Key signaling pathway defective in Alzheimer’s disease patients

alzheimer'sA new study published in the journal Neuron has revealed a defect in the key cell-signaling pathway that contributes to both overproduction of toxic protein in the brains of Alzheimer’s disease patients as well as loss of communication between neurons.

The pathway involved, called Wnt signaling, is known to play a critical role in cell survival, embryonic development and synaptic activity the electrical and chemical signals necessary for learning and memory. Any imbalance in this pathway (too much or too little activity) leads to disease; causing an accumulation of cells including the plaque build up. The overgrowth of cells in cancer is one example of over-activation of this pathway.

The researchers used a mouse model and discovered the key defect that leads to suppressed Wnt signaling in Alzheimer patients. It was determined that the low-density lipoprotein receptor-related protein 6 (LRP6) is deficient, and that LRP6 regulates both production of amyloid beta, the protein that builds up in the brains of AD patients, and communication between neurons. That means lower than normal levels of LRP6 leads to a toxic buildup of amyloid and impairs the ability of neurons to talk to each other.

“This defect is likely not the sole contributor to development of Alzheimer’s disease, but our findings suggest it is very important, and could be therapeutically targeted to possibly prevent Alzheimer’s or treat early disease,” said the study’s lead investigator, Guojun Bu, Ph.D., a neuroscientist at Mayo Clinic, Jacksonville, Fla.

“Our finding makes sense, because researchers have long known that patients with cancer are at reduced risk of developing Alzheimer’s disease, and vice versa,” Dr. Bu says. “What wasn’t known is that Wnt signaling was involved in that dichotomy.”

“Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer’s disease,” he says. “This is a really exciting new strategy — a new and fresh approach.”


Chia-Chen Liu, Chih-Wei Tsai, Ferenc Deak, Justin Rogers, Michael Penuliar, You Me Sung, James N. Maher, Yuan Fu, Xia Li, Huaxi Xu, Steven Estus, Hyang-Sook Hoe, John D. Fryer, Takahisa Kanekiyo, Guojun Bu. Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease. Neuron, 2014; DOI: 10.1016/j.neuron.2014.08.048

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