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The researchers also observed a significant decrease in the levels of a protein known as YAP in Alzheimer's disease model mice and human patients with MCI. YAP positively affects the activity of a second protein called TEAD, a deficiency of which leads to neuronal necrosis. Microscopic examination revealed that the missing YAP was sequestered within beta-amyloid plaques, which have also been linked to neuronal toxicity.
By directly injecting a gene therapy vector expressing YAP analog into the cerebral spinal fluid of mice that were genetically engineered to provide a model of Alzheimer's, the researchers were able to prevent early-stage neuron loss, restore cognitive function, and prevent the development of beta-amyloid plaques.
"Confirming that neuronal necrosis was dependent on YAP was really the pivotal moment for us, but observing the almost transformative effects of YAP supplementation was hugely exciting," says senior author of the study Hitoshi Okazawa. "By showing that neuronal necrosis is YAP-dependent and begins prior to the onset of most symptoms, we predict that novel Alzheimer's disease therapies will be developed to prevent the initiation of Alzheimer's disease."
"Another important issue is that the necrosis of neurons accumulating intracellular beta-amyloid occurs before formation of beta-amyloid plaques," continues Professor Okazawa. "Residual beta-amyloid after neuronal necrosis seems to be the seed for beta-amyloid plaques outside of neurons. This discovery might change the amyloid hypothesis considering that extracellular beta-amyloid plaque is the top of pathological cascade of Alzheimer's disease." Source:
Tokyo Medical and Dental University Journal reference:
Tanaka, H., et al. (2020) YAP-dependent necrosis occurs in early stages of Alzheimer’s disease and regulates mouse model pathology. Nature Communications . doi.org/10.1038/s41467-020-14353-6 .
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