Summary: A new study reports reduced levels of Rheb result in memory loss in animal models of dementia.
Source: Scripps Research Institute.
Scientists from the Florida campus of The Scripps Research Institute (TSRI) have made an important discovery toward the development of drugs to treat age-related memory loss in diseases like Alzheimer’s. 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 TSRI Staff Scientist 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.
Funding: 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).
Source: Scripps Research Institute
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Abstract for “Forebrain Depletion of Rheb Elicits Spatial Memory Deficits in Mice” by Neelam Shahani, Wen-Chin Huang, Megan Varnum, Damon T. Page, Srinivasa Subramaniam in Neurobiology of Aging. Published online November 21 2016 doi:10.1016/j.neurobiolaging.2016.11.006
[cbtabs][cbtab title=”MLA”]Scripps Research Institute “Uncover Potential Driver of Age and Alzheimer’s Related Memory Loss.” NeuroscienceNews. NeuroscienceNews, 10 December 2016.
<https://neurosciencenews.com/age-alzheimers-memory-loss-5720/>.[/cbtab][cbtab title=”APA”]Scripps Research Institute (2016, December 10). Uncover Potential Driver of Age and Alzheimer’s Related Memory Loss. NeuroscienceNew. Retrieved December 10, 2016 from https://neurosciencenews.com/age-alzheimers-memory-loss-5720/[/cbtab][cbtab title=”Chicago”]Scripps Research Institute “Uncover Potential Driver of Age and Alzheimer’s Related Memory Loss.” https://neurosciencenews.com/age-alzheimers-memory-loss-5720/ (accessed December 10, 2016).[/cbtab][/cbtabs]
Abstract
Forebrain Depletion of Rheb Elicits Spatial Memory Deficits in Mice
The precise molecular and cellular events responsible for age-dependent cognitive dysfunctions remain unclear. We report that small guanine nucleotide-binding protein Rheb (ras homolog enriched in brain), an activator of mammalian target of rapamycin (mTOR), regulates memory functions in mice. Conditional depletion of Rheb selectively in the forebrain of mice obtained from crossing Rhebflox/flox and CamKIICre results in spontaneous signs of age-related memory loss, i.e., spatial memory deficits (T-maze, Morris water maze) without affecting locomotor (open-field test), anxiety-like (elevated plus maze), or contextual fear conditioning functions. Partial depletion of Rheb in forebrain was sufficient to elicit memory defects with little effect on the neuronal size, cortical thickness or mTOR activity. Rheb depletion, however, increased the levels of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein elevated in aging and Alzheimer disease (AD). Overall, our study demonstrates that forebrain Rheb promotes aging-associated cognitive defects. Thus, targeting the Rheb pathway may provide therapeutic potentials for aging and/or AD-associated memory deficits.
“Forebrain Depletion of Rheb Elicits Spatial Memory Deficits in Mice” by Neelam Shahani, Wen-Chin Huang, Megan Varnum, Damon T. Page, Srinivasa Subramaniam in Neurobiology of Aging. Published online November 21 2016 doi:10.1016/j.neurobiolaging.2016.11.006
