title: Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression.
abstract: Despite a key role of amyloid-beta (Aβ) in Alzheimer's disease (AD), mechanisms that link Aβ plaques to tau neurofibrillary tangles and cognitive decline still remain poorly understood. The purpose of this study was to quantify proteins in the sarkosyl-insoluble brain proteome correlated with Aβ and tau insolubility in the asymptomatic phase of AD (AsymAD) and through mild cognitive impairment (MCI) and symptomatic AD. Employing label-free mass spectrometry-based proteomics, we quantified 2711 sarkosyl-insoluble proteins across the prefrontal cortex from 35 individual cases representing control, AsymAD, MCI and AD. Significant enrichment of Aβ and tau in AD was observed, which correlated with neuropathological measurements of plaque and tau tangle density, respectively. Pairwise correlation coefficients were also determined for all quantified proteins to Aβ and tau, across the 35 cases. Notably, six of the ten most correlated proteins to Aβ were U1 small nuclear ribonucleoproteins (U1 snRNPs). Three of these U1 snRNPs (U1A, SmD and U1-70K) also correlated with tau consistent with their association with tangle pathology in AD. Thus, proteins that cross-correlate with both Aβ and tau, including specific U1 snRNPs, may have potential mechanistic roles in linking Aβ plaques to tau tangle pathology during AD progression.
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Chadwick M
authors.initials: CM
authors.lastname: Hales
authors.affiliation: Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Eric B
authors.initials: EB
authors.lastname: Dammer
authors.affiliation: Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Qiudong
authors.initials: Q
authors.lastname: Deng
authors.affiliation: Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Duc M
authors.initials: DM
authors.lastname: Duong
authors.affiliation: Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.|Department of Experimental Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Marla
authors.initials: M
authors.lastname: Gearing
authors.affiliation: Departments of Pathology and Neurology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
authors.forename: Juan C
authors.initials: JC
authors.lastname: Troncoso
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
authors.forename: Madhav
authors.initials: M
authors.lastname: Thambisetty
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Lah
authors.affiliation: Departments of Neurology, Neuroscience, and Molecular & Human Genetics and Program in Developmental Biology, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Joshua M
authors.initials: JM
authors.lastname: Shulman
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Allan I
authors.initials: AI
authors.lastname: Levey
authors.affiliation: Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA.|Center for Neurodegenerative Disease, Emory University School of Medicine, Atlanta, GA, USA.|Department of Biochemistry, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Nicholas T
authors.initials: NT
authors.lastname: Seyfried
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016022:Case-Control Studies; D060825:Cognitive Dysfunction / Q000378:metabolism / Q000473:pathology; D003902:Detergents / Q000737:chemistry; D005260:Female; D006801:Humans; D008297:Male; D011506:Proteins / Q000032:analysis / Q000737:chemistry / Q000378:metabolism*; D020543:Proteome / Q000032:analysis / Q000737:chemistry; D040901:Proteomics / Q000379:methods; D017412:Ribonucleoprotein, U1 Small Nuclear / Q000737:chemistry / Q000378:metabolism; D053719:Tandem Mass Spectrometry / Q000379:methods; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D003902:Detergents; C054369:MAPT protein, human; D011506:Proteins; D020543:Proteome; D017412:Ribonucleoprotein, U1 Small Nuclear; D016875:tau Proteins
keywords: Aggregation; Biomedicine; Mass spectrometry; Neurodegeneration; Proteostasis; Spliceosome