Alzheimer’s breaks the first law of neuronal safety—stay out of the cell cycle

News from The American Society for Cell Biology
52nd Annual Meeting San Francisco, California
December 15–19, 2012

by George S. Bloom, University of Virginia, Department of Biology

The loss of neurons in the brain is what causes the devastating symptoms of Alzheimer’s disease (AD). A typical patient loses ~30% of the neurons responsible for memory and thinking by the time of death. Why do these neurons die? At late stages of the disease, looking at the brain under the microscope reveals two striking abnormalities: “plaques,” which are composed of a protein fragment called amyloidbeta (Aβ), and “tangles,” which are composed of the protein tau. Do these structures or these proteins kill the neurons? If so, how? Alternatively, is their presence an incidental byproduct of the disease? Mutations in the gene-encoding APP, the parent protein of Aβ, are clearly sufficient to cause AD, and mutations in the tau gene cause related diseases. How does this happen?

George Bloom of the University of Virginia (UVA) now reports that neurons in AD are on the road to cell death before plaques and tangles. Neurons start dying, according to Bloom, because they break the first law of human neuronal safety—stay out of the cell cycle. Most normal adult neurons are permanently postmitotic; that is, they have finished dividing and are locked out of the cell cycle. In contrast, AD neurons frequently re-enter the cell cycle, fail to complete mitosis, and ultimately die. By considering this novel perspective on AD as a problem of the cell cycle, Bloom and colleagues at UVA and at the University of Alabama, Birmingham, have discovered what they call an “ironic pathway” to neuronal cell death. The process requires the coordinated action of both Aβ and tau. These proteins are also the building blocks of plaques and tangles, respectively, but Bloom’s results establish how the proteins are toxic when they are free in solution and not aggregated into plaques and tangles.

Using mouse neurons grown in culture, the UVA researchers found that Aβ oligomers, which are small aggregates of just a few Aβ molecules each, induce the neurons to re-enter the cell cycle. Interestingly, the neurons must make and accumulate tau in order for this cell cycle re-entry to occur. The mechanism for this misplaced re-entry into the cell cycle requires that Aβ oligomers activate multiple protein kinase enzymes, each of which must then attach a phosphate to a specific site on the tau protein.

Following up on the cell culture results, Bloom and colleagues confirmed that Aβ- induced, tau-dependent cell cycle re-entry occurs in the brains of mice that were genetically engineered to mimic brains with human AD. The mouse brains were found to accumulate massive numbers of neurons that had transitioned from a permanent cell cycle stop, known as G0 (G zero), to G1, the first stage of the cell cycle, by the time they were 6 months old. Remarkably, otherwise identical mice that lacked functional tau genes showed no sign of cell cycle re-entry, confirming the cell culture results.

Neuronal cell cycle re-entry, a key step in the development of AD, can therefore be caused by signaling from Aβ through tau. In this setting, Aβ and tau co-conspire to trigger seminal events in AD pathogenesis independently of their incorporation into plaques and tangles. Most important, Bloom believes that the activated protein kinases and phosphorylated forms of tau identified in this study represent potential targets for early diagnosis and treatment of AD.

Join the More Than The Score talk Is it Possible to Eradicate Alzheimer’s Disease in Our Lifetime?

September 21, 2013

with Speakers:
George Bloom, Professor, Biology, A&S and Professor, Cell Biology, Medicine
Timothy Salthouse, Brown-Forman Professor, Psychology, A&S and Director, Virginia Cognitive Aging Project