AD synapses contain abundant Aβ monomer and multiple soluble oligomers, including a 56-kDa assembly

NEUROBIOLOGY OF AGING

卷:33

Article

Sokolow, Sophie^1,2  Henkins, Kristen M.³  Bilousova, Tina^1,2  Miller, Carol A.^4,5,6  Vinters, Harry V.^7,8  Poon, Wayne⁹  Cole, Gregory M.^8,10,11  Gylys, Karen Hoppens^1,2,3 

[1] Univ Calif Los Angeles, Sch Nursing, Los Angeles, CA 90024 USA

[2] Univ Calif Los Angeles, Mary S Easton Ctr Alzheimers Res, Los Angeles, CA USA

[3] Univ Calif Los Angeles, Sch Med, Neurosci Interdept Program, Los Angeles, CA USA

[4] Keck USC Sch Med, Dept Pathol, Los Angeles, CA USA

[5] Keck USC Sch Med, Dept Neurol, Los Angeles, CA USA

[6] Keck USC Sch Med, Dept Program Neurosci, Los Angeles, CA USA

[7] Univ Calif Los Angeles, Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90024 USA

[8] Univ Calif Los Angeles, Sch Med, Dept Neurol, Los Angeles, CA 90024 USA

[9] UC Irvine, Inst Memory Impairments & Neurol Disorders, Irvine, CA USA

[10] Univ Calif Los Angeles, Sch Med, Dept Med, Los Angeles, CA 90024 USA

[11] Univ Calif Los Angeles, Sch Med, Sepulveda VAMC GRECC, Los Angeles, CA USA

关键词: Synaptosome;    Flow cytometry;    Parkinson's disease;    Synaptophysin;    PSD-95;    A11 antibody;    OC antibody;   

DOI  :  10.1016/j.neurobiolaging.2011.05.011

来源: Elsevier

【 摘 要 】

Much evidence indicates that soluble amyloid beta (A beta) oligomers are key mediators of early cognitive loss, but the localization and key peptide species remain unclear. We have used flow cytometry analysis to demonstrate that surviving Alzheimer's disease (AD) synapses accumulate both A beta and phosphorylated tau (p-tau). The present experiments use peptide-specific X-map assays and Western blot analyses to identify the A beta peptide species in synaptosome-enriched samples from normal human subjects, neurologic controls, and AD cases. A beta 40 peptide levels did not vary, but both A beta 42 and A beta oligomers were increased in soluble AD extracts, with oligomer levels 20-fold higher in aqueous compared with detergent extracts. In Western blot analysis, a ladder of sodium dodecyl sulfate (SDS)-stable oligomers was observed in AD cases, varying in size from monomer, the major peptide observed, to larger assemblies up to about 200 kDa and larger. Multiple oligomers, including monomer, small oligomers, a 56-kDa assembly, and amyloid precursor protein (APP) were correlated with the A beta level measured in flow cytometry-purified synaptosomes. These results suggest that multiple amyloid precursor protein processing pathways are active in AD synapses and multiple soluble oligomeric assemblies may contribute to synaptic dysfunction. (C) 2012 Elsevier Inc. All rights reserved.

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