Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease

Abstract

The accumulation of pathological tau in the brain is associated with neuronal deterioration and cognitive impairments in tauopathies including Alzheimer's disease. Tau, while primarily localized in the axons of healthy neurons, accumulates in the soma and dendrites of neurons under pathogenic conditions. Tau is found in both presynaptic and postsynaptic compartments of neurons in Alzheimer's disease. New research supports that soluble forms of tau trigger pathophysiology in the brain by altering properties of synaptic and neuronal function at the early stages of disease progression, before neurons die. Here we review the current understanding of how tau-mediated synaptic and neuronal dysfunction contributes to cognitive decline. Delineating the mechanisms by which pathogenic tau alters synapses, dendrites and axons will help lay the foundation for new strategies that can restore neuronal function in tauopathy.

Figure 1

Pathogenic forms of tau, including soluble tau oligomers and tau with abnormal post-translational modifications (PTMs), can promote neuronal dysfunction by multiple mechanisms at the early stages of neurodegenerative disease. At postsynaptic sites, pathogenic tau reduces glutamate receptor levels and inhibits receptor trafficking during synaptic plasticity. The tau-mediated loss of mushroom spines is associated with increased filipodia on dendrites. Axonal function is compromised by tau due to the destabilization of the axon initial segment and deficient axonal transport. At the presynaptic terminal, tau decreases the release of neurotransmitter-containing synaptic vesicles by reducing their mobility in the terminal.