Tau-mediated synaptic and neuronal dysfunction in neurodegenerative disease

•Soluble tau oligomers promote pathophysiology in neurons.•Pathogenic tau affects mechanisms that regulate both presynaptic and postsynaptic function.•Deterioration of axons in tauopathy involves the dysregulation of the axon initial segment and impaired axonal transport.•Loss of dendritic spines underlies memory impairments in tauopathy mouse models. 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.