Editors' ChoiceNeuroscience

Acetylated tau disrupts synaptic plasticity in Alzheimer’s disease

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Science Signaling  03 May 2016:
Vol. 9, Issue 426, pp. ec102
DOI: 10.1126/scisignal.aag0022

Alzheimer’s disease (AD) is a neurodegenerative disorder for which there are likely multiple causes. Among these, the accumulation of neurofibrillary tangles composed of a cleaved form of tau protein is implicated in the synaptic dysfunction and consequent cognitive decline in AD patients. Tracy et al. found a mechanism by which tau may do this. Postmortem brain tissue from AD patients with dementia and the hippocampi from AD model mice had increased abundance of Lys274- and Lys281-acetylated tau. Transgenic mice expressing human tau that was mutated to mimic acetylation at Lys274 and Lys281 (tauKQ) had increased abundance of cleaved (pathogenic) tau in the brain; exhibited diminished long-term potentiation (LTP, a form of synaptic plasticity) in hippocampal slices; and performed poorly on behavioral tests assessing spatial memory and context discrimination. The insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in the postsynaptic membrane of dendritic spines is required for LTP, and AMPAR trafficking requires actin polymerization. The surface abundance of the AMPAR subunit GluA1 and the total abundance of F-actin (the polymerized form of actin) increased in the spines of stimulated cultured mouse hippocampal neurons transfected with tau or a nonacetylatable tau mutant (tauKR) but not with tauKQ. The protein KIBRA is abundant in the postsynaptic density of healthy neurons. However, the abundance of KIBRA was decreased and strongly negatively correlated to that of acetylated tau in postmortem brain tissue from AD patients with dementia. The abundance of KIBRA was decreased in the spines of hippocampal neurons in brain tissue from tauKQ mice compared with those from wild-type mice. Overexpressing KIBRA restored the recruitment of GluA1 to synapses and the abundance of F-actin in neurons expressing tauKQ. The findings suggest that aberrant acetylation of tau contributes to the cognitive deficits in AD patients by impairing KIBRA-mediated AMPAR trafficking in neurons.

T. E. Tracy, P. D. Sohn, S. S. Minami, C. Wang, S.-W. Min, Y. Li, Y. Zhou, D. Le, I. Lo, R. Ponnusamy, X. Cong, B. Schilling, L. M. Ellerby, R. L. Huganir, L. Gan, Acetylated tau obstructs KIBRA-mediated signaling in synaptic plasticity and promotes tauopathy-related memory loss. Neuron 90, 245–260 (2016). [PubMed]

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