Scientists at the University of Rochester Medical Center have targeted a new culprit and method of attack on neurologic functions in diseases such as Alzheimer's and dementia associated with HIV.
In an article in the Nov. 1 issue of The Journal of Clinical Investigation, the Rochester scientists describe a new mechanism by which brain cells can be damaged during chronic neurodegenerative diseases. When inflammation occurs in the brain, nerve impulses that are passed between cells during routine activities like learning and memory can become toxic. Instead of triggering the formation of memories, these impulses can inflict injury on neurons and disrupt neurologic function.
Understanding this mechanism could provide a new path for drugs to treat the diseases. Working in collaboration with researchers at the University of California at San Diego, the Rochester scientists propose a strategy of chemical preconditioning to induce adaptations in nerve cells that would enable the cells to better withstand toxic attacks, prevent injury, and preserve function.
"Preconditioning would allow the nervous system to experience stress and become more resistant to future encounters with stress and the damage it can trigger," said Harris A. Gelbard, M.D., professor of Neurology at the University of Rochester Medical Center and the research project's principal investigator.
A long-standing villain in neurodegenerative disease has been glutamate, an amino acid that normally acts as a neurotransmitter. Excess glutamate, however, can overly excite neurons, causing damage and death -- a process called excitotoxicity. Some drugs developed for the treatment of Alzheimer's disease, for example, are designed to lower the production of glutamate or block its transmission to reduce excitotoxic injury.
"But just blocking glutamate doesn't seem to work efficiently in neurodegenerative diseases with inflammation," said Gelbard. "We reconsidered how excitotoxicity actually damages the nervous system in a functional way."
The scientists focused on dendrites, the crooked branches of neurons that carry impulses toward the body of the nerve cell, and synapses, the places where impulses pass from neuron to neuron. Injury to dendrites -- characterized by swelling or beading, loss of dendrite spines, and reduction in size -- is seen in HIV-1-associated dementia and Alzheimer's.
In laboratory studies, brain cells and slices were exposed to platelet-activating factor, or PAF, a compound that promotes inflammation and plays many roles in the brain. It can be produced by neurons and takes part in the working of synapses, including activity associated with learning and remembering. It also is produced by immune cells during inflammation. The amount of PAF in the brain increases dramatically in HIV-1-associated dementia and other neurodegenerative diseases.
"We found that disease makes dendrites more vulnerable to excitotoxicity," said Matthew J. Bellizzi, a researcher and student in the M.D./Ph.D. program at the Medical Center and corresponding author of the journal article. "We also found that damage to the dendrites may not require abnormal glutamate exposure."
The lab studies showed that elevated levels of PAF promoted beading on dendrites and injury to synapses following bursts of synaptic activity similar to those thought to be involved in learning and memory.
"This mechanism does not just apply to HIV," Gelbard said. "It applies to Alzheimer's, multiple sclerosis, Parkinson's and any neurodegenerative diseases that have synaptic dysfunction with inflammation, which is virtually all of them."
In lab studies, brain cells were treated with diazoxide, a drug investigated for use in ischemic heart disease and strokes. Pretreatment before exposure to PAF prevented dendritic beading and preserved synaptic functions, the studies showed.
"Stressing the cells with small amounts could trigger protective genes and induce adaptations that will make the dendrites more able to withstand insults," Bellizzi said.
Diazoxide is not the only drug that would work, and others might be better, the researchers said. Memantine, a drug that blocks glutamate receptors, is used in the treatment of Alzheimer's. Chemical preconditioning could represent an alternate or complementary strategy.
"Preconditioning to protect the synapse is likely to be more important in the early and middle phases of neurodegenerative diseases than simply preserving the cell body," Gelbard said.
The research was supported by grants from the National Institutes of Health.
In addition to Gelbard and Bellizzi, the research team included Shao-Ming Lu, Ph.D., research assistant professor of Neurology at the Medical Center, and Eliezer Masliah, M.D., professor of Neuroscience and Pathology at the University of California at San Diego.
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