Normally post-mitotic neurons that aberrantly re-enter the cell cycle without dividing account for a substantial fraction of the neurons that die in Alzheimer's disease (AD). We now report that this ectopic cell cycle re-entry (CCR) requires soluble amyloid-β (Aβ) and tau, the respective building blocks of the insoluble plaques and tangles that accumulate in AD brain. Exposure of cultured wild type (WT) neurons to Aβ oligomers caused CCR and activation of the non-receptor tyrosine kinase, fyn, the cAMP-regulated protein kinase A and calcium-calmodulin kinase II, which respectively phosphorylated tau on Y18, S409 and S416. In tau knockout (KO) neurons, Aβ oligomers activated all three kinases, but failed to induce CCR. Expression of WT, but not Y18F, S409A or S416A tau restored CCR in tau KO neurons. Tau-dependent CCR was also observed in vivo in an AD mouse model. CCR, a seminal step in AD pathogenesis, therefore requires signaling from Aβ through tau independently of their incorporation into plaques and tangles.
M.E.S. performed all of the biochemical and most of the cell biological experiments, and along with G.S.B., participated in the overall design and analysis of the research. E.S. prepared most primary neuron cultures and provided guidance for immunofluorescence of brain sections. E.D.R. provided the brain sections and editorial advice. J.N.C. and R.L. performed immunofluorescence microscopy of brain sections. A.R. and A.N. contributed to the cultured neuron immunofluorescence. G.S.B. supervised the project and authored the manuscript.
This work was supported by the Alzheimer's Association [grant number 4079 to G.S.B.]; the Owens Family Foundation (to G.S.B.); the National Institutes for Heath (NIH)/National Institute of General Medical Sciences (NIGMS) [training grant number T32 GM008136, which funded part of M.E.S.'s and E.S.'s pre-doctoral training]; and the NIH [grant number R01-NS075487 to E.D.R.]. Deposited in PMC for release after 12 months.
Supplementary material available online at http://jcs.biologists.org/lookup/suppl/doi:10.1242/jcs.1125880/-/DC1
- Accepted December 21, 2012.
- © 2013. Published by The Company of Biologists Ltd