Scientists at the Scripps Institute (TSRI) have revealed a major mechanism of toxicity in Alzheimer's disease. The article was published in Neuron on April 10. This research will help people better understand the progression of Alzheimer's disease and help develop new drugs for treatment.
The researchers found that brain damage in Alzheimer's disease is related to the overactivity of the AMPK enzyme. They blocked the AMPK enzyme in a mouse model of Alzheimer's disease, preventing synaptic loss of neurons. Synapses are the connection points between neurons, and synapse loss is a typical phenomenon in the early stages of Alzheimer's disease.
"This discovery opens up new research avenues to develop upstream mechanisms for drug targets to make AMPK too active," said Franck Polleux, a TSRI professor who led the study.
Alzheimer's disease is a fatal neurodegenerative disease. Polleux pointed out that this research not only brought inspiration to related drug research and development, but also reminded people to take further safety research on metformin. Studies have shown that metformin, which is commonly used to treat type 2 diabetes, can activate AMPK.
It has long been known that β-amyloid oligomers cause the loss of synapses in neurons, but the mechanism is not understood. In 2011, Polleux's laboratory found in animal models that metformin can overactive AMPK and destroy the ability of neurons to grow axons. In addition, studies have shown that β-amyloid activates AMPK in neurons, which leads to phosphorylation of tau protein. In the brain of Alzheimer's disease patients, the hyperphosphorylated tau protein forms tangles and accumulates in neurons. Polleux hopes to analyze the interaction of AMPK, β-amyloid and tau through this new study.
The researchers confirmed that β-amyloid in oligomers does activate AMPK. They found that β-amyloid oligomers stimulated specific neuronal receptors, which allowed calcium ions to flow into neurons, thereby activating the CAMKK2 enzyme, which is the main activator of AMPK .
If β-amyloid oligomers are added to neurons, the dendritic spines of many neurons will disappear quickly. Studies have shown that β-amyloid oligomers can cause dendritic spine loss only when AMPK is too active. The researchers pointed out that AMPK in neurons is too active and is necessary for β-amyloid to destroy synapses.
Subsequently, the researchers conducted research on J20 mice. This genetically engineered mouse overexpresses mutant β-amyloid protein and will develop symptoms similar to Alzheimer's disease. "When we block the activity of CAMKK2 or AMPK in neurons, we can completely avoid the loss of dendritic spines," said the main investigator of the study, Mairet-Coello.
Under normal circumstances, tau protein is a structural element in nerve axons, but in Alzheimer's disease, tau is hyperphosphorylated and transferred to other areas such as dendritic spines, and its appearance is related to the loss of dendritic spines. A 2004 Drosophila study showed that phosphorylation of specific sites of tau protein can trigger further phosphorylation and nerve cell degeneration.
Now researchers have confirmed that one of the above sites, S262, is phosphorylated by AMPK. And the phosphorylation of this site allows β-amyloid to destroy synapses. "We blocked the phosphorylation of S262 through mutant tau and successfully prevented the harmful effects of β-amyloid on dendritic spines," Mairet-Coello said.
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