Amyloid-beta signals through tau to drive ectopic neuronal cell cycle re-entry in Alzheimer%26apos;s disease

作者：Seward Matthew E; Swanson Eric; Norambuena Andres; Reimann Anja; Cochran J Nicholas; Li Rong; Roberson Erik D; Bloom George S^*

来源：Journal of Cell Science, 2013, 126(5): 1278-1286.

DOI：10.1242/jcs.1125880

• Alzheimer%26apos
• s disease
• Tau
• Amyloid
• Cell cycle
• Phosphorylation

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%26apos;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.

• 出版日期2013-3-1