Researchers here provide evidence for significant levels of cell death to occur in the brain earlier than expected in the development of Alzheimer's disease, during the stage of mild cognitive impairment thought to be driven by the aggregation of amyloid-β. The researchers identify some portions of a mechanism by which amyloid-β might be triggering this cell death, and propose a novel class of therapeutic approaches that will interfere in this link. Given the artificial nature of animal models in Alzheimer's research, and the comparatively sparse nature of human data, it is good to adopt a cautious wait and see approach in response to this sort of news. It is similar in character to numerous other lines of research in the Alzheimer's field that ultimately didn't translate from mice to humans.
The exact cause of Alzheimer's disease is unknown, but pathological changes in the brain, including neuron loss and an accumulation of protein aggregates called beta-amyloid plaques, are a diagnostic hallmark of Alzheimer's disease. Mild cognitive impairment (MCI) describes the slight but measurable changes in cognitive function that are often a precursor to Alzheimer's disease. However, despite the importance of MCI, very little is known about the changes that occur in the brain during the progression from MCI to Alzheimer's.
Researchers have now found that neuronal death occurs much earlier than originally thought, with higher levels of necrosis seen in patients with MCI than in patients with full-blown Alzheimer's disease. 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 cerebrospinal 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. 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."