title: Proteomic differences in amyloid plaques in rapidly progressive and sporadic Alzheimer's disease.
abstract: Rapidly progressive Alzheimer's disease (rpAD) is a particularly aggressive form of Alzheimer's disease, with a median survival time of 7-10 months after diagnosis. Why these patients have such a rapid progression of Alzheimer's disease is currently unknown. To further understand pathological differences between rpAD and typical sporadic Alzheimer's disease (sAD) we used localized proteomics to analyze the protein differences in amyloid plaques in rpAD and sAD. Label-free quantitative LC-MS/MS was performed on amyloid plaques microdissected from rpAD and sAD patients (n = 22 for each patient group) and protein expression differences were quantified. On average, 913 ± 30 (mean ± SEM) proteins were quantified in plaques from each patient and 279 of these proteins were consistently found in plaques from every patient. We found significant differences in protein composition between rpAD and sAD plaques. We found that rpAD plaques contained significantly higher levels of neuronal proteins (p = 0.0017) and significantly lower levels of astrocytic proteins (p = 1.08 × 10-6). Unexpectedly, cumulative protein differences in rpAD plaques did not suggest accelerated typical sAD. Plaques from patients with rpAD were particularly abundant in synaptic proteins, especially those involved in synaptic vesicle release, highlighting the potential importance of synaptic dysfunction in the accelerated development of plaque pathology in rpAD. Combined, our data provide new direct evidence that amyloid plaques do not all have the same protein composition and that the proteomic differences in plaques could provide important insight into the factors that contribute to plaque development. The cumulative protein differences in rpAD plaques suggest rpAD may be a novel subtype of Alzheimer's disease.
authors.affiliation: Department of Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, USA. eleanor.drummond@nyumc.org.
authors.forename: Eleanor
authors.initials: E
authors.lastname: Drummond
authors.affiliation: Proteomics Laboratory, Division of Advanced Research Technologies, NYU School of Medicine, New York, NY, USA.
authors.forename: Shruti
authors.initials: S
authors.lastname: Nayak
authors.affiliation: Department of Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, USA.
authors.forename: Arline
authors.initials: A
authors.lastname: Faustin
authors.affiliation: Department of Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, USA.
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Pires
authors.affiliation: Department of Pathology, NYU School of Medicine, New York, NY, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Hickman
authors.affiliation: Biomedical Hosting LLC, Arlington, MA, USA.
authors.forename: Manor
authors.initials: M
authors.lastname: Askenazi
authors.affiliation: Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Cohen
authors.affiliation: Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Tracy
authors.initials: T
authors.lastname: Haldiman
authors.affiliation: Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Chae
authors.initials: C
authors.lastname: Kim
authors.affiliation: Departments of Population Health and Environmental Medicine, NYU School of Medicine, New York, NY, USA.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Han
authors.affiliation: Departments of Population Health and Environmental Medicine, NYU School of Medicine, New York, NY, USA.
authors.forename: Yongzhao
authors.initials: Y
authors.lastname: Shao
authors.affiliation: Departments of Pathology and Neurology, National Prion Disease Pathology Surveillance Center, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Jiri G
authors.initials: JG
authors.lastname: Safar
authors.affiliation: Proteomics Laboratory, Division of Advanced Research Technologies, NYU School of Medicine, New York, NY, USA.|Department of Biochemistry and Molecular Pharmacology, NYU School of Medicine, New York, NY, USA.
authors.forename: Beatrix
authors.initials: B
authors.lastname: Ueberheide
authors.affiliation: Department of Neurology, Center for Cognitive Neurology, NYU School of Medicine, New York, NY, USA. thomas.wisniewski@nyumc.org.|Department of Pathology, NYU School of Medicine, New York, NY, USA. thomas.wisniewski@nyumc.org.|Department of Psychiatry, NYU School of Medicine, New York, NY, USA. thomas.wisniewski@nyumc.org.
authors.forename: Thomas
authors.initials: T
authors.lastname: Wisniewski
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D002853:Chromatography, Liquid; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D008297:Male; D042282:Microdissection; D018613:Microscopy, Confocal; D008875:Middle Aged; D016501:Neurites / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D020543:Proteome; D040901:Proteomics; D053719:Tandem Mass Spectrometry
chemical_list: D020543:Proteome