Study finds link to abnormal Tau protein accumulation in brain
Researchers have discovered a new gene that is associated with susceptibility to an abnormal accumulation in the brain of a protein called Tau, a common form of brain pathology. This accumulation occurs in several different conditions, including Alzheimer’s disease, certain forms of dementia, Parkinsonian syndromes and chronic traumatic encephalopathy, which occurs in athletes and others with repeated head injuries.
Investigators at Rush University Medical Center and the Brigham and Women’s Hospital in Boston (a teaching affiliate of Harvard Medical School) reported this discovery in an article published online March 21 by the journal Molecular Psychiatry. The manuscript describes the identification and validation of a variant in what is known as the PTPRD gene (an abbreviation of protein tyrosine phosphatase receptor-type delta gene).
The study centered on a pathological accumulation of Tau protein known as neurofibrillary tangles, or NFT for short, which are a hallmark of Alzheimer’s disease and other degenerative neurological conditions. “Aging leads to the accumulation of many different pathologies in the brain, and one of the most common forms of pathology are NFT” says co-principal investigator David Bennett, MD, director of the Rush Alzheimer Disease Center and the Robert C. Borwell Professor of Neurological Sciences at Rush.
“The NFT is more closely related to memory decline than other forms of aging-related pathologies, so understanding the genetics behind it is crucial to fighting these illnesses, but there are still very few genes that have been implicated in the accumulation of this key feature of Alzheimer’s disease and other brain diseases,” Bennett adds.
Study used genetic analysis of 909 organ donors’ brain tissue
The study examined the results of autopsies on brain tissue samples from 909 deceased individuals who while living participated in one of two studies of aging based at Rush University. As part of the studies, they agreed to donate their brains to research after their deaths. Brains from persons with a wide range of cognition — from very high functioning to moderate to severe dementia — were studied, almost two-thirds of them with pathologic Alzheimer’s disease.
The research team assessed the human genome in these persons for evidence that a genetic variant could affect NFT and found the PTPRD gene variant. The finding was replicated in a separate study of 369 brains. “We found that this variant is the second strongest variant associated with NFT after the widely-known APOE variant,” Bennett added.
“The variant that we discovered is common: Most people have one or two copies of the version of the gene, which is linked to accumulating more pathology as you get older," says lead author Lori Chibnik , PhD, MPH, of the Harvard T.H. Chan School of Public Health. "Interestingly, tangles can accumulate through several different mechanisms, and the variant that we discovered appears to affect more than one of these mechanisms.”
Results suggest possible direction for new Alzheimer’s drugs
The reported results offer an important new lead as the field of neurodegeneration searches for robust novel targets for drug development. Such new prospects are especially needed given the disappointing recent results in Alzheimer’s disease trials targeting amyloid, the other major form of pathology related to Alzheimer’s disease.
Tau pathology is more closely connected than amyloid to loss of brain function with advancing age, and it may be more effective as a target for drug intervention. In addition, the advent of new techniques to measure Tau in the brains of living individuals using positron emission tomography offers a biomarker — that is, an indication of disease or the risk of disease — that can guide the use of therapies targeting Tau.
“This study is an important first step," says Philip De Jager, MD, PhD, a co-principal investigator of the study now at the Columbia University Medical Center. "However, the result needs further validation, and the mechanism by which the PTPRD gene and the variant in it that we have discovered contribute to the accumulation of NFT remains elusive.
“Other studies in mice and flies implicate PTPRD in memory dysfunction and worsening of Tau pathology, suggesting that altering the level of PTPRD activity could be helpful in reducing an individual’s burden of Tau pathology.”
Alzheimer disease is the most common form of dementia in older age. While symptomatic treatments exist, current treatments are not robust, and there are currently no preventive therapies.
The study was supported by the National Institute on Aging. The investigators thank the thousands of participants in the Religious Orders Study and Memory and Aging Project for their participation and donation.
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