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| Mice without LRP6 in neurons had greater buildup of amyloid protein in their brains (right) compared to control subjects (left).--Courtesy of the Mayo Clinic |
A buildup of the protein amyloid β has long been associated with Alzheimer's disease, but scientists have been left in the dark about what causes these so-called plaques and how to effectively target them.
Now, researchers may have found the key to destroying these amyloid-β clumps, which could spur new approaches to drug discovery in a field that has seen more than its share of failures.
Investigators at the Mayo Clinic in Jacksonville, FL, have discovered a defect in a major cell-signaling pathway they say contributes to both the overproduction of amyloid β in the brains of Alzheimer's patients and loss of communication between neurons.
Working with researchers from the University of Kentucky, Xiamen University in China, the University of Oklahoma and the Korea Brain Research Institute, the Mayo scientists published their findings in the journal Neuron.
The pathway in question is called Wnt, which plays a central role in cell survival, embryonic development and synaptic activity--the electrical and chemical signals needed for learning and memory. When this pathway is thrown off balance with either too much or too little activity, disease can occur. When Wnt becomes overactive, for example, it prompts cancer cells to proliferate.
While overactive Wnt has been heavily studied, the new findings underline the connection between underactive Wnt and Alzheimer's disease.
In mice, researchers pinpointed the defect that causes suppressed Wnt signaling and in turn leads to Alzheimer's: low-density lipoprotein receptor-related protein 6, or LRP6. In mice without LRP6, Wnt signaling was also impaired. LRP6 also appears to regulate production of amyloid β and communication between neurons, because LRP6-deficient mice had Alzheimer's-like side effects, including cognitive impairment, neuroinflammation and excess amyloid.
Postmortem brain tissue from Alzheimer's patients confirmed the findings in mice. In brain samples, LRP6 levels were deficient and Wnt signaling was obstructed.
"Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer's disease," said Guojun Bu, a neuroscientist at the Mayo Clinic and the study's lead investigator, in a statement.
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