Journal
JOURNAL OF NEUROCHEMISTRY
Volume 133, Issue 3, Pages 368-379Publisher
WILEY
DOI: 10.1111/jnc.12991
Keywords
Alzheimer's disease; flow cytometry; synaptosome; tau cleavage; tau fragment; tau release
Categories
Funding
- Alzheimer's association [NIRG-11-200508]
- UCLA School of Nursing
- NIA [R01AG27465, R01AG18879]
- Daljit S. and Elaine Sarkaria Chair in Diagnostic Medicine
- Alzheimer's Disease Research Center Neuropathology Cores of USC [NIA P50 AG05142]
- UCLA [NIA P50 AG 16970]
- UC Irvine [NIA P50 AG016573]
- NIH [CA16042, AI 28697]
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine
- Chancellor's Office at UCLA
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The microtubule-associated protein tau has primarily been associated with axonal location and function; however, recent work shows tau release from neurons and suggests an important role for tau in synaptic plasticity. In our study, we measured synaptic levels of total tau using synaptosomes prepared from cryopreserved human postmortem Alzheimer's disease (AD) and control samples. Flow cytometry data show that a majority of synaptic terminals are highly immunolabeled with the total tau antibody (HT7) in both AD and control samples. Immunoblots of synaptosomal fractions reveal increases in a 20kDa tau fragment and in tau dimers in AD synapses, and terminal-specific antibodies show that in many synaptosome samples tau lacks a C-terminus. Flow cytometry experiments to quantify the extent of C-terminal truncation reveal that only 15-25% of synaptosomes are positive for intact C-terminal tau. Potassium-induced depolarization demonstrates release of tau and tau fragments from pre-synaptic terminals, with increased release from AD compared to control samples. This study indicates that tau is normally highly localized to synaptic terminals in cortex where it is well-positioned to affect synaptic plasticity. Tau cleavage may facilitate tau aggregation as well as tau secretion and propagation of tau pathology from the pre-synaptic compartment in AD.
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