Abstract
The accumulation of neurofibrillary tangles in Alzheimer’s disease (AD) propagates with characteristic spatiotemporal patterns which follow brain network connections, implying trans-synaptic transmission of tauopathy. Since misfolded tau has been shown to transmit across synapses in AD animal models, we hypothesized that synapses in AD patients may contain misfolded tau. By immunofluorescence imaging of bipartite synapses from AD subjects, we detected tau protein in 38.4% of presynaptic and 50.9% of postsynaptic terminals. The pre/post distribution for hyperphosphorylated tau was 26.9%/30.7%, and for misfolded tau 18.3%/19.3%. In the temporal cortex, microscopic aggregates of tau, containing ultra-stable oligomers, were estimated to accumulate within trillions of synapses, outnumbering macroscopic tau aggregates such as tangles by 10000 fold. Non-demented elderly also showed considerable synaptic tau hyperphosphorylation and some misfolding, implicating the synapse as one of the first subcellular compartments affected by tauopathy. Misfolding of tau protein appeared to occur in situ inside synaptic terminals, without mislocalizing or mistrafficking. Misfolded tau at synapses may represent early signs of neuronal degeneration, mediators of synaptotoxicity, and anatomical substrates for transmitting tauopathy, but its actual role in these processes remain to be elucidated.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-014-0146-2) contains supplementary material, which is available to authorized users.
Highlights
The pathological hallmarks of Alzheimer’s disease (AD) are senile plaques and neurofibrillary tangles (NFT) [1,2]
For the propagation model to be credible in human diseases, tau would need to be found at the synapse; if present at the synapse, the identification of tau species differentially present in pre- or post-synaptic elements, and in AD compared to controls, will test the further hypotheses that misfolded tau accumulates presynaptically before “release” into postsynaptic space, and that tau is mislocalized to the synapse in AD compared to normal neurons
Misfolded tau oligomers deposited at synapses have the potential to spread tauopathy In this study, we detected misfolded tau in a significant fraction of presynaptic and postsynaptic terminals in AD subjects, which had two significant functional implications: (1) it could impair brain network function; (2) it could represent the anatomical substrate of tau synaptic transmission
Summary
The pathological hallmarks of Alzheimer’s disease (AD) are senile plaques and neurofibrillary tangles (NFT) [1,2]. Studies in animal models have demonstrated that tauopathy can spread in the living brain, using either transgenic mice that express mutant human tau proteins in the entorhinal cortex [11,17], or by injecting tau aggregates into specific brain regions [18,19]. These processes are relatively inefficient, taking weeks to months to observe, and occur only in situations of high levels of exogenous or transgenic tau. For the propagation model to be credible in human diseases, tau would need to be found at the synapse (at least in the disease state); if present at the synapse, the identification of tau species differentially present in pre- or post-synaptic elements, and in AD compared to controls, will test the further hypotheses that misfolded tau accumulates presynaptically before “release” into postsynaptic space, and that tau is mislocalized to the synapse in AD compared to normal neurons
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