New research by scientists at the University of Medicine and Dentistry of New Jersey-School of Osteopathic Medicine (UMDNJ-SOM) demonstrates how dying or damaged brain cells release debris into the bloodstream and give rise to specific autoantibodies that appear to be reliable biomarkers for early diagnosis of Alzheimer's and other neurodegenerative diseases. The researchers also identify a key mechanism in the development of Alzheimer's that mirrors a process that is common in such autoimmune disorders as rheumatoid arthritis.
The study appears online in the Journal of Autoimmunity.
"Our earlier research showed that human blood contains perhaps thousands of autoantibodies for clearing cellular debris, and that some of these autoantibodies can potentially be used to accurately diagnose neurodegenerative diseases like Alzheimer's and Parkinson's," said Robert Nagele, PhD, a professor of medicine at the New Jersey Institute for Successful Aging at UMDNJ-SOM and the study's corresponding author. "Here, we found that the release of damaged proteins from dying neurons triggers the production of specific brain-reactive autoantibodies that are directed against this protein debris, a response similar to that seen in some autoimmune disorders."
The researchers focused on the role of enzymes, called PADs, in citrullination, a process that converts one type of amino acid into another (amino acids are the building blocks of proteins). After examining postmortem human brain tissue from individuals with Alzheimer's disease and healthy controls, the researchers found that neurons located in the area of the brain first affected by Alzheimer's disease accumulate both citrullinated proteins and a PAD enzyme. In addition, they demonstrated that a specific type of protein, PTCD2, which has been shown to be a potent biomarker for Alzheimer's, was present in citrullinated form in the neuron cells of the Alzheimer's disease brain samples.
Their results suggest that when neuron cells die, they release their contents into the fluid that surrounds the brain. The cellular remains then enter the bloodstream and their presence generates the production of specific autoantibodies that target this neuronal debris. This same protein citrullination process has been linked to the development of autoantibodies in rheumatoid arthritis, one of the most common forms of autoimmune disease.
"Our previous studies provided evidence that some of these autoantibodies may be able to return to the brain through breaches in the blood-brain barrier," said lead author Nimish Acharya of the UMDNJ-Graduate School of Biomedical Sciences and the New Jersey Institute for Successful Aging. "Once there, they selectively bind to the surfaces of neurons, disrupting the function of the brain cells and accelerating the accumulation of beta amyloid deposits. This chronic cycle of protein-debris-generating autoantibodies that can then seep through the blood-brain barrier helps explain the long-term, progressive degeneration that results from Alzheimer's disease."
The above story is based on materials provided by University of Medicine and Dentistry of New Jersey (UMDNJ). Note: Materials may be edited for content and length.
- Nimish K. Acharya, Eric P. Nagele, Min Han, Nicholas J. Coretti, Cassandra DeMarshall, Mary C. Kosciuk, Paul A. Boulos, Robert G. Nagele. Neuronal PAD4 expression and protein citrullination: Possible role in production of autoantibodies associated with neurodegenerative disease. Journal of Autoimmunity, 2012; 38 (4): 369 DOI: 10.1016/j.jaut.2012.03.004
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