Impact of cellular prion protein expression on disease progression and pathology in two mouse models of Alzheimer's disease

The aggregation of amyloid-{beta} (A{beta}) monomers increases their neurotoxicity, and these oligomeric species are thought to be central to the pathogenesis of Alzheimers disease. Unsurprisingly for such a complex disease, current Alzheimers disease mouse models fail to fully mimic the clinical disease in humans. Moreover, results obtained in a given mouse model are not always reproducible in a different model. Cellular prion protein (PrPC) is now an established receptor for A{beta} oligomers. However, different groups studying the A{beta}-PrPC interaction in vivo using a variety of mouse models have obtained contradictory results. Here we performed a longitudinal study in two commonly used AD mouse models using a range of biochemical, histological and behavioural techniques and found similar contradictory results and a possible explanation for the discrepancy. We propose that these two mouse models produce A{beta} oligomers with different conformations. Therefore, binding to PrPC and the subsequent activation of toxic signalling cascade will occur only when the A{beta} oligomer species with appropriate conformation are present. Hence, it is crucial to select the appropriate model producing the appropriate species of A{beta} oligomers to study specific aspects of {beta}-amyloidosis and its downstream pathways. Further conformational characterisation of A{beta} oligomers and their binding to PrPC is required to better understand A{beta} neurotoxicity.