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Amyloid beta conformational strains induce distinct pathology in animal models of Alzheimer’s

Amyloid beta conformational strains induce distinct pathology in animal models of Alzheimer’s disease: Opportunities for personalized therapies in AD?

Ruben Gomez-Gutierrez

University of Malaga (Spain)/UTHealth Houston

Accumulation of the amyloid-β (Aβ) in the brain is associated with Alzheimer’s disease (AD). Compelling evidence suggest that Aβ deposition in AD follow similar mechanisms as the ones described for infectious prions. In that sense, several features of prions have been described for Aβ aggregates, including the existence of different conformational variants or “strains”. In fact, amyloid fibrils commonly exhibit distinct morphologies as a consequence of variations in their molecular structure. In the case of Aβ1-40, two morphologically distinct fibrils, 2F and 3F, have been produced in vitro and extensively characterized for their structural motifs. Both, the morphology of these fibrils and the molecular structure of their protofilaments, are self-propagating in vitro. We hypothesized that specific Aβ strains in AD are responsible for pathological progression including toxicity, tissue and cell tropism and prion-like rate of propagation. In the present study, brains collected from AD patients showing distinct pathology were injected intracerebrallly (IC) in 30 days-old APP/PS1 mice. Treated animals were sacrificed at 180 days old and brains were analyzed for their content of Aβ. To analyze the in vivo self-propagating properties of purified Aβ, and to make correlations between specific structural features and pathological outcomes, we also injected 2F or 3F fibrils IC into Tg2576 AD transgenic mice which were sacrificed at different time points. Results show that animals treated with the different AD-derived extracts displayed diverse Aβ pathology. Interestingly, when comparing the specific efficiency of each inoculum, we observed different seeding potentials. In the case of the in vitro prepared fibrils, animals receiving 2F fibrils preferentially accumulates Aβ40, differently from brain-derived propagons that recruited Aβ40 and Aβ42 in similar proportions. Moreover, 2F injected animals also presented a significant increase in aggregated Aβ42 levels with respect to 3F injected animals. Other parameters, such as astro- and micro-glial activation and vascular Aβ accumulation, etc. were also explored. Overall, we found that brain extracts from AD patients displaying a variety of Aβ deposits propagate differently in susceptible animals. A similar scenario was found for structurally defined synthetic Aβ aggregates. These results raise the possibility that different amyloid morphologies lead to specific pathological events affecting the clinical outcome of AD pa

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