Open AccessExtensive p‐Tau Pathology and SDS‐Stable p‐Tau Oligomers in Alzheimer's Cortical Synapses
Author(s) -
Henkins Kristen M.,
Sokolow Sophie,
Miller Carol A.,
Vinters Harry V.,
Poon Wayne W.,
Cornwell Lindsey B.,
Saing Tommy,
Gylys Karen Hoppens
Publication year - 2012
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2012.00598.x
Subject(s) - tau protein , immunolabeling , synapse , chemistry , alzheimer's disease , flow cytometry , neuroscience , biology , microbiology and biotechnology , pathology , immunohistochemistry , medicine , disease , immunology
Like amyloid beta (Aβ) 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 Aβ 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 Aβ in individual synaptosomes in dual labeling experiments, and flow cytometry sorting of Aβ‐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 Aβ accumulations in surviving synaptic terminals, particularly in late‐stage AD.