A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer’s disease
Rosie Freer¹, Pietro Sormanni¹, Prajwal Ciryam¹ ², Christopher M. Dobson¹ and Michele Vendruscolo¹
1, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
2, Department of Molecular Biosciences, Northwestern University, Evanston IL 60208, USA
In Alzheimer’s disease, aberrant aggregates primarily composed of amyloid-beta and tau develop progressively across brain tissues following a specific spatio-temporal pattern. Although this pattern has been characterised for more than two decades [1], the mechanisms that govern the selective vulnerability of tissues remain under debate. To address this problem, we use transcriptional analysis of normal brains to identify an expression signature that predicts the vulnerability of different tissues to disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the specific expression patterns of the proteins that co-aggregate with amyloid-beta and tau, together with protein homeostasis components that regulate amyloid-beta and tau. Our analysis provides an explanatory link between a tissue-specific risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease [2].
1. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 82, 239-259 (1991).
2. Freer et al. Science Advances (2016)
Rosie Freer¹, Pietro Sormanni¹, Prajwal Ciryam¹ ², Christopher M. Dobson¹ and Michele Vendruscolo¹
1, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK
2, Department of Molecular Biosciences, Northwestern University, Evanston IL 60208, USA
In Alzheimer’s disease, aberrant aggregates primarily composed of amyloid-beta and tau develop progressively across brain tissues following a specific spatio-temporal pattern. Although this pattern has been characterised for more than two decades [1], the mechanisms that govern the selective vulnerability of tissues remain under debate. To address this problem, we use transcriptional analysis of normal brains to identify an expression signature that predicts the vulnerability of different tissues to disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the specific expression patterns of the proteins that co-aggregate with amyloid-beta and tau, together with protein homeostasis components that regulate amyloid-beta and tau. Our analysis provides an explanatory link between a tissue-specific risk of protein aggregation and a corresponding vulnerability to Alzheimer’s disease [2].
1. Braak, H. & Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta neuropathologica 82, 239-259 (1991).
2. Freer et al. Science Advances (2016)
