Dendritic function of tau mediates amyloid-beta toxicity in Alzheimer's disease mouse models.
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.
Ittner
Lars M
LM
Alzheimer's and Parkinson's Disease Laboratory, Brain and Mind Research Institute, University of Sydney, Sydney NSW 2050, Australia. littner@med.usyd.edu.au
Ke
Yazi D
YD
Delerue
Fabien
F
Bi
Mian
M
Gladbach
Amadeus
A
van Eersel
Janet
J
Wölfing
Heidrun
H
Chieng
Billy C
BC
Christie
MacDonald J
MJ
Napier
Ian A
IA
Eckert
Anne
A
Staufenbiel
Matthias
M
Hardeman
Edna
E
Götz
Jürgen
J
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity; D000818:Animals; D001921:Brain / Q000473:pathology; D003712:Dendrites / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D008569:Memory Disorders / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D013569:Synapses / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051528:Guanylate Kinases