Description
In the field of ageing, protein aggregation and the downstream pathologies implicated in neurodegenerative diseases have been extensively studied in the brain. The retina, often termed the window to the brain, has been suggested to exhibit maladaptive processes similar to those seen in the brain, however, the extent to which aggregation-prone proteins accumulate in the healthy aged retina remains underexplored. Progress in this area has been limited by long-lived animal models, which hinder experimental throughput, while the use of shorter living models often compromises translational relevance. The African turquoise killifish (Nothobranchius furzeri), a naturally compressed-lifespan vertebrate displaying conserved retinal structure and hallmarks of human ageing, offers a powerful model to address this question. Here, we investigated retinal distribution of aggregation-prone proteins and whether reducing amyloid-precursor protein-a (appa) burden using appa-/- killifish will improve ageing-associated retinal phenotypes. We analysed retinas from young (6-week) and aged (36-week) wild-type killifish and compared these with age-matched appa-/- fish, focusing on amyloid-β, tau, hyperphosphorylated tau (p-Tau) and ⍺-synuclein. Immunohistochemistry analysis showed that protein accumulation was most prominent within outer segments of photoreceptors, amacrine cells and ganglion cells, which are retinal populations known to be vulnerable to degenerative stress. Furthermore, parallel staining on human retinas revealed comparable layer-specific localisation patterns of aggregation-prone proteins. Notably, appa-/- appears to alter retinal p-Tau distribution in aged killifish, potentially due to reduced p-Tau levels or altered cell-type localisation. Future work will determine whether appa KO alters upstream proteostasis pathways, including ubiquitin-proteasome, lysosomal and autophagic systems, as well as downstream mitochondrial dysfunction and cell death. Together, these findings further support the killifish as a tractable model for studying age-related neurodegenerative mechanisms and may aid development of retinal biomarkers for diagnosis, disease staging, and severity assessment.
Lay Abstract
In ageing, the build-up of damaged proteins and the harmful effects that follow are well studied in the brain, particularly in conditions such as Alzheimer’s disease. The retina, often described as a window to the brain, may show similar changes. Questions remain regarding how much these harmful proteins accumulate in the healthy ageing retina. Studying this has been difficult, as traditional animal models live too long to efficiently observe ageing, while shorter-lived models often do not reflect human biology as closely. The African turquoise killifish is a powerful model that overcomes these challenges. Despite its short lifespan, it resembles human ageing and retains a comparable retinal structure. In this study, we investigated how proteins linked to neurodegenerative diseases are distributed in the retina during ageing, and whether reducing levels of a key Alzheimer’s-related protein (APP) improves retinal health. We found that disease-associated proteins accumulate in specific retinal cells that are particularly vulnerable to stress, including photoreceptors and neurons involved in visual processing. Importantly, similar patterns were observed in human retinal tissue. Future work will explore how these changes are linked to the cell’s ability to clear damaged proteins and maintain energy balance.
| Lay Title | The impact of amyloid precursor protein knockout on protein homeostasis in the ageing retina of African turquoise killifish |
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| Role | Master Student |