ARTICLE IN BRIEF
For the first time, scientists took what they believe to be the critical brain material responsible for initiating Alzheimer disease and asked what it does to the function and structure of nerve cells in normal adult animals.
Harvard scientists took brain tissue from people who died with Alzheimer disease (AD) and injected extracts of it into rodents to see whether amyloid-beta (Abeta) protein could have acute effects on brain synapses and on behavior. And it did.
Dennis Selkoe, MD, the Coates Professor of Neurology at the Brigham & Women's Hospital and Harvard Medical School, and his colleagues reported that small, soluble forms of Abeta protein from the brain of typical AD patients blocked long-term potentiation, an electrical correlate of learning and memory, whereas similar material from non-Alzheimer brains had no such effect.
They also found that synapses of neurons in the hippocampus, an area critical for memory, were not as efficient when bathed with the soluble material from the Alzheimer brain, and that synapses actually decreased in number. The study was published June 22 online in advance of print in Nature Medicine.
This was the first time scientists took what they believe to be the critical brain material responsible for initiating AD and asked what it does to the function and structure of nerve cells in normal adult animals. They conducted behavioral studies to determine whether extracts from diseased brains could affect memory.
Specifically, they taught adult rats to be afraid of entering a dark chamber. But after intracerebral injections of the Abeta extracts, the rats forgot that they should avoid entering the chamber. The memory impairment was transient. Animals that received injections of extracts depleted of soluble Abeta proteins had no deficit in memory.
In addition to aged normal brain tissue, they also conducted the same studies with tissue from patients diagnosed with other forms of dementia and did not find any synaptic deficits. The investigators also found that injections of Abeta antibodies protected against this memory block, suggesting that Abeta is the rogue protein in the AD brain extracts involved in altering memory.
To address how this happens, the scientists set out to analyze various assembly forms of Abeta in the human brain extracts. They found that single Abeta molecules (monomers) did not harm neuronal synapses. But when a monomer teamed up with another monomer to form a dimer, it apparently folded into a different conformation that bound to nerve cells and interfered with synaptic functions.
Once they knew that the soluble dimer form could have this effect, they isolated amyloid plaques from the same brains. In a test tube, they used a strong solvent to dissolve and release the dimers and monomers. They infused the hippocampal slices with the extract (from human AD brains) and observed what happened. With the extract present, it blocked long-term potentiation and when the antibody was put into the test tube before the extract, it prevented the blockage of long-term potentiation.
“It is a story I think is coming together nicely,” said Dr. Selkoe. “Nobody had taken material from Alzheimer brains and seen what functional effects they have on normal animal brains.”
“The plaques did not acutely impair neuronal synapses,” Dr. Selkoe added. He noted that this might help explain why some people who have no clear-cut symptoms of AD at autopsy can have brains riddled with insoluble plaques. It is not unlike what can happen in the heart, he said. Many people have never had clinical heart events despite having lots of atherosclerotic plaques lining their arteries.
If the findings are confirmed, scientists can pursue new ways to block this process of dimer accumulation by either stopping the pairing of the two monomers, breaking apart the dimer once it is formed, or coating the dimers in such a way that they don't bind to neurons.
The Harvard team is already working to find small molecules that bind to monomers or coat dimers and prevent them from binding to neuronal targets and damaging the ability of a synapse to carry out normal communication.
For example, they tested a compound called scyllo-inositol that Joanne McLaurin, PhD, of the Center for Research in Neurodegenerative Diseases at the University of Toronto, discovered blocks the oligomerization of Abeta. (The study, led by Dr. McLaurin, was published last June in the Journal of Molecular Medicine.) The investigators put the chemical, a naturally occurring sugar, into the drinking water of adult rats and then injected dimers and trimers into the rats' brains. The compound protected against acute memory loss.
Dr. Selkoe and his colleague Ganesh M. Shankar, PhD, contend that Abeta protein builds up slowly in humans and it is only when dimers are formed in critical amounts that they can exert toxic effects on synapses. Some dimers may leach out of plaques once they are formed and continue to cause local damage.
“The field has converged onto a new path of neuronal dysfunction and injury,” Dr. Selkoe said. “Our work and that of other labs has shown that a few monomers can stick together and impair synapses but that they aggregate into larger assemblies that are much less toxic. So, it may be the process leading up to the formation of plaques that is particularly harmful.”
David Holtzman, MD, professor and chairman of neurology at Washington University in St. Louis, said that the study doesn't completely prove that the toxic material is the Abeta dimers.
The material injected into the brains was ground up from the tissue of the Alzheimer brain, and it could be another substance that is causing the damage to the synapses, said Dr. Holtzman, who was not involved with the current study. Also, it is not clear whether the monomers are in equilibrium with the fibrils and plaques. “In order to get the toxicity, does the brain need the plaques present?” Dr. Holtzman asked. “I don't think we can say that this finding means that plaques are not important in the disease process.”
Dr. Holtzman and his colleagues are also trying to determine how the dimers damage synapses, and in turn destroy nearby brain cells.
• Shankar GM, Li S, Selkoe DJ, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med 2008: E-pub 2008 June 22.
• Fenili D, Brown M, McLaurin J, et al. Properties of scyllo-inositol as a therapeutic treatment of AD-like pathology. J Mol Med