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

Ruben Gomez-Gutierrez

University of Malaga (Spain)/UTHealth Houston


Objectives: Accumulation of the amyloid beta (Aβ) peptide as amyloid fibrils in the brain is associated with Alzheimer’s disease (AD) progression. These amyloid fibrils can be manifested in distinct conformations or “strains” as a consequence of variations in their molecular structure. Aβ strain variation may be crucial for drug discovery and therapeutic purposes. In the case of synthetic Aβ1-40, two different fibrils, 2F and 3F, have been produced in vitro and extensively characterized for their structural motifs. These fibrils are faithfully propagated in vitro in a prion-like fashion. Here, we aimed to analyze the in vivo propagation of these Aβ “strains”. Methods: In the present study, the 2F and 3F fibrils were further characterized by TEM, protease resistance and in vitro aggregation assays. To analyze the in vivo prion-like features of these aggregates, 2F and 3F fibrils were intracerebrally administered in 50 days old tg2576 mice. Prion-like transmission of these aggregates was assessed in their brains 100 and 250 days post administration by immunohistochemistry and ELISA. Results: Our results show that the 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, vascular Aβ accumulation, and tau deposition, etc. were also explored. Conclusion: Our results show that structurally distinct Aβ fibrils differentially induce brain amyloidosis in vivo, thus raising the possibility that different amyloid conformers have different pathogenicity affecting the outcome of AD patients. These results should be taken into account in order to develop new drugs for Alzheimer’s disease since compounds could have distinct activities against different Aβ strains. We strongly believe that this discovery will lead to personalized, Aβ conformation-dependent, therapies for Alzheimer’s disease.

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