerative disorders. Here, we present an integrated view of current understanding of the retinal Aβ deposition discussing the accumulation mechanisms, anticipated impacts and outlining ameliorative approaches that can be extrapolated to the retina for potential therapeutic benefits. Further longitudinal investigations in humans and animal models will determine retinal Aβ association as a potential pathognomonic, diagnostic or prognostic biomarker.

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Abbreviations

AD:

Alzheimer’s disease

AMD:

Age-related macular degeneration

Aβ:

Amyloid beta

RGC:

Retinal ganglion cell

APP:

Amyloid precursor protein

RNFL:

Retinal nerve fibre layer

PERG:

Pattern electroretinogram

VEP:

Visual evoked potential

OCT:

Optical coherence tomography

RPE:

Retinal pigment epithelium

BrM:

Bruch’s membrane

IOP:

Intra ocular pressure

BDNF:

Brain derived neurotrophic factor

CNTF:

Ciliary neurotrophic factor

GDNF:

Glial derived neurotrophic factor

Arc:

Activity regulated cytoskeleton-associated protein

BACE:

β Secretase

ACE:

Angiotensin converting enzyme

AGE:

Advanced glycation end product

VEGF:

Vascular endothelial growth factor

INL:

Inner nuclear layer

ROS:

Reactive oxygen species

ONH:

Optic nerve head

NSAID:

Non-steroidal anti-inflammatory drugs

HRT:

Hormone replacement therapy

LH:

Luteinizing hormone

GRH:

Gonadotrophin releasing hormone

SOD:

Superoxide dismutase

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Acknowledgments

We acknowledge research funding from the NHMRC, ORIA, MQRDG and Hillcrest foundation.

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Authors and Affiliations

  1. Faculty of Medicine and Health Sciences, Macquarie University, Sydney, Australia

    Vivek Gupta, Nitin Chitranshi, Sumudu Gangoda, Roshana Vander Wall, Mojdeh Abbasi, Mojtaba Golzan, Yogita Dheer, Alberto Avolio, Roger Chung & Stuart Graham

  2. School of Medical Sciences, Edith Cowan University, Perth, Australia

    Veer B. Gupta, Tejal Shah & Ralph Martins

  3. Save Sight Institute, Sydney University, Sydney, Australia

    Stuart Graham

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  1. Vivek Gupta
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Gupta, V., Gupta, V.B., Chitranshi, N. et al. One protein, multiple pathologies: multifaceted involvement of amyloid β in neurodegenerative disorders of the brain and retina. Cell. Mol. Life Sci. 73, 4279–4297 (2016). https://doi.org/10.1007/s00018-016-2295-x

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