Dramatic stories in cell biology often have sequels—”Duel of the Alzheimer’s Proteins, Part XV”—and indeed this work is a nail-biting sequel to George Bloom’s hypothesis that interaction between amyloid-beta peptides and the protein tau drives adult neurons into the forbidden pathway of “cell cycle re-entry” (CCR). The long-term result is Alzheimer’s disease (AD). Bloom and colleagues at the University of Virginia (UVA) now say that they have found the critical balance point between tau and a master cellular regulator that amyloid-beta oligomers disrupt.
Dramatic stories in cell biology often have sequels—”Duel of the Alzheimer’s Proteins, Part XV”—and indeed this work is a nail-biting sequel to George Bloom’s hypothesis that interaction between amyloid-beta peptides and the protein tau drives adult neurons into the forbidden pathway of “cell cycle re-entry” (CCR). The long-term result is Alzheimer’s disease (AD). Bloom and colleagues at the University of Virginia (UVA) now say that they have found the critical balance point between tau and a master cellular regulator that amyloid-beta oligomers disrupt.
As reported at last year’s ASCB Annual Meeting, Bloom says that most normal adult neurons are supposed to be permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. Yet in Alzheimer’s, neurons frequently re-enter the cell cycle, fail to complete mitosis, and ultimately die. In late stage AD, up to 30 percent of the neurons in the frontal lobes of the brain are dead, surrounded by large amyloid plaques and tau-associated neurofibrillary tangles.
Much of the debate in AD research has been about which protein—amyloid-beta or tau— is the symptom and which the cause, but Bloom and his UVA colleagues have moved in a different direction. They see AD as a problem of the cell cycle, with both amyloid-beta and tau required for the interaction that pushes neurons into destructive CCR. “The massive neuron death that occurs in AD therefore appears to be caused by the raw ingredients of plaques and tangles working in concert with each other, rather than by the plaques and tangles themselves,” Bloom explains.
Last spring, the UVA researchers described in greater detail how amyloid-beta activates multiple enyzmes called protein kinases to add phosphates to specific sites on tau, setting neurons on the pathway to CCR. Now in this new molecular “sequel,” Andrés Norambuena, Lloyd McMahon, and others in the Bloom lab implicate a novel group of proteins— Rac1, Gαs (Gs alpha), and NCAM—and two protein kinases complexes— mTORC1 and mTORC2—as required participants to set off CCR.
Their identification reveals a how a fundamental balance is upset, placing neurons on the road to AD. “The mTOR complexes are master regulators of cellular proliferation, growth, and metabolism,” Bloom explains. “Most importantly, our results indicate that tau normally inhibits mTOR from promoting neuronal cell replication, but that this inhibition is reversed by an amyloid beta oligomer-induced, mTOR-dependent mechanism that modifies tau. In other words, tau and mTOR regulate each other.”
This delicate balance is compromised by amyloid-beta oligomers in a way that allows neurons that should never replicate to re-enter the cell cycle. They fail to divide and eventually die instead. “Some of the earliest events in AD pathogenesis are therefore caused by amyloid-beta oligomers altering a fundamental neuronal signaling axis centered around tau and mTOR,” Bloom proposes. He believes that the proteins identified in this signaling axis are potential biomarkers and therapeutic targets for very early stages of AD, leaving the door open for an even more exciting sequel down the road.
The Bloom lab’s work on CCR has been generously supported by the Owens Family Foundation, the Alzheimer’s Association (grant 4079) and NIH/NIGMS training grant T32 GM008136.
About the Author:
Christina Szalinski is a science writer with a PhD in Cell Biology from the University of Pittsburgh.
