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Ajay Ashok, Suman Chaudhary, Neil Akash Rana, Alexander Kritikos, Rithvik V Ayyagari, Neena Singh; The prion protein as a mediator of amyloid-β toxicity in retinal and glaucomatous degeneration associated with Alzheimer’s disease. Invest. Ophthalmol. Vis. Sci. 2020;61(7):244.
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© ARVO (1962-2015); The Authors (2016-present)
Retinal and glaucomatous degeneration are prominent features of Alzheimer's disease (AD). The underlying cause is unclear, though accumulation of amyloid-β (Aβ) in the retina has been implicated as a potential cause. Here, we explored whether the prion protein (PrPC), a receptor and mediator of Aβ-induced toxicity, plays a role in AD-associated glaucomatous and retinal degeneration.
The retina, trabecular meshwork (TM), aqueous humor (AH) and vitreous humor (VH) were isolated from human cadaveric eyes. Primary human TM cells were cultured in our facility. ARPE19 cells were obtained from ATCC and used until passage 20. Expression of PrPC, amyloid precursor protein (APP), their proteolytic cleavage products, and expression of ADAM10 and ADAM17, enzymes responsible for the cleavage of PrPC and APP, was assessed in the above tissues using a combination of Western blotting, RT-PCR, and siRNA techniques.
PrPC is expressed in retinal and TM tissue and cells. However, in contrast to the brain where majority of PrPC undergoes α-cleavage that eliminates both Aβ-binding sites on cell-associated C-terminal PrPC or C1, most of the PrPC in the retina and TM is cleaved at the β-site, leaving one Aβ binding site on cell-associated PrPC or C2. The respective N-terminal fragments N1 and N2 in the AH and VH carry two and one Aβ-binding sites respectively. Full-length APP is also expressed in the retina, and surprisingly, in the TM as well. Soluble APPα and Aβ oligomers are present in the AH and VH. ADAM 10 and ADAM17 are synthesized and expressed in the retina and TM, and their downregulation in ARPE19 cells increases β-cleavage of APP, an obligatory cleavage that, when followed by gamma-cleavage, releases toxic Aβ.
The expression of APP in the retina and TM provides a local source of Aβ in AD cases. Expression of mainly β-cleaved PrPC in the retina and TM leaves an available Aβ binding site, increasing the vulnerability of these cells to Aβ-mediated toxicity. The N1 and N2 fragments of PrPC are likely to sequester soluble Aβ in the AH and VH, thus playing an opposing role to cell membrane-bound PrPC. Thus, PrPC plays a significant role in AD associated glaucomatous and retinal degeneration, and α vs. β-cleavage of PrPC is a major determinant of this process.
This is a 2020 ARVO Annual Meeting abstract.
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