Since the discovery of Alzheimer’s disease over a century ago, two features of this devastating disease have taken center stage.
The former, known as amyloid plaques, are dense accumulations of misfolded amyloid proteins, occurring in the spaces between nerve cells. Most efforts to halt the progression of Alzheimer’s disease have targeted amyloid protein plaques. To date, all have met with disheartening failure.
The second classic trait has, until recently, received less scrutiny. It consists of chain-like formations in the body of neurons, produced by another crucial protein – tau. These are known as neurofibrillary tangles.
In a new study, researchers at the ASU-Banner Center for Neurodegenerative Diseases at the Biodesign Institute and their colleagues are studying these tangles in the brain – pathologies not only characteristic of Alzheimer’s disease, but other neurodegenerative conditions as well.
The research focuses on a particular protein known as Rbbp7, the deregulation of which appears to be linked to the eventual formation of tau protein tangles and rampant cell death associated with Alzheimer’s disease and other neurodegenerative diseases.
“We thought this protein was involved in Alzheimer’s disease, especially because we know the protein was decreased in postmortem brain tissue from Alzheimer’s disease compared to normal brains,” says Nikhil Dave, lead author of the new study.
Research shows a correlation between decreased levels of Rbbp7 and increased tangling formation and associated neuronal loss and reduction in brain weight in brains with Alzheimer’s disease. Oddly enough, cell loss and tangling formation was reversed in the transgenic mice whose Rbbp7 levels were restored to baseline levels.
The findings open a new avenue of research that could aid in the development of effective treatments for Alzheimer’s disease as well as a wide range of tau-related conditions, collectively referred to as tauopathies, including Pick’s disease, frontotemporal dementia and traumatic brain injury.
The new study appears in the current issue of the journal Acta Neuropathologica.
Alzheimer’s disease remains one of the most enigmatic diseases known to medical science. Its clinical symptoms appear furtively over a period of years and can be masked by normal aging processes. However, once it takes control of the brain, the progression of the disease is often rapid and unforgiving.
Patients can experience a bewildering array of symptoms, including confusion, physical disorientation, delusions, forgetfulness, aggression, agitation, and progressive loss of motor control.
Researchers now know that by the time the disease’s first outward appearances become apparent, Alzheimer’s disease has silently ravaged the brain for decades, typically leaving its calling card in the form of plaques and tangles.
Alzheimer’s disease remains the leading cause of dementia, with aging being the main risk factor. The disease has followed a frightening upward trajectory as life expectancy increases and other once-fatal diseases have become treatable, if not curable. Currently, 5.8 million people in the United States alone suffer from Alzheimer’s disease, and the number is expected to increase to 14 million by 2060, according to the Centers for Disease Research.
Many other factors besides old age play a role in this complex disorder, from hereditary predisposition to vascular conditions such as diabetes and obesity. Lifestyle choices, including diet and exercise, can also affect vulnerability. The disease typically affects people over 65, although early versions of the disease can occur much earlier.
The new study examines another area of risk for neurodegenerative disease, which relates to an individual’s genes and how they are expressed. Although the three billion letter DNA code that makes up an individual’s genome remains fixed throughout life, researchers now know that chemical messengers of great variety and complexity can act on the genome, delivering instructions. to DNA and guiding its behavior.
These epigenetic changes as they are known can turn genes on and off or regulate the amount of proteins that these genes produce. Earlier notions in biology emphasizing a static view of genomic destinies have given way to a new picture of life in which environmental changes can profoundly affect the behavior of our genes. Scientists are just beginning to understand the tremendous influence of the epigenome on human health and disease.
Current research describes the epigenetic changes that occur in the brain when the level of the Rbbp7 protein is reduced, which researchers have detected in post-mortem brain tissue from patients with Alzheimer’s disease.
One function of Rbbp7 is to regulate gene expression. It does this by altering the interaction of DNA with proteins called histones, which DNA winds like sewing thread around a spool. When the DNA strand is loosely wrapped around the histone coil, the cellular machinery can read the exposed DNA message and transcribe it into mRNA, which is then translated into protein. However, if the DNA strand is tightly wrapped around the histone, the DNA genes are hidden from view and transcription can be partially or fully blocked, thereby reducing or deactivating protein expression.
The researchers observed that when the levels of Rbbp7 are reduced, the level of another protein known as p300 increases, causing a post-translational change in the tau protein, known as acetylation. This has the effect of causing the tau protein to detach from cellular structures called microtubules, with which tau usually binds. The detached tau is then free to accumulate in neurons, eventually forming the telltale tangles associated with Alzheimer’s disease. (See attached graphic.)
Acetylation of tau caused by low Rbbp7 results in increased phosphorylation of tau, further promoting tangling formation and subsequent neuronal loss in the brain.
In the new study, transgenic mice with tau pathology showed decreased levels of Rbbp7 and increased neuronal loss. Restoring Rbbp7 to normal levels in mice reversed these pathologies, although cognitive deficits remained.
Ramon Velazquez, corresponding lead author of the new study, speculates that the reason is because the study only targeted a small subregion of the hippocampus, while other areas of the brain associated with cognition were still endemic. with the formation of tangles. “We plan to examine the overall effect of Rbbp7 overexpression in our future research to see if we can save learning, memory, and other facets of cognition.”
The light at the end of the tunnel?
The associations described in the study between Rbbp7 levels and tau entanglement formation, cell death, and loss of cognitive function in the brain are compelling. The results suggest that Rbbp7 may be an attractive target for drug discovery and the development of effective therapies for Alzheimer’s disease and other conditions associated with tau. Treatments based on such studies could be ready for clinical trials within the next five years.
Nevertheless, the authors stress that other molecular actors are probably involved in these complex processes. In future studies, researchers plan to perform in-depth and unbiased probes of protein interactions, DNA-to-mRNA transcription pathways, and epigenetic changes that may lead to neurodegenerative diseases.