Minimizing memory loss

TSRI scientists uncover potential clues regarding Alzheimer’s disease

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JUPITER, Fla.—“Neurodegenerative diseases are quickly becoming one of the most significant problems facing both the scientific community and the world at large,” according to Srinivasa Subramaniam, associate professor of neuroscience at the Florida campus of The Scripps Research Institute (TSRI).
Although scientists have been able to “provide symptomatic relief” for some of these diseases, they have not been able to develop therapies to modify or stop disease progression, Subramaniam said. His lab, which focuses on identification and characterization of signaling networks in neurodegenerative diseases, is attempting to develop clinical therapeutics. Using numerous techniques to study protein-protein interactions, posttranslational modifications and signaling pathways, the researchers hope to discover druggable target genes and eventually develop novel therapeutics.
Recently, these scientists 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. The study, led by Subramaniam, was published recently in the journal Neurobiology of Aging. In the article, “Forebrain depletion of Rheb GTPase elicits spatial memory deficits in mice,” the researchers described how they investigated the link between Rheb and an important enzyme called BACE1, which is elevated in older adults and people with Alzheimer’s disease.
According to Subramaniam, “We know that Rheb regulates BACE1, which is a major drug target in Alzheimer’s disease. 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 determine the impact of eliminating Rheb, the researchers put genetically altered mice through behavior tests beginning at around six months of age. Rheb depletion had selective effects on certain memory tasks, 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, demonstrating that higher BACE1 levels could be a contributing factor for memory deficits.
Because some research shows that Rheb messenger RNA is induced during protein starvation in fruit flies, Subramaniam and his colleagues theorized 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. According to Subramaniam, “This is an indication that nutrient signaling might regulate cognitive functions in mammals through alteration of Rheb–BACE1 pathway activity.”
He added, “Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness, or mammalian target of rapamycin activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in aging and Alzheimer’s disease.”
“Overall, our study demonstrates that forebrain Rheb depletion promotes aging-associated cognitive defects,” concluded 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.”

Scripps Florida scientists expand toolbox to study cellular function
JUPITER, FLA.—In other news of the TSRI Florida campus, scientists there have developed a new tool for studying the molecular details of protein structure.
Their new study, published recently in the journal Proceedings of the National Academy of Sciences, explores how evolution can be used to discover new and useful enzyme tools, called proteases. Proteases cleave proteins into smaller peptide pieces that scientists can then analyze to determine the identity of the protein and whether a cell has made chemical changes to the protein that might alter its function.
The new protease developed in the study helps shed light on these chemical changes, called post-translational modifications. Post-translational modifications are alterations made to proteins after the proteins are translated from RNA.
“We have to observe these protein modifications directly through chemical analysis; we can’t read them out of DNA sequence,” explained study senior author Brian M. Paegel, associate professor at TSRI.
With the current practice of studying post-translational modifications with mass spectrometry, scientists analyze peptides to see if their mass changes—a bit like zooming in on that protein to see hidden details. An unexpected change in mass can indicate the occurrence of a post-translational modification.
Many scientists today use a protease called trypsin to break proteins into peptides. Because there are few other proteases available for mass spectrometry, trypsin has become the workhorse of the field. However, Paegel explained, it’s luck of the draw if trypsin generates a peptide with a modified site. So, Paegel and co-workers thought it would be useful to have a new tool that cleaved directly at the modified site.
To solve this problem, Paegel developed a new trypsin “mutant” using a technique called “directed evolution,” and they discovered a mutant that could cut proteins at citrulline, which is one type of modification.
Paegel believes this new approach could be useful for mapping a wider range of post-translational modifications, and he hopes to use directed evolution to discover proteases that target many other post-translational modifications. “I think we’re on the brink of an explosion of new tools for mass spectrometry,” he said.

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