Brain damage in Alzheimer`s linked to overactivation of enzyme
Washington: Scientists at The Scripps Research Institute (TSRI) have unravelled one of the major toxic mechanisms of Alzheimer`s disease.
The discoveries could lead to a much better understanding of the Alzheimer`s process and how to prevent it.
The findings showed that brain damage in Alzheimer`s disease is linked to the overactivation of an enzyme called AMPK. When the scientists blocked this enzyme in mouse models of the disease, neurons were protected from loss of synapses-neuron-to-neuron connection points-typical of the early phase of Alzheimer`s disease.
In addition to having implications for Alzheimer`s drug discovery, TSRI Professor Franck Polleux, who led the new study, noted the findings suggest the need for further safety studies on an existing drug, metformin. Metformin, a popular treatment for Type 2 Diabetes, causes AMPK activation.
Georges Mairet-Coello, a postdoctoral research associate in the Polleux lab, performed most of the experiments for the new study.
He began by confirming that amyloid beta, in the small-aggregate ("oligomer") form that is toxic to synapses, does indeed strongly activate AMPK; amyloid beta oligomers stimulate certain neuronal receptors, which in turn causes an influx of calcium ions into the neurons.
He found that this calcium influx triggers the activation of an enzyme called CAMKK2, which appears to be the main activator of AMPK in neurons.
The team then showed that this AMPK overactivation in neurons is the essential reason for amyloid beta`s synapse-harming effect. Normally, the addition of amyloid beta oligomers to a culture of neurons causes the swift disappearance of many of the neurons` dendritic spines-the rootlike, synapse-bearing input stalks that receive signals from other neurons.
With a variety of tests on mice, the scientists showed that amyloid beta oligomers can`t cause this dendritic spine loss unless AMPK overactivation occurs-and indeed AMPK overactivation on its own can cause the spine loss.
Next Mairet-Coello investigated the role of the tau protein. Ordinarily it serves as a structural element in neuronal axons, but in Alzheimer`s it somehow becomes hyperphosphorylated and drifts into other neuronal areas, including dendrites where its presence is associated with spine loss.
Recent studies have shown that amyloid beta`s toxicity to dendritic spines depends largely on the presence of tau, but just how the two Alzheimer`s proteins interact has been unclear.
The team took a cue from a 2004 study of Drosophila fruit flies, in which an AMPK-like enzyme`s phosphorylation of specific sites on the tau protein led to a cascade of further phosphorylations and the degeneration of nerve cells. The scientists confirmed that one of these sites, S262, is indeed phosphorylated by AMPK.
They then showed that this specific phosphorylation of tau accounts to a significant extent for amyloid beta`s synapse toxicity.
"Blocking the phosphorylation at S262, by using a mutant form of tau that can`t be phosphorylated at that site, prevented amyloid beta`s toxic effect on spine density," Mairet-Coello said.
The result suggests that amyloid beta contributes to Alzheimer`s via AMPK, mostly as an enabler of tau`s toxicity.
The findings were recently reported in the journal Neuron.
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