Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.

By L. Ittner, Y. Ke, F. Delerue, Mian Bi, Amadeus Gladbach, Janet van Eersel, Heidrun Wölfing, B. Chieng, M. Christie, I. Napier and 4 more. Cell, 2010

1,853 citations recorded by the source corpus.

Alzheimer's disease (AD) is characterized by amyloid-beta (Abeta) and tau deposition in brain. It has emerged that Abeta 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 (Deltatau) and absence of tau in tau(-/-) mice both disrupt postsynaptic targeting of Fyn. This uncouples NR-mediated excitotoxicity and hence mitigates Abeta toxicity. Deltatau expression and tau deficiency prevent memory deficits and improve survival in Abeta-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 Abeta toxicity at the postsynapse with direct implications for pathogenesis and treatment of AD.

Subfields: Cellular and Molecular Neuroscience, Pharmacology, Physiology

View Paper: https://www.semanticscholar.org/paper/8d9cd2d161baeb131e2060954c7abec89fb8217a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cellular and Molecular Neuroscience

1. D. Holtzman
2. J. Götz
3. K. Ashe
4. J. Herz
5. G. Bu
6. L. Ittner

In Pharmacology

1. J. Herz
2. D. Holtzman
3. G. Bu
4. J. Götz
5. L. Ittner
6. D. Selkoe

In Physiology

1. D. Holtzman
2. J. Herz
3. G. Bu
4. L. Ittner
5. J. Götz
6. K. Ashe
7. Huaxi Xu
8. D. Selkoe

Citations in the corpus

• Amyloid β-based therapy for Alzheimer’s disease: challenges, successes and future (2023, background): “Missorted tau proteins at postsynaptic terminals interacts with the subunits of AMPARs and NMDARs, leading to the excessive activation of glutamate receptors, Ca influx, impaired LTP and enhanced LTD.(92,100,101) It has been demonstrated that the absence of tau proteins prevent Aβ-induced LTP impair”
• Apolipoprotein E and apolipoprotein E receptors: normal biology and roles in Alzheimer disease. (2012, background): “…supported by a series of recent studies that showed a broad effect of mislocalized, phosphorylated tau on the spinodendritic targeting of Fyn (Ittner et al. 2010) and of the scaffolding protein JIP1 (Ittner et al. 2010), as well as on the disruption of glutamate receptor trafficking and…”
• Tau mislocalization to dendritic spines mediates synaptic dysfunction independently of neurodegeneration (2010, background): “Interestingly, a recent study demonstrated that tau decreased NMDAR expression in the PSD complex, though no alterations in NMDAR-mediated currents were detected (Ittner et al., 2010).”
• Amyloid-β and tau — a toxic pas de deux in Alzheimer's disease (2011, background): “Under physiological conditions, tau has also been localized to dendrites, although levels there are much lowe”