Frequent and symmetric deposition of misfolded tau oligomers within presynaptic and postsynaptic terminals in Alzheimer¿s disease

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.

Local Somatodendritic Translation and Hyperphosphorylation of Tau Protein Triggered by AMPA and NMDA Receptor Stimulation

“…Previous authors reported that glutamate activates CaMKIIα to induce synaptic plasticity (Miller et al, 2002, Coultrap et al, 2014), and that activity-dependent increases in tau protein in excitatory synpases (Frandemiche et al, 2014) represents a physiological mechanism that contributes to synaptic plasticity (Kimura et al, 2013). Notably, tau protein is detectable in postsynaptic terminals in AD brains (Tai et al, 2014); this finding suggests that high AMPA and NMDA receptor stimulation can trigger the aberrant local translation of tau to induce AD pathology. Stress granules are likely to participate in dendritic tau-triggered neurodegeneration since tau is known to interact with the RNA-binding protein T-cell intracellular antigen 1 (TIA1) in stress granules (Vanderweyde et al, 2016).…”

The Study of Postmortem Human Synaptosomes for Understanding Alzheimer’s Disease and Other Neurological Disorders: A Review

“…We need to address critically to what extent these animal models actually mimic the pathogenesis and pathology of AD in humans, beyond the superficial resemblance of accumulating plaques and tangles, which were artificially driven by overexpressing mutant proteins. For instance, when we first discovered the presence of tau oligomers inside human synaptic terminals [9, 27], we also checked a common animal model of tauopathy, rTg4510 mice overexpressing P301L human mutant tau [28], but its synaptosomes were free of tau oligomers (unpublished data). It is plausible that the mutant tau misfolded so aggressively that they became aggregated before reaching the synapse, causing a marked distinction between mouse and human neuropathology.…”

“…Based on our experience of examining synaptically enriched preparations with electron microscopy, immunofluorescence microscopy [9, 27], flow cytometry, and super-resolution microscopy (unpublished data), with both human and mouse samples, it appears that at least five classes of nerve ending particles can be found (Fig. 2): (I) intact bipartite synapses, which show snowman-like structures; (II) presynaptic terminals with membrane-free PSD attached; (III) presynaptic terminals with membrane-enclosed PSD, but missing much of the postsynaptic cytoplasm; (IV) isolated presynaptic terminals; (V) isolated postsynaptic terminals.…”

“…In our experience, synaptosome preparation protocols developed for rodent brains are equally applicable to postmortem human tissues [9, 27]. The only noticeable difference is that, after grinding brain tissues, human samples contain more insoluble debris than rodent samples, which can be removed by additional centrifugation or 20 μm nylon filters.…”

Analyzing dendritic spine pathology in Alzheimer’s disease: problems and opportunities

“…In contrast to amyloid beta, however, the verdict seems to be clearer that neurofibrillary tangles themselves are functionally inert [84, 101, 167] and that soluble tau aggregates mediate synaptic damage [148, 219, 223]. Hyperphosphorylated tau was shown to localize to both pre- and postsynapses in multiple studies [81, 86, 88, 148, 188, 189, 191, 219], where it causes synaptic dysfunction by impairing the trafficking or synaptic anchoring [86] as well as the excitability [130]. In THY-Tau22 mice, which express tau with the G272V and P301S mutations, the synaptic enhancement induced by exogenous BDNF was lost due to impaired NMDA receptor function [28].…”