title: Synaptic Amyloid-β Oligomers Precede p-Tau and Differentiate High Pathology Control Cases.
abstract: Amyloid-β (Aβ) and hyperphosphorylated tau (p-tau) aggregates form the two discrete pathologies of Alzheimer disease (AD), and oligomeric assemblies of each protein are localized to synapses. To determine the sequence by which pathology appears in synapses, Aβ and p-tau were quantified across AD disease stages in parietal cortex. Nondemented cases with high levels of AD-related pathology were included to determine factors that confer protection from clinical symptoms. Flow cytometric analysis of synaptosome preparations was used to quantify Aβ and p-tau in large populations of individual synaptic terminals. Soluble Aβ oligomers were assayed by a single antibody sandwich enzyme-linked immunosorbent assay. Total in situ Aβ was elevated in patients with early- and late-stage AD dementia, but not in high pathology nondemented controls compared with age-matched normal controls. However, soluble Aβ oligomers were highest in early AD synapses, and this assay distinguished early AD cases from high pathology controls. Overall, synapse-associated p-tau did not increase until late-stage disease in human and transgenic rat cortex, and p-tau was elevated in individual Aβ-positive synaptosomes in early AD. These results suggest that soluble oligomers in surviving neocortical synaptic terminals are associated with dementia onset and suggest an amyloid cascade hypothesis in which oligomeric Aβ drives phosphorylated tau accumulation and synaptic spread. These results indicate that antiamyloid therapies will be less effective once p-tau pathology is developed.
authors.affiliation: University of California Los Angeles School of Nursing, Los Angeles, California; Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California.
authors.forename: Tina
authors.initials: T
authors.lastname: Bilousova
authors.affiliation: Departments of Pathology, Neurology, and the Program in Neuroscience, University of Southern California Keck School of Medicine, Los Angeles, California.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Miller
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California.
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Poon
authors.affiliation: Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California; Department of Pathology and Laboratory Medicine, University of California Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Harry V
authors.initials: HV
authors.lastname: Vinters
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California; Department of Neurology, University of California Irvine, Irvine, California.
authors.forename: Maria
authors.initials: M
authors.lastname: Corrada
authors.affiliation: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, California; Department of Neurology, University of California Irvine, Irvine, California; Department of Neurobiology & Behavior, University of California Irvine, Irvine, California.
authors.forename: Claudia
authors.initials: C
authors.lastname: Kawas
authors.affiliation: Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California; Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California.
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Hayden
authors.affiliation: Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California; Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California.
authors.forename: David B
authors.initials: DB
authors.lastname: Teplow
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California.
authors.forename: Charles
authors.initials: C
authors.lastname: Glabe
authors.affiliation: Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, California.
authors.forename: Ricardo
authors.initials: R
authors.lastname: Albay
authors.affiliation: Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California; Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California; Department of Medicine, University of California Los Angeles School of Medicine, Los Angeles, California; Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: Gregory M
authors.initials: GM
authors.lastname: Cole
authors.affiliation: Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California; Department of Neurology, University of California Los Angeles School of Medicine, Los Angeles, California; Geriatric Research, Education and Clinical Center, VA Greater Los Angeles Healthcare System, Los Angeles, California.
authors.forename: Edmond
authors.initials: E
authors.lastname: Teng
authors.affiliation: University of California Los Angeles School of Nursing, Los Angeles, California; Mary S. Easton Center for Alzheimer's Research at the University of California Los Angeles, Los Angeles, California. Electronic address: kgylys@sonnet.ucla.edu.
authors.forename: Karen H
authors.initials: KH
authors.lastname: Gylys
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000032:analysis*; D000818:Animals; D001921:Brain / Q000473:pathology; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D018613:Microscopy, Confocal; D010766:Phosphorylation; D051381:Rats; D055647:Rats, Transgenic; D013569:Synapses / Q000473:pathology*; D016875:tau Proteins / Q000032:analysis*
chemical_list: D016229:Amyloid beta-Peptides; D016875:tau Proteins