Titration of biologically active amyloid-beta seeds in a transgenic mouse model of Alzheimer's disease

Experimental evidence in animal models suggests that misfolded Amyloid-beta (A beta) spreads in disease following a prion-like mechanism. Several properties characteristics of infectious prions have been shown for the induction of A beta aggregates. However, a detailed titration of A beta misfolding transmissibility and estimation of the minimum concentration of biologically active A beta seeds able to accelerate pathological changes has not yet been performed. In this study, brain extracts from old tg2576 animals were serially diluted and intra-cerebrally injected into young subjects from the same transgenic line. Animals were sacrificed several months after treatment and brain slices were analyzed for amyloid pathology. We observed that administration of misfolded A beta was able to significantly accelerate amyloid deposition in young mice, even when the original sample was diluted a million times. The titration curve obtained in this experiment was compared to the natural A beta load spontaneously accumulated by these mice overtime. Our findings suggest that administration of the largest dose of A beta seeds led to an acceleration of pathology equivalent to over a year. These results show that active A beta seeds present in the brain can seed amyloidosis in a titratable manner, similarly as observed for infectious prions.