P006 - SYNTHETIC AND NATURAL CONFORMATIONAL VARIANTS OF MISFOLDED AΒ INDUCE DIFFERENT PATHOLOGICAL FEATURES IN SUSCEPTIBLE MICE. (ID 1742)

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Abstract

Aims

Compelling evidence in humans and experimental rodents suggest that Alzheimer’s disease (AD)-associated Aβ exists in a variety of conformational strains. The biological significance of Aβ strain variation in AD has not been addressed. This acquires relevance considering that mixtures of Aβ strains seems to exist in the brains of patients. Aβ strain variation may explain pathological and clinical differences observed among people afflicted by AD.

Methods

Here, we used brain-derived and synthetic Aβ strains to assess for potential differences in propagation and pathological manifestations.

Results

In a first set of experiments, two synthetic-Aβ40 strains (2F and 3F) that have been thoroughly studied for their structural motifs, were biochemically characterized and injected in the brains of 50 days-old Tg2576 mice. We assessed prion-like transmission of these materials by analyzing Aβ deposition 250 days later. A second set of experiments involved the administration of AD brain homogenates from individuals displaying diverse amyloid pathology. These brain extracts were intra-cerebrally injected into 30 days-old APP/PS1 mice that were sacrificed 150 days later. Pathological differences in both experiments were found at different levels, including the type and anatomical distribution of the aggregates, Aβ40/Aβ42 ratios, reactivity of amyloid deposits to dyes able to discriminate among misfolded protein conformations, among others. Importantly, differences in astro- and micro-glial activation were also observed.

Conclusions

Our data support the concept and biological relevance of conformational strain variation in non-prion protein misfolding disorders. Our findings may help to identify the most deleterious particles responsible for AD and design conformation-specific strategies for diagnosis and treatment.

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