Journal
JOURNAL OF CELL SCIENCE
Volume 126, Issue 5, Pages 1278-1286Publisher
COMPANY BIOLOGISTS LTD
DOI: 10.1242/jcs.1125880
Keywords
Alzheimer's disease; Tau; Amyloid; Cell cycle; Phosphorylation
Categories
Funding
- Alzheimer's Association [4079]
- Owens Family Foundation
- National Institutes for Heath (NIH)/National Institute of General Medical Sciences (NIGMS) [T32 GM008136]
- NIH [R01-NS075487]
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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-beta (A beta) 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 A beta 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, A beta 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 A beta through tau independently of their incorporation into plaques and tangles.
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