Journal
BRAIN PATHOLOGY
Volume 22, Issue 6, Pages 826-833Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1750-3639.2012.00598.x
Keywords
Alzheimer's disease; amyloid beta; flow cytometry; pS422 antibody; synaptosome; tau
Categories
Funding
- NIH [5AG016570, CA 16042, AI 28697, AG27465, CA16042]
- NIA [AG18879]
- Daljit S and Elaine Sarkaria Chair in Diagnostic Medicine
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine
- Chancellor's Office at UCLA
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Like amyloid beta (A beta) 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 A beta 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 A beta in individual synaptosomes in dual labeling experiments, and flow cytometry sorting of A beta-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 A beta accumulations in surviving synaptic terminals, particularly in late-stage AD.
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