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Does tau in synaptic contacts disrupt neuronal activity in the cortex of Alzheimer's patients ?


In Alzheimer's disease, the tau protein accumulates in fibrillar form in the brain of affected individuals. As described in my book on neuronal degeneration for α-synuclein in PD in chapter 2.3.5, tau can also be passed from one neuron to another. In the healthy recipient cell, the formation of tau fibrils is then induced in a prion-like manner. The tau fibrils are considered to be particularly toxic for the affected neurons. In the case of pyramidal cells with large dendritic trees, the tau aggregates first appear in the distal sections of the dendrites, i.e. further away from the cell body, then in the perikaryon itself and only finally in the axon, which suggests a transfer of pathological tau forms from the input contact site (presynapse) to the output contact site (postsynapse). It was previously unclear whether these findings, obtained in cell culture and animal models, also apply to humans.


In a recent study by Colom-Cadena and colleagues published recently in Neuron, synaptic tau accumulation in the postmortem cortex of Alzheimer's disease patients was now examined in comparison to control subjects using high-resolution microscopy and various antibodies directed against either total tau, misfolded tau (Alz50), or tau phosphorylated to serine 202 and threonine 205 (pTau AT8). In particular, oligomeric tau was detected in the presynaptic and postsynaptic terminals, even in areas without fibrillar tau deposits, the so-called tangles. Thus, the accumulation of oligomeric tau in synapses appears to be an early event in Alzheimer's disease pathogenesis.


Interestingly, the distribution of oligomeric tau in synapses is asymmetric, i.e., the larger fraction is localized in the presynapse, providing indirect evidence for transsynaptic anterograde transmission of tau also in humans (see Fig. below). The observation that oligomeric tau accumulates in synaptic contacts will have implications for understanding disease pathogenesis. Indeed, while many studies have focused on Aβ as a trigger for synaptic damage, it appears that tau protein may be equally responsible for synaptic loss. Therefore, given the early onset of changes in the oligomerization and intraneuronal distribution of tau, therapeutic approaches targeting tau should be pursued vigorously.


Fig. Oligomeric assemblies of tau are passed from the presynaptic side to the postsynaptic side of neuronal contact sites in the AD brain (graphic from Colom-Cadena et al., 2023. Neuron 111:2170).


Reference:


Colom-Cadena M, Davies C, Sirisi S, ..., Lleó A, Spires-Jones TL (2023) Synaptic oligomeric tau in Alzheimer's disease - A potential culprit in the spread of tau pathology through the brain. Neuron 111:2170


Image credit: iStock/selvanegra

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