Abstract
The spatiotemporal transmission of pathological tau in the brain is characteristic of Alzheimer’s disease. Release of both soluble and abnormal tau species from healthy neurons is increased upon stimulation of neuronal activity. It is not yet understood whether the mechanisms controlling soluble tau release from healthy neurons is the same as those involved in the spread of pathological tau species. To begin to understand these events, we have studied tau distribution and release using organotypic brain slice cultures. The slices were cultured from postnatal wild-type and 3xTg-AD mice for up to 1 month. Tau distribution in subcellular compartments was examined by western blotting, and tau release into culture medium was determined using a sensitive sandwich ELISA. We show here that 3xTg-AD cultures have an accelerated development of pathological tau abnormalities including the redistribution of tau to synaptic and membrane compartments. The 3xTg-AD slice cultures show elevated basal tau release relative to total tau when compared with wild-type cultures. However, tau release from 3xTg-AD slices cannot be further stimulated when neuronal activity is increased with potassium chloride. Moreover, we report that there is an increased pool of dephosphorylated membrane-associated tau in conditions where tau release is increased. These data suggest that there may be differential patterns of tau release when using integrated slice culture models of wild-type and transgenic mouse brain, although it will be important to determine the effect of tau overexpression for these findings. These results further increase our knowledge of the molecular mechanisms underlying tau release and propagation in neurodegenerative tauopathies.
Highlights
The characteristic progressive accumulation of tau pathology in affected brain regions during the development of Alzheimer’s disease (AD) is believed to result from the spread of aggregated tau along anatomically connected pathways.[1,2,3]
To investigate these mechanisms further, we have examined tau release from organotypic brain slice cultures prepared from wild-type and 3xTg-AD mice.[18,19]
These results suggest that the mechanisms governing the release of physiological and pathological forms of tau may be differentially regulated by neuronal stimulation. These findings might support the existence of functionally distinct pools of extracellular tau with physiological tau contributing to neuronal signalling in a healthy brain environment[28] and pathological tau driving the spread of tau pathology in diseased brain
Summary
The characteristic progressive accumulation of tau pathology in affected brain regions during the development of Alzheimer’s disease (AD) is believed to result from the spread of aggregated tau along anatomically connected pathways.[1,2,3]. We previously showed that tau release from neurons is a physiological process that is stimulated by neuronal activity in cultured rat neurons.[11] Similar findings have since been reported in vivo.[12] The relationship between tau release and neuronal activity appears to be bi-directional since both extracellular tau and Aβ feedback to neurons to perpetuate further tau release.[13] Released endogenous tau is reported to be released free in a dephosphorylated full-length form[11] or as N-terminally truncated fragments.[13,14] A small proportion of tau released under these conditions is associated with ectosomes, plasma membrane-derived vesicles.[15] when tau is exogenously expressed or in a highly phosphorylated misfolded state, it is released from cells in association with exosomes[7,16] and can be highly phosphorylated.[17] The apparent discrepancies in these findings raise the question of whether physiological species of soluble tau are released via the same mechanisms as are involved in the propagation of pathological tau forms To investigate these mechanisms further, we have examined tau release from organotypic brain slice cultures prepared from wild-type and 3xTg-AD mice.[18,19] Recent publications have highlighted the utility of using organotypic nervous tissue slices for modelling neurodegenerative diseases. Potential effects of overexpression on tau localisation and release must be taken into account when interpreting the results of this work as it is possible that saturation of synaptic activity is responsible for the lack of effect of neuronal stimulation on tau release from 3xTg-AD slices
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