New data on the role of beta-amyloid and tau protein in Alzheimer's disease
Neurons in Alzheimer's disease die due to an attempt to proliferate
LifeSciencesToday based on ScienceDaily:
Neurons Die in Alzheimer's Because of Faulty Cell Cycle Control Before Plaques and Tangles AppearTwo notorious proteins, beta-amyloid and tau, characteristic of Alzheimer's disease, direct healthy neurons to the path of cell death long before the appearance of plaques and tangles.
According to a study presented at the annual meeting of The American Society for Cell Biology (The American Society for Cell Biology) in San Francisco, their joint actions reactivate the cell cycle considered blocked in the neurons of the brain.
Working on a mouse model of Alzheimer's disease, George Bloom, PhD, from the University of Virginia (UVA) found that with this disease, nerve cells begin to die because they violate the first law of human neuron safety – to stay out of the cell cycle.
Most normal adult neurons are constantly in a postmitotic state, that is, they have finished dividing, and their cell cycle is now and forever blocked. Unlike healthy ones, neurons in Alzheimer's disease often re-enter the cell cycle, but cannot complete mitosis and eventually die.
Considering Alzheimer's disease as a cell cycle problem, Dr. Bloom and his colleagues at UVA and The University of Alabama at Birmingham discovered what they called the "ironic pathway" to nerve cell death. This process requires coordinated actions of beta-amyloid and tau protein, which are, respectively, the building blocks of plaques and tangles. Dr. Bloom's research shows how toxic these two proteins can be, even when in solution and without forming clusters.
Using cultured mouse neurons, scientists have found that the oligomers of beta-amyloid – small aggregates of only a few of its molecules - force neurons to enter the cell cycle. But for this to happen, neurons must synthesize and accumulate tau. The mechanism of abnormal entry into the cell cycle requires that beta-amyloid oligomers activate several protein kinase enzymes, each of which must then bind phosphate to a specific tau protein site.
Based on the results obtained on cell culture, Dr. Bloom and his colleagues confirmed that beta-amyloid-induced tau-dependent re-entry into the cell cycle also occurs in the brains of genetically modified mice with an Alzheimer's disease model. By the age of six months, a huge number of neurons were found in the brains of such animals, transitioning from the cell cycle stop, known as G0, to G1 – its first phase. It is noteworthy that mice identical in all respects with the only difference – the absence of functional tau protein genes - showed no signs of neurons re–entering the cell cycle, which confirms the results obtained on cell culture.
The re–entry of neurons into the cell cycle – a key stage in the development of Alzheimer's disease - can thus be caused by beta-amyloid signaling through tau protein. Beta-amyloid and tau "collude" and become the trigger of fundamental events in the pathogenesis of Alzheimer's disease, regardless of their inclusion in plaques and tangles. According to Dr. Bloom, the most important result of the study is that the activated protein kinases and phosphorylated forms of tau protein established in it represent potential targets for early diagnosis and treatment of Alzheimer's disease.
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