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

Purro, S. A.; Farmer, M.; Noble, E.; Sarell, C. J.; Powell, M.; Yip, D. C.-M.; Giggins, L.; Zakka, L.; Thomas, D. X.; Farrow, M. A.; Nicoll, A. J.; Walsh, D. M.; Collinge, J.

doi:10.1101/2022.09.25.508690

bioRxiv · 10.1101/2022.09.25.508690

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

Purro, S. A.·Farmer, M.·Noble, E.·Sarell, C. J.·Powell, M.·Yip, D. C.-M.·Giggins, L.·Zakka, L.·Thomas, D. X.·Farrow, M. A.·Nicoll, A. J.·Walsh, D. M.·Collinge, J.

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Abstract

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.

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Purro, S. A., Farmer, M., Noble, E., Sarell, C. J., Powell, M., Yip, D. C.-M., Giggins, L., Zakka, L., Thomas, D. X., Farrow, M. A., Nicoll, A. J., Walsh, D. M., Collinge, J.. 2022-09-27. Impact of cellular prion protein expression on disease progression and pathology in two mouse models of Alzheimer's disease. https://doi.org/10.1101/2022.09.25.508690

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