Newly-Studied REST Protein Provides More Clues to Cause of Alzheimer’s Disease

Martha Snyder Taggart, BrightFocus Editor, Science Communications
  • Science News
Published on:
Sisters holding a photo of themselves and their father, who has Alzheimer's disease

This week, researchers at Harvard posted a new and encouraging milestone along our path to a better understanding of Alzheimer’s disease. Bruce A. Yankner, MD, PhD, and his team, have found that a protein known as repressor element 1-silencing transcription factor, or “REST,” may prove instrumental in protecting the aging brain. Their findings were published online in Nature (Lu, T. et al. Nature).

Possible Insight into the Plaques Puzzle?

Ever since scientists discovered that the brains of advanced-stage Alzheimer’s patients are “littered” with deposits of amyloid-beta (amyloid β) protein deposits, known as plaques, they’ve been trying to solve another puzzle. Why, in about one-third of cases, do similar plaques appear in the brains of patients without Alzheimer’s symptoms?

Yankner, who was interviewed in The New York Times, said that he was similarly puzzled, at first, by the fact that levels of the protein he was studying—REST—are high in fetuses before birth, decline afterwards, and then appeared to resurge in healthy older brains. He hypothesized that REST might serve to protect and extend neurons’ life during periods of great stress—like birth and old age.

Utilizing tissue from brain banks and dementia trials, the team sampled human brains and learned that those of young adults (aged 20 to 35 years) contained the least REST, while those of healthy adults between the ages of 73 and 106 had plenty. The older people got, the higher their REST levels grew—as long as they retained normal cognitive functioning. However, the brains of older adults with Alzheimer’s and other forms of dementia contained much less REST than healthy brains, particularly in regions critical to learning, memory and planning (the prefrontal cortex and hippocampus).

These tissue studies were then confirmed in laboratory testing involving mice, roundworms and cells.

What Testing Showed

Through molecular testing, the researchers discovered that REST represses genes that promote cell death and Alzheimer’s-linked tissue changes, and that it switches on stress response genes that protect neurons from threats like oxidative (sometimes called “environmental”) stress, inflammation, energy loss, and amyloid ß-protein toxicity. Experimenting in mice, they found that mice genetically engineered to lack REST also lost neurons as they aged in the same brain areas affected in human Alzheimer’s patients.

Yankner now speculates that REST may be “neuroprotective” or “neurodegenerative” for the aging brain, depending on the circumstances. In healthy brain tissue, it appears to travel to a neuron’s nucleus in response to stress and confers neuroprotection; however, in brains of people with Alzheimer’s and other forms of dementia, it might get diverted to another part of the neuron and be destroyed by toxic dementia-related proteins.

Some Caveats on the Research

There are still missing pieces to the hypothesis, including a “chicken and egg” question as to whether lower REST levels are a cause or consequence of Alzheimer’s disease.

Other scientists have cautioned that more research is needed before the specific role of REST is revealed. Dr. John Hardy of University College London, a BrightFocus Scientific Review Committee member, cautioned in press statements that information from post-mortem brains could not prove that a decline in REST caused dementia, because death might produce unrelated damage to brain cells.

However, the Harvard REST findings provide some fascinating clues to a possible “switch” that, when turned on, might help explain why some amyloid β-protein plaques are associated with Alzheimer’s, and others not. Learning what causes Alzheimer’s could, in turn, lead to diagnosis and treatment at earlier stages, possibly even before symptoms develop.

Glossary Terms

  • Shrinkage of the brain caused from neural damage and neuron cell loss, resulting in a measurable loss of brain volume. 

  • Evidence points to beta amyloid (Aβ) peptide accumulation as a culprit in preclinical Alzheimer’s disease.

  • The hippocampus is a part of the brain that plays a significant role in the formation of long-term memories. The plural of hippocampus is hippocampi.

  • One of the hallmarks of Alzheimer's disease is the accumulation of amyloid plaques between nerve cells (neurons) in the brain. Amyloid is a general term for protein fragments that the body produces normally. Beta amyloid is a protein fragment snipped from an amyloid precursor protein (APP). In a healthy brain, these protein fragments are broken down and eliminated. In Alzheimer's disease, the fragments accumulate to form hard, insoluble plaques.