 |
Research Publications
Extensive p-Tau Pathology and SDS-Stable p-Tau Oligomers in Alzheimer's Cortical Synapses.Henkins KM, Sokolow S, Miller CA, Vinters HV, Poon WW, Cornwell LB, Saing T, Gylys KH.Neuroscience Interdepartmental Program School of NursingDepartments of Pathology and Laboratory Medicine Neurology, UCLA School of Medicine, Los Angeles, CA Departments of Pathology, Neurology, and Program in Neuroscience, Keck USC School of Medicine, Los Angeles, CA Institute on Brain Aging and Dementia, UC Irvine, Irvine, CA. Like amyloid beta (Aß) oligomers, tau aggregates are increasingly recognized as potential key toxic intermediates in Alzheimer's disease (AD) and as therapeutic targets. P-tau co-localizes with Aß in cortical AD synapses and may contribute to synapse dysfunction and loss. Flow cytometry analysis of synaptosomes from AD compared with aged cognitively normal cortex demonstrates increased immunolabeling for three p-tau antibodies (AT8, PHF-1 and pS422), indicating phosphorylation at multiple tau epitopes. Sequential extraction experiments show increased soluble p-tau in AD synapses, but a sizable pool of p-tau requires detergent solubilization, suggesting endosomal/lysosomal localization. P-tau is co-localized with Aß in individual synaptosomes in dual labeling experiments, and flow cytometry sorting of Aß-positive synaptosomes from an AD case reveals a marked enrichment of p-tau aggregates. The p-tau enrichment, a 76-fold increase over the initial homogenate, is consistent with sequestration of p-tau in internal synaptic compartments. Western analysis of a series of AD and normal cases shows SDS-stable tau oligomers in the dimer/trimer size range in AD samples. These results indicate that widespread synaptic p-tau pathology accompanies Aß accumulations in surviving synaptic terminals, particularly in late-stage AD. |
