Wednesday, April 2, 2025
4/2/2025
Seeding activity of misfolded Abeta in eyes of Alzheimer's disease patients - Compelling evidence collected in in vitro and in vivo experimental systems, and data from autopsied human brains, suggest that misfolded Aβ spread similarly as infectious prions do. In fact, several features defining prions as infectious particles have been found for Aβ peptides, including the acceleration of brain amyloidosis by peripheral exposure to preformed aggregates in animal models and humans. Recently, we described that ocular exposure to misfolded Aβ is the most efficient route of peripheral pathological induction. This acquires relevance as Aβ deposits have been identified in the eyes of Alzheimer’s disease (AD) patients, and that several surgical procedures, including corneal transplants, are commonly performed in humans. At present, no studies linking eye surgical procedures and AD are available. However, recent reports demonstrate the transmission of Aβ amyloidosis and AD between humans in the context of the administration of cadaveric human-derived formulations. Although these transmission events are rare, and prone to occur under specific circumstances, the evidence discussed above warrants additional research in this area to either identify or discard not noticed detrimental events occurring as a consequence of medical procedures. For that purpose, we plan to i) characterize the biochemical and biological properties of eye´s misfolded Aβ and compare it to its brain counterpart; and ii) evaluate the seeding potential of eye’s misfolded Aβ using mouse bioassays. This will be done by utilizing a diverse and complementary array of techniques, including biochemical and histological assays in human eyes and brains, in vitro and in vivo seeding models, behavioral testing in mouse models of AD receiving intra-cerebral injections of eye extracts, and pathological characterizations of the same. It is accepted that misfolded Aβ share multiple properties with prions. Whether these include inter-individual transmission is still debated. Solid evidence in mouse models and few reports in human samples strongly suggest that this has occurred but in specific conditions. The experiments proposed here plan to provide initial (proof-of-concept) evidence of Aβ misfolding transmission events involving eye tissues. If positive, future studies will test whether ocular exposure to AD patients’ cornea or other surgical eye procedures accelerate pathology in established mouse models and non-human primates. On the contrary, the absence of seeding activity will indicate us that corneal transplants are safe in the context of inter-individual transmission of protein misfolding.
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