Pathway in Brain Contributes to Alzheimer’s Disease

A new study entitled “Deficiency in LRP6-Mediated Wnt Signaling Contributes to Synaptic Abnormalities and Amyloid Pathology in Alzheimer’s Disease,” published in the online issue of Neuron, reports the discovery of a key pathway to the progression of Alzheimer’s Disease.

Alzheimer’s disease is characterized by synaptic loss and dementia. Previously, genetic variants of a receptor for low-density lipoprotein 6 (LRP6) were linked with Alzheimer’s disease. Now a team of scientists from the Mayo Clinic in Jacksonville, Florida discovered that LRP6 in the neurons mediates a signal, via Wnt, which is crucial for hypnotic function and cognition.

A conditional deletion of the Lpr6 gene in mouse forebrain neurons impaired Wnt signaling and exhibited a deficit in synaptic integrity and memory. Additionally, the authors found that this defect exacerbates amyloid beta deposits in the brain (the main protein in amyloid plaques found in Alzheimer’s disease patients).

Wnt signaling has crucial functions in cell survival and synaptic activity and imbalance Wnt activity was linked to cancer. Now, the team led by Guojun Bu, Ph.D., a neuroscientist at MayoClinic, Jacksonville, Florida is the first linking suppressed Wnt signaling and Alzheimer’s disease.

“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. What wasn’t known is that Wnt signaling was involved in that dichotomy,” said Dr. Bu.

Shifting from mice to humans in their experiments, the authors found LRP6 and Wnt signaling to be significantly impaired in postmortem Alzheimer’s patients brains.

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Dr. Bu noted, “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.”

Therapeutics targeting Wnt signaling are currently being tested in cancer patients. Thus, in the future restoring LPR6-mediated Wnt signaling might prove a viable therapeutical strategy for Alzheimer’s disease. “Of course, we don’t want to inhibit Wnt in people with Alzheimer’s or at risk for the disease, but it may be possible to use the science invested in inhibiting Wnt to figure out how to boost activity in the pathway,” Dr. Bu commented. “Identifying small molecule compounds to restore LRP6 and the Wnt pathway, without inducing side effects, may help prevent or treat Alzheimer’s disease. This is a really exciting new strategy — a new and fresh approach.”