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Natural Anti-amyloid Autoantibodies in Alzheimer's Disease
Abstract & Commentary
By Norman Relkin, MD, PhD, Director, Memory Disorders Program, and Associate Professor of Clinical Neurology, Weill Cornell Medical College. Dr. Relkin reports that he receives grant/research support from Baxter Bioscience, and is a consultant to Eisai, Pfizer, Myriad, and Smart Genetics. Dr. Relkin also reports he is leading a Phase 3 clinical trial of Intravenous Immunoglobulin for treatment for Alzheimer's disease, funded by the National Institute on Aging and Baxter Healthcare.
Synopsis: The spontaneous development of anti-amyloid antibodies may have an impact on the development of plaques and Alzheimer's disease.
Source: Kellner A, Matschke J, Bernreuther C, et al. Autoantibodies against beta-amyloid are common in Alzheimer's disease and help control plaque burden. Ann Neurol 2009;65:24-31.
Autoantibodies against beta amyloid are common in the blood of Alzheimer's disease (AD) patients and may play a role in controlling the density of neuritic plaques in the brain, according to a recently published study. Dr. Kellner of the University Hospital in Hamburg, working with colleagues in Switzerland and Spain, developed a tissue microarray (TMA) platform to quantitatively examine brain tissue from 48 autopsy-proven AD patients and an equal number of elderly controls. The TMA platform enables quantitative measures of parameters such as plaque burden, microglial activation, and microhemorrhage to be carried out on serial brain sections.
The study showed that the majority of neuritic plaques in AD patients in areas such as the entorhinal cortex were decorated with IgG autoantibodies. The degree of staining differed across AD patients. When the investigators divided the cohort into low versus high IgG-staining subjects, an interesting relationship became apparent. AD patients with higher levels of IgG binding had less amyloid burden in their brain. There was no increase in microhemorrhage in the high IgG group, which is a notable positive in that microhemorrhage has been a side effect of certain anti-amyloid immunotherapies in recent AD clinical trials. The study also confirmed that immune activation in the form of activated and phagocytic microglial cells is common in the AD brain. More phagocytic microglia were found in the brains of AD patients with high IgG binding.
In another set of experiments, the investigators took serum from eight AD patients and studied the binding of autoantibodies to brain tissue obtained from a transgenic mouse model of AD. They divided the patients' serum into high and low binding groups based on the degree to which they stained amyloid plaques in the mouse brains. Once again, patients with serum that exhibited high binding to the mouse brain had lower plaque burden at autopsy. The difference in amyloid burden was most apparent for diffuse plaques, which were relatively increased in the low plaque binding group.
Based upon these studies, the authors concluded that naturally occurring anti-amyloid autoantibodies may help to maintain amyloid homeostasis in the brain. If so, such antibodies may be relevant to the pathophysiology and potentially the treatment of Alzheimer's disease.
Several past studies have shown that autoantibodies against the beta amyloid molecule are present in the blood of normal individuals as well as patients with Alzheimer's disease. The physiologic relevance of the antibodies has been questioned. Their titers are relatively low compared to antibodies that are induced by anti-amyloid vaccination. This is not unexpected, since beta amyloid is a physiologic peptide that is present throughout life. Recent evidence has emerged that special classes of conformation-selective antibodies against beta amyloid aggregates are also present in blood, and bind to oligomeric and fibrillar forms of beta amyloid. Such antibodies could well account for the staining observed in the Kellner study.
The finding that anti-amyloid IgG binding is inversely correlated with plaque burden in AD is encouraging evidence that naturally occurring antibodies are involved in the body's innate defenses against proteins that undergo misfolding such as beta-amyloid. The value of such antibodies for the treatment of AD is currently being tested in multicenter AD studies of intravenous immunoglobulin, a polyclonal mixture of human antibodies that contains significant anti-amyloid activity.