Originally Posted on Scientific Reports | 23 March 2015
Experimental evidence in animal model of Alzheimer’s Disease suggests that misfolded Amyloid-b (Ab) spreads in disease following a prion-like mechanism. Several properties characteristics of infectious prions have been shown for the induction of Ab aggregates. However, a detailed titration of Ab misfolding transmissibility and estimation of the minimum concentration of biologically active Ab seeds able to accelerate pathological changes has not yet been performed.
In this study, brain extracts from old tg2576 animals were serially diluted and intracerebrally 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 Ab 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 Ab load spontaneously accumulated by these mice overtime. Our findings suggest that administration of the largest dose of Ab seeds led to an acceleration of pathology equivalent to over a year. These results show that active Ab seeds present in the brain can seed amyloidosis in a titratable manner, similarly as observed for infectious prions.
Brain deposition of amyloid-b (Ab) aggregates is a hallmark feature of Alzheimer’s disease (AD). Accumulation of misfolded Ab has been linked to cell and synaptic toxicity in both in vitro and in vivo models. The most promising therapeutic strategies aimed to combat AD principally focus to modify the production and aggregation of this peptide.
Protein aggregates sharing similar biophysical properties to those formed by Ab in AD are found in various other diseases, termed Protein Misfolding Disorders (PMDs). PMDs include several neurodegenerative disorders, such as Parkinson’s and Huntington’s diseases, and prion diseases or transmissible spongiform encephalopaties (TSEs), among others. TSEs are so far the only PMDs considered to be infectious. The infectious agent in TSEs, known as prion, is thought to be composed exclusively by the misfolded form (PrPSc) of a normally synthesized protein, termed PrPC. The mechanism of prion transmission is best accounted by the seeding/nucleation model, in which aggregates or ‘‘seeds’’ of the infectious protein are able to recruit monomeric PrPC into the growing aggregate, where they acquire the misfolded conformation and can serve to further replicate prions. As extensively reported, the formation of amyloid aggregates in PMDs also follows the seeding/nucleation model, and therefore these aggregates have the potential for prion-like transmission.
Several studies have shown that Ab and other disease-associated misfolded protein aggregates are experiment-ally transmissible in vivo. However, the lack of epidemiological data showing inter-individual transmission in other PMDs besides TSEs, suggests that prion-like mechanisms mostly operate to spread these deleterious aggregates between different tissues and cells within the affected individual. In the specific case of Ab, most of the experiments have been performed by accelerating spontaneous deposition of aggregates produced by over-expression of mutant genes. Nevertheless, some experiments have shown induced aggregation in animal models that normally do not develop amyloid deposits during their natural lifespan, a fact approaching better to the situation in naı¨ve prion infected animals.
One of the important characteristics of the prion agent is that its capacity to transmit pathology is directly proportional to the quantity of the misfolded protein inoculated and that transmission can be observed even after administration of highly diluted concentrations of prion-infected brain extracts. Titration of infectious prions is useful to estimate the load of infectious agent in specific samples, as well as to quantitatively determine the therapeutic effect of candidate drugs or treatments. The main goal of this study was to titrate biologically active Ab seeds in vivo in a similar way as performed for infectious prions.