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Author Notes:

Address correspondence to: Nicholas T. Seyfried, Departments of Biochemistry, Emory University School of Medicine, 1510 Clifton Road, Atlanta, Georgia 30322. Tel. 404.712.9783, nseyfri@emory.edu

We are grateful to participants in the Baltimore Longitudinal Study of Aging (BLSA) and Emory brain bank donors for their invaluable contribution.

The authors have no conflicts of interest to report.

Subjects:

Research Funding:

Support was provided by the Accelerating Medicine Partnership AD grant U01AG046161-02, the NINDS Emory Neuroscience Core (P30NS055077), and the Emory Alzheimer’s Disease Research Center (P50AG025688).

This research was also supported in part by the Intramural Research Program of the NIH, National Institute on Aging. CMH is supported by NINDS K08NS087121 and by the American Brain Foundation.

NTS is supported in part by an Alzheimer’s Association (ALZ), Alzheimer’s Research UK (ARUK), The Michael J. Fox Foundation for Parkinson’s Research (MJFF), and the Weston Brain Institute Biomarkers Across Neurodegenerative Diseases Grant (11060).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Biochemical Research Methods
  • Biochemistry & Molecular Biology
  • Aggregation
  • Biomedicine
  • Mass spectrometry
  • Neurodegeneration
  • Proteostasis
  • Spliceosome
  • A-BETA
  • NEURODEGENERATIVE DISEASE
  • NEUROFIBRILLARY TANGLES
  • PROTEINS
  • DEMENTIA
  • TOXICITY
  • COMPLEX
  • THERAPEUTICS
  • AGGREGATION
  • ASSOCIATION

Changes in the detergent-insoluble brain proteome linked to amyloid and tau in Alzheimer's Disease progression

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Journal Title:

Proteomics

Volume:

Volume 16, Number 23

Publisher:

, Pages 3042-3053

Type of Work:

Article | Post-print: After Peer Review

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.

Copyright information:

© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

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