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.

Synaptic distributions of pS214‐tau in rhesus monkey prefrontal cortex are associated with spine density, but not with cognitive decline

“…A high frequency of axon terminals, and of dendritic spines (> 85%) contained pS214-tau, which was present in presynaptic and postsynaptic compartments of the same synaptic complex in over three-quarters of synapses, and across age and treatment groups. These findings are in line with those of another recent study wherein~80% of bipartite neocortical synapses from nondemented elderly control and AD subjects alike were identified as tau-positive (Tai et al, 2014). Like our own observations, modified tau protein (e.g., hyperphosphorylated) was also abundantly distributed on both sides of the synapse.…”

Synaptic Contacts Enhance Cell-to-Cell Tau Pathology Propagation

“…Furthermore, we demonstrate that synaptogenic mechanisms also promoted Tau pathology dissemination within an artificial neuronal network. The presence of abnormal Tau within the pre-and post-synaptic compartments of AD brains supports the idea that this species can be a substrate for trans-synaptic transmission (Tai et al, 2014). We therefore hypothesize that a form of Tau-seeding species that is present at the synapse can be trans-synaptically transmitted to connected neurons, thereby disseminating Tau pathology by inducing aggregation of soluble Tau (Guo and Lee, 2014;Tai et al, 2014).…”

Mango leaf extract improves central pathology and cognitive impairment in a type 2 diabetes mouse model

“…Whereas we cannot point toward a single mechanism, it is feasible that cell death is reduced while neuronal population is protected by MGF treatment. In this line, it has been suggested that misfolded tau at synapses may represent early signs of neuronal degeneration and mediate synaptotoxicity (51). At central level, tau hyperphosphorylation is a marker of neuropil dysfunction observed in neurodegenerative diseases, including AD and VaD (10,48).…”

“…Early alterations, and not necessarily tangles, may contribute to cognitive malfunction (23). In this line, it has been suggested that misfolded tau at synapses may represent early signs of neuronal degeneration and mediate synaptotoxicity (51). Also, autopsy studies have reported brains with neurofibrillary tangles that are indistinguishable from those of AD, in the absence of amyloid plaques, usually associated with mild cognitive impairment (8).…”