Pre-synaptic C-terminal truncated tau is released from cortical synapses in Alzheimer's disease.
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 20 kDa 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. Results demonstrate the abundance of tau, mainly C-terminal truncated tau, in synaptic terminals in aged control and in Alzheimer's disease (AD) samples. Tau fragments and dimers/oligomers are prominent in AD synapses. Following depolarization, tau release is potentiated in AD nerve terminals compared to aged controls. We hypothesize (i) endosomal release of the different tau peptides from AD synapses, and (ii) together with phosphorylation, fragmentation of synaptic tau exacerbates tau aggregation, synaptic dysfunction, and the spread of tau pathology in AD. Aβ = amyloid-beta.
UCLA School of Nursing, Los Angeles, California, USA; UCLA Brain Research Institute, Los Angeles, California, USA; UCLA Center for the Advancement of Gerontological Nursing Sciences, Los Angeles, California, USA; UCLA Clinical and Translational Science Institute, Los Angeles, California, USA.
Sophie
S
Sokolow
Kristen M
KM
Henkins
Tina
T
Bilousova
Bianca
B
Gonzalez
Harry V
HV
Vinters
Carol A
CA
Miller
Lindsey
L
Cornwell
Wayne W
WW
Poon
Karen H
KH
Gylys
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology*; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017729:Presynaptic Terminals / Q000378:metabolism*; D013569:Synapses / Q000378:metabolism*; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins
Alzheimer's disease; flow cytometry; synaptosome; tau cleavage; tau fragment; tau release