ACTIVITY-DEPENDENT TAU RELEASE: IMPLICATIONS FOR TAU PROPAGATION

Abstract

The pathological progression of tau through the brain in Alzheimer's disease and related tauopathies appears to involve the cell-to-cell transmission of aggregated tau. The spread of tau may be initiated by a potential seeding mechanism in which uptake of pathogenic tau species results in neurodegeneration in affected brain regions. Tau transmission between neurons also occurs trans-synaptically, suggesting that disease progression through tau propagation is an active process associated with synapses. Tau release from cultured cortical neurons and organotypic brain slice cultures under basal and stimulated conditions was measured using ELISA. We have shown that tau release from cultured cortical neurons is a physiological process that is regulated by neuronal activity. Thus, extracellular tau is present in low amounts under basal conditions but, in response to neuronal depolarisation, there is a rapid and substantial increase in the amount of tau expelled by neurons. Pharmacological blockade of neuronal activity, or inhibition of AMPA receptor activation, ablates the stimulated release of tau from cultured neurons. Notably, under both basal and stimulated conditions, tau release from neurons is independent of cell death. Recently, we have extended our investigation of tau release from neurons to organotypic brain slice cultures from wild-type and 3xTg-AD mice, which express mutant forms of tau, amyloid precursor protein, and presenilin-1. We found that tau release under basal conditions was elevated in slices cultured from 3xTg-AD mice in comparison to those from wild-type mice. However, tau release from 3xTg-AD slices could not be further stimulated when neuronal activity was increased using potassium chloride. These results could suggest differential regulation of tau release, possibly due to altered synaptic activity, in Alzheimer's disease. Taken together, our findings suggest that alterations in neuronal excitability in Alzheimer's disease and other tauopathies might result in impaired release of tau from neurons. Since activity-dependent removal of tau from neurons might influence the propagation of tau pathology in tauopathies, targeting tau release could represent a new therapeutic approach for these disorders.