Neuron paper shows that amyloid-beta precursor cleavage regulates apolipoprotein E, a cholesterol carrier.

Researchers at Washington University School of Medicine in St. Louis found an aspect of cholesterol transport and metabolism in the brain that links molecules involved in early- and late-onset Alzheimer’s disease.

The scientists believe that their study strengthens the case for another cause of Alzheimer’s besides build up of amyloid-beta (A-beta) plaques. “Cholesterol metabolism in the brain is an understudied area, and our findings could inspire Alzheimer’s researchers to look further into the role of the cholesterol pathway,” says senior author Guojun Bu, Ph.D., professor of pediatrics and cell biology and physiology.

Early-onset Alzheimer’s can be traced to mutations in one of three genes including the gene coding for A-beta’s precursor, APP. The genetic origins of late-onset Alzheimer’s are unknown, but studies have shown that a particular mutation in the gene for a cholesterol carrier, called apolipoprotein E, increases risk.

The Washington University team report that when APP is cleaved by gamma-secretase in the brain, it releases A-beta plus a small protein fragment, APP intracellular domain (AICD). AICD regulates apolipoprotein E, which moves cholesterol in the brain from support cells to neurons, through the lipoprotein receptor LRP1.

“Right now,” Dr. Bu adds, “research on Alzheimer’s treatment focuses largely on reducing A-beta production or increasing its clearance from the brain. Our study suggests that there could be an alternate way to treat the disease, perhaps by modulating the function of apolipoprotein E and cholesterol in the brain.”

The study was published in the October 4 issue of Neuron.

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