title: Different β-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity.
abstract: In this study, we examined the relationship between various β-amyloid (Aβ) oligomer assemblies in autopsy brain with the levels of fibrillar Aβ and cholinergic synaptic function. Brain tissues obtained from the frontal cortex of 14 Alzheimer's disease (AD) patients grouped into early-onset AD (EOAD) and late-onset AD (LOAD) and 12 age-matched control subjects were used to extract and quantify Aβ oligomers in soluble (TBS), detergent soluble (TBST), and insoluble (GuHCl) fractions. The predominant oligomeric Aβ assemblies detected were dodecamers, decamers, and pentamers, and different patterns of expression were observed between EOAD and LOAD patients. There was no association between any of the detected Aβ oligomer assemblies and fibrillar Aβ levels measured by N-methyl[(3)H] 2-(40-methylaminophenyl)-6-hydroxy-benzothiazole ([(3)H]PIB) binding. Levels of pentamers in the soluble fraction significantly correlated with a reduction in choline acetyltransferase activity in AD patients. The number of nicotinic acetylcholine receptors negatively correlated with the total amount of Aβ oligomers in the insoluble fraction in EOAD patients, and with decamers in the soluble fraction in LOAD patients. These novel findings suggest that distinct Aβ oligomers induce impairment of cholinergic neurotransmission in AD pathogenesis.
authors.affiliation: Alzheimer Neurobiology Center, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Fuxiang
authors.initials: F
authors.lastname: Bao
authors.forename: Linn
authors.initials: L
authors.lastname: Wicklund
authors.forename: Pascale N
authors.initials: PN
authors.lastname: Lacor
authors.forename: William L
authors.initials: WL
authors.lastname: Klein
authors.forename: Agneta
authors.initials: A
authors.lastname: Nordberg
authors.forename: Amelia
authors.initials: A
authors.lastname: Marutle
mesh_terms: D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000814:Aniline Compounds; D001057:Apolipoproteins E / Q000235:genetics; D052160:Benzothiazoles / Q000493:pharmacokinetics; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D018678:Cholinergic Agents / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D005838:Genotype; D006801:Humans; D047468:Immunoprecipitation; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000493:pharmacokinetics; D018722:Nicotinic Agonists / Q000493:pharmacokinetics; D010446:Peptide Fragments / Q000378:metabolism*; D011180:Postmortem Changes; D011485:Protein Binding / Q000187:drug effects; D013223:Statistics as Topic; D013844:Thiazoles; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: C475519:2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole; D016229:Amyloid beta-Peptides; D000814:Aniline Compounds; D001057:Apolipoproteins E; D052160:Benzothiazoles; D018678:Cholinergic Agents; D018722:Nicotinic Agonists; D010446:Peptide Fragments; D013844:Thiazoles; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); D014316:Tritium; D009538:Nicotine