Scripps Florida Scientists Uncover Potential Driver of Age- and Alzheimer’s-Related Memory Loss

They found that reduced levels of a protein called Rheb result in spontaneous symptoms of memory loss in animal models and are linked to increased levels of another protein known to be elevated in the brains of Alzheimer’s disease patients.

Their study, led by TSRI Associate Professor Srinivasa Subramaniam, was published recently online ahead of print in the journal Neurobiology of Aging.

Link to Known Alzheimer’s Trigger

In the new study, Subramaniam’s group investigated the link between Rheb and an important enzyme called BACE1, which is elevated in older adults and people with Alzheimer’s disease.

“We know that Rheb regulates BACE1, which is a major drug target in Alzheimer’s disease,” Subramaniam said. “Studies of the autopsied brains of Alzheimer’s patients have found a significant reduction in Rheb, so it is possible that an increase in Rheb could reverse the buildup of amyloid plaque or help reduce or even reverse age-related memory loss.”

To uncover the impact of eliminating Rheb, Subramaniam and his colleagues put genetically altered mice through a battery of behavior tests beginning at around six months of age.

While Rheb depletion did not affect the overall body weight or motor activity of the animals, it did have subtle and selective effects on certain memory tasks they performed, such as navigating a maze and memory recall. The researchers compared these symptoms to memory deficits that occur in humans with Alzheimer’s disease and related dementia.

They also found that Rheb depletion increased BACE1 levels, which was consistent with previous research showing that higher BACE1 levels may be a contributing factor for memory deficits.

The fact that some research shows that Rheb messenger RNA is induced during protein starvation in fruit flies, led Subramaniam and his colleagues to theorize that a high-protein diet in humans might be a risk factor for decreasing Rheb levels with age, resulting in mild-to-severe cognitive deficits, as seen in animal models.

“This is an indication that nutrient signaling might regulate cognitive functions in mammals through alteration of Rheb–BACE1 pathway activity,” Subramaniam said.“Overall, our study demonstrates that forebrain Rheb depletion promotes aging-associated cognitive defects,” said Neelam Shahani, the first author of the study. “Targeting the Rheb pathway may offer some therapeutic potential for aging- or Alzheimer’s disease-associated memory deficits.”

In addition to Subramaniam and Shahani, other authors of the study, “Forebrain Depletion of Rheb GTPase Elicits Spatial Memory Deficits in Mice,” are TSRI’s Wen-Chin Huang, Megan Varnum and Damon T. Page.

This work was supported by the National Institutes of Health (grants NIH/NINDS R01-NS087019, NIH/NINDS R01-NS094577, and NIH/NIMH R01-MH105610), Ms. Nancy Lurie Marks and the Alzheimer’s Disease Association (grant 2015-NIRG-344356).

About The Scripps Research Institute

The Scripps Research Institute (TSRI) is one of the world's largest independent, not-for-profit organizations focusing on research in the biomedical sciences. TSRI is internationally recognized for its contributions to science and health, including its role in laying the foundation for new treatments for cancer, rheumatoid arthritis, hemophilia, and other diseases. An institution that evolved from the Scripps Metabolic Clinic founded by philanthropist Ellen Browning Scripps in 1924, the institute now employs more than 2,500 people on its campuses in La Jolla, CA, and Jupiter, FL, where its renowned scientists—including two Nobel laureates and 20 members of the National Academy of Science, Engineering or Medicine—work toward their next discoveries. The institute's graduate program, which awards PhD degrees in biology and chemistry, ranks among the top ten of its kind in the nation. For more information, see www.scripps.edu.