More Evidence for the Importance of BACE1 in Alzheimer's Disease

BACE1 is a target for Alzheimer's therapies as it is involved in the production of amyloid-β. The condition is characterizing by rising levels of this form of amyloid in the brain, which in turn produces a halo of harmful biochemical interactions that damage and kill brain cells. Researchers are working on a range of ways to reduce the amount of amyloid-β, and interfering with its production is one approach, albeit so far not as effective as striving to remove the amyloid, such as via immunotherapies. Here, researchers explore some of the biochemistry surrounding BACE1; cellular machinery never acts in isolation, and there are always relationships linking many different proteins relevant to any mechanism. Thus there are always multiple options and targets when it comes to achieving a specific result in the operation of cells.

Scientists have 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 researchers 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. 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, researchers 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 researchers 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. Overall, our study demonstrates that forebrain Rheb depletion promotes aging-associated cognitive defects. Targeting the Rheb pathway may offer some therapeutic potential for aging- or Alzheimer's disease-associated memory deficits."

Link: http://www.scripps.edu/news/press/2016/subramaniam20161207.html

Comments

A potential problem --

Rheb increases mTORC1 expression, which is associated with accelerated aging.

Posted by: Lou Pagnucco at December 14th, 2016 11:42 AM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.