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Dendritic Function of Tau Mediates Amyloid-β Toxicity in Alzheimer's Disease Mouse Models

2010; Cell Press; Volume: 142; Issue: 3 Linguagem: Inglês

10.1016/j.cell.2010.06.036

1097-4172

Lars M. Ittner, Yazi D. Ke, Fabien Delerue, Mian Bi, Amadeus Gladbach, Janet van Eersel, Heidrun Wölfing, Billy Chieng, MacDonald J. Christie, Ian A. Napier, Anne Eckert, Matthias Staufenbiel, Edna C. Hardeman, Jürgen Götz,

Cholinesterase and Neurodegenerative Diseases

Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) and tau deposition in brain. It has emerged that Aβ toxicity is tau dependent, although mechanistically this link remains unclear. Here, we show that tau, known as axonal protein, has a dendritic function in postsynaptic targeting of the Src kinase Fyn, a substrate of which is the NMDA receptor (NR). Missorting of tau in transgenic mice expressing truncated tau (Δtau) and absence of tau in tau−/− mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Aβ toxicity. Δtau expression and tau deficiency prevent memory deficits and improve survival in Aβ-forming APP23 mice, a model of AD. These deficits are also fully rescued with a peptide that uncouples the Fyn-mediated interaction of NR and PSD-95 in vivo. Our findings suggest that this dendritic role of tau confers Aβ toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.