June 27, 2000 Penn scientists create first plaque-binding molecular probe in animal model that effectively passes the blood-brain barrier
Philadelphia, PA -- Planned clinical strategies to treat Alzheimer's disease (AD) will involve the use of drugs designed to decrease or eliminate the formation of waxy extracellular clumps, or amyloid plaques, that appear in the brains of AD patients and which are believed to contribute to the inevitable decline in neurological function. Unfortunately, the effectiveness of such drugs cannot be determined as no method currently exists that permits physicians to visually monitor changes in the plaque formations of the brains of living patients. Such monitoring would require the development of a probe, or dye-like compound, capable of not only crossing the stalwart blood-brain barrier but subsequently binding to the plaque formations so that visualization of the amyloid clumps could occur using PET or SPECT imaging.
An innovative solution to that problem may have been found in the work done by researchers at the University of Pennsylvania School of Medicine. There, Virginia M.-Y. Lee, MD, and her team have created a stealth-like molecule, called BSB, that can effectively breach the obstinate blood-brain barrier in mouse models and bind specifically and sufficiently to the resident plaque formations so that they can be visualized by existing imaging techniques. Their work -- which represents the first time that Alzheimer's-like plaques have been visualized in vivo in living animals -- sets the stage for the refinement of this dye-like compound so it may be used to diagnose and monitor the treatment of patients with Alzheimer's disease. At the present time, diagnostic confirmation and visualization of the plaque burden in the brains of Alzheimer's patients can occur only after death, during postmortem autopsy.
"This is definitely proof of concept," says Dr. Lee, Professor of Pathology & Laboratory Medicine at Penn and lead author of the study that appears in the June 20 issue of Proceedings of the National Academy of Science. "We have demonstrated for the first time that a flurogenic probe can cross the blood-brain barrier and bind to amyloid plaques in the brains of transgenic mice that develop such plaques. This is an essential first step for the development of an antemortem diagnostic for Alzheimer's disease."
"This research is an enormously important step toward developing an imaging method that could pinpoint the telltale signs of plaque development associated with Alzheimer's disease in a living brain," echoes Marcelle Morrison-Bogorad, PhD, Associate Director of Neuroscience and Neuropsychology of Aging at the National Institute on Aging in Bethesda, Maryland, which provided the major funding for the study. "This tool could help clinicians peer into a person's brain and monitor amyloid levels in response to treatment. We definitely need something like this to advance the diagnosis and treatment of dementia."
For now, Dr. Lee and her research team will continue to fine-tune BSB (by, perhaps, further increasing its solubility and/or decreasing its molecular weight) and also work to develop an efficient radioactive marker to enhance visualization during PET or SPECT imaging. "The exciting promise of our agent is that, when clinically applied, it will demonstrate efficacy of therapy in treatments designed to inhibit the growth of amyloids," explains Dr. Lee.
As described by the published study, the step-by-step development of the BSB molecular probe was meticulously charted. The design and synthesis of BSB was the ingenious work of Dr. Hank Kung, a co-author of the study, who is highly regarded for creating other imaging molecules that have become essential diagnostic brain-imaging probes now in use throughout the United States and abroad. After determining that BSB could enter cells (by using human cells in culture) and that the agent could be picked-up by normal brain cells (by injecting the compound into the brains of non-diseased mice), the scientists focused their attention on transgenic mice modeled for Alzheimer's disease. At this point, they injected BSB directly into the hippocampus of about a half-dozen transgenic mice to see if they could induce labelling of the plaques close to the injection site. Post-mortem analysis of those brain sections showed that BSB produced clear and distinctive visual identification of the amyloid plaques.
"Our next step was the Holy Grail," remembers Dr. Lee, whose team still had to prove that their new compound was strong enough, small enough, and soluble enough to efficiently pass through the Berlin Wall-like defense of the blood-brain barrier. To that end, BSB was injected into the veins of transgenic mice. Again, post-mortem studies of the animals' brains showed clearly-discernible plaques. In addition, the investigators learned that BSB bound to amyloid plaques remained stable for at least 18 hours. "We demonstrated unequivocably that the compound can go through the blood-brain barrier and bind to amyloid," says Dr. Lee.
The work was supported by grants from the National Institute on Aging and by the estate of Mona Schneidman. Other investigators on the study included Daniel M. Skovronsky ,PhD; Bin Zhang, PhD; Mei-Ping Kung, PhD; Hank F. Kung, PhD; and John Q. Trojanowski, MD, PhD.
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