title: A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease.
abstract: In Alzheimer's disease, aggregates of Aβ and tau in amyloid plaques and neurofibrillary tangles spread progressively across brain tissues following a characteristic pattern, implying a tissue-specific vulnerability to the disease. We report a transcriptional analysis of healthy brains and identify an expression signature that predicts-at ages well before the typical onset-the tissue-specific progression of the disease. We obtain this result by finding a quantitative correlation between the histopathological staging of the disease and the expression patterns of the proteins that coaggregate in amyloid plaques and neurofibrillary tangles, together with those of the protein homeostasis components that regulate Aβ and tau. Because this expression signature is evident in healthy brains, our analysis provides an explanatory link between a tissue-specific environmental risk of protein aggregation and a corresponding vulnerability to Alzheimer's disease.
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Rosie
authors.identifier: 0000-0003-4203-0964
authors.initials: R
authors.lastname: Freer
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Pietro
authors.initials: P
authors.lastname: Sormanni
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Giulia
authors.initials: G
authors.lastname: Vecchi
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.; Department of Molecular Biosciences, Northwestern University, Evanston, IL 60208, USA.
authors.forename: Prajwal
authors.identifier: 0000-0002-1445-0577
authors.initials: P
authors.lastname: Ciryam
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
mesh_terms: D000328:Adult; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000096:biosynthesis* / Q000235:genetics; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D001931:Brain Mapping; D018450:Disease Progression; D006706:Homeostasis; D006801:Humans; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D009928:Organ Specificity; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000235:genetics; D059467:Transcriptome; D016875:tau Proteins / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins
keywords: Alzheimer’s disease; protein aggregation; protein homeostasis; tissue vulnerability