[o2–15–06]: seeding of cerebral amyloid‐beta misfolding by different routes of administration

Previous results by us and others demonstrate that cerebral deposition of amyloid-beta (Aβ) can be promoted by the administration of pre-formed aggregates, similarly as observed for infectious prions. In light of this data, we hypothesize that the prion-like properties of Aβ play important roles in the spread of misfolded particles. In this work, we assessed the contribution of peripheral Aβ aggregates in the acceleration of brain amyloidosis. In these studies, brain derived or purified recombinant Aβ aggregates were used as inocula. Experiments were done in Tg2576 and APP/PS1 mice. Animals were challenged with these aggregates by different routes including intra-cerebral, intra-venous, intra-peritoneal, intra-muscular, per oral and eye drops. Also, blood transfusions from old to young transgenic mice were tested. Pathological changes in experimental subjects were compared to amyloid deposition naturally developed in transgenic animals at different ages. Our results show that several routes of administration of Aβ seeds, with the sole exception of oral gavages, were able to accelerate brain amyloidosis. Importantly, we show that peripherally administered Aβ oligomers were more efficient in promoting pathological changes when compared to fibrils. Interestingly, seeded aggregates displayed different morphological and tinctorial features when compared to endogenous deposits naturally generated in old mice. Blood transfusions also accelerated Aβ deposition, albeit in a low degree compared to administrations of brain derived or recombinant inocula. Seeded aggregates were mostly associated to blood vessels, suggesting an important contribution of vasculature in periphery-to-brain transport. The brain anatomical distribution of seeded aggregates by peripheral administration was also explored. Our findings, together with previously published reports, suggest that peripherally administered Aβ aggregates are able to accelerate protein misfolding in the brain. Also, we show that oligomeric arrangements are more efficient to spread pathological changes in vivo when compared to their fibrillar counterparts. These results contribute to understand the mechanisms implicated in the initiation and progression of Aβ pathology. Also, our data may be useful to identify new targets for therapeutic intervention and diagnosis.