Dementia of the Eye- Alzheimer’s-linked Amyloid beta proteins provide new insights into retinal degeneration

Abstract

Purpose: age-related Macular Degeneration (AMD) is the most common cause of irreversible blindness in the developed world for which there is no effective treatment. Advanced stages of the disease manifests as two broadly-defined phenotypes; geographic atrophy or neovascular AMD. The disease has a complex aetiology underlying a mixture of genetic and non-genetic/environmental risk factors that are still incompletely understood. Adding to this complexity is the Alzheimer’s-associated Amyloid beta (A) family of misfolding proteins which accumulate in aged and AMD retinas. The deposition of A within pathogenic deposits under the retina and its dysregulation in plasma of AMD patients offers the possibility of studying degenerative changes in the retina from a new perspective.

Methods: we developed a mouse model of A-induced retinal degeneration in order to study its effects in the living retina. We then exploited a cell culture model to determine its effects at single-cell resolution.

Results: sub-retinally injected human oligomeric A aggregated in murine eyes in a manner consistent with amyloid deposition in donor tissues, and caused progressive retinal degeneration. Two weeks after treatment, A injected eyes showed features similar to neovascular AMD. However, overall retinal function remained unaffected as non-invasive OCT and ERG scans revealed this damage to be highly localised. Studies at single-cell resolution revealed that A was internalised by RPE cells to accumulate within late endosomes and lysosomes. The activity of the lysosomal proteolytic enzyme cathepsin B was upregulated in response to lysosomal A cargos. However, A persisted after cathepsin B activity had returned to baseline levels suggesting a potential new mechanism through which A can accumulate within RPE lysosomes over time. The ability to degrade POS cargos were also diminished in RPE with lysosomal A, revealing an altogether novel cellular mechanism through which A can contribute to AMD.

Conclusions: our findings reveal a novel disease-causing pathway in the senescent retina. They also shed light on how impaired cargo-handling processes including poor responses to the accumulation of aggregate-prone/high-molecular-weight molecules within lysosomes underpin related pathophysiologies such as Alzheimer’s disease. As an unhealthy diet and metabolic disorders are associated with increased A pathology in the eye and brain, our results provide further evidence of shared pathophysiology in these tissues.

Disclosures: none

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Identifiers

ORCID for J. Arjuna Ratnayaka: orcid.org/0000-0002-1027-6938

ORCID for Tracey Newman: orcid.org/0000-0002-3727-9258

ORCID for Andrew Lotery: orcid.org/0000-0001-5541-4305

ORCID for Angela Cree: orcid.org/0000-0002-1987-8900

ORCID for Helena Lee: orcid.org/0000-0002-2573-9536

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