UR Medical Center scientists have recently targeted their newest offender – the neurologic functions in diseases such as Alzheimer’s and dementia associated with HIV.

The Journal of Clinical Investigation issued an article on Nov. 1 in which these URMC scientists describe the newest mechanism through which brain cells are capable of being damaged during chronic neurodegenerative diseases.

It has been shown that when there is inflammation in the brain, nerve impulses passed between cells during regular activities, even those as simple as learning and memory, can become toxic.

“What we want from these impulses is the formation of memories, but instead what we get is an impulse that can bring with it injury on neurons as well as disruption of neurologic function,” Professor of neurology at URMC Harris Gelbard said. Gelbard is also the research project’s principal investigator.

“HIV-1 is a problem that simply has not gone away,” he said. “Even more unfortunately, the prevalence of the neurologic disease that occurs during the HIV-1 infection, despite highly active antiretroviral therapy, continues to increase. This means we need to look for more adjunctive therapies to protect the brain. HIV-1 causes inflammation in the brain and this inflammation leads to neurologic disease. In contrast, diseases like Alzheimer’s disease probably happen because of complicated interactions between genes and environment, but inflammation in the brain still occurs.”

Since doctors now understand this new mechanism, it is possible that a new treatment drug for these diseases is within reach.

Working together with researchers at the University of California-San Diego, the scientists at URMC have proposed a strategy of chemical preconditioning that they are hoping will activate adaptations in various nerve cells that would allow the cells to better withstand such toxic attacks as well as prevent injury and preserve function.

“Our research suggests that normal brain communication that is the basis for learning and memory, in the presence of inflammation, causes damage to synapses,” Gelbard said. “It’s this type of damage that is likely to cause the neurologic symptoms in patients suffering from AIDS and Alzheimer’s disease. We have identified a molecular target and a type of therapy – chemical preconditioning – to prevent this type of damage.”

In a recent press release, Gelbard said, “Preconditioning would allow for the nervous system to experience stress and become more resistant to future encounters with stress and the damage it can trigger. For as long as anyone can remember, the ceaseless and continual villain in neurodegenerative disease has been glutamate.”

Glutamate is an amino acid that usually acts as a neurotransmitter.

It is possible for glutamate to overexcite many neurons causing damage and cell death.

This process is known as excitotoxicity. Many of the drugs that have been designed to treat Alzheimer’s are drugs that lower glutamate production or at least block its transmission.

Gelbard continued in the press release, “Just blocking glutamate really doesn’t seem to work efficiently in neurodegenerative diseases with inflammation. We reconsidered how excitotoxicity actually damages the nervous system in functional ways.”

The scientists have been focusing mainly on dendrites, which are the crooked processes that branch out of neurons.

Dendrites carry impulses toward the body of the nerve cell and synapses, which are the places where impulses pass from neuron to neuron.

Injury to dendrites is often found in HIV-1-associated dementia as well as Alzheimer’s. In recent lab studies, scientists exposed brain cells to platelet-activating factor – PAF – which is a compound that promotes inflammation and plays a large role in the brain.

It is possible for PAF to be produced by neurons and takes a large role in activity associated with memory as well as learning. PAF is also produced during inflammation by immune cells.

In HIV-1-associated dementia and other neurodegenerative diseases, the amount of PAF within the brain takes a dramatic increase.

“We found that disease makes dendrites more vulnerable to excitotoxicity,” researcher and URMC student Matthew J. Bellizi said in the press release. “We also found that damage to the dendrites may not exactly require abnormal glutamate exposure.”

Lab studies have shown that high levels of PAF promote beading on dendrites and injury to synapses, which follow bursts of synaptic activity similar to those thought to be involved with activities such as learning and memory.

Gelbard made sure to stress that this mechanism does not just apply to HIV, but also to Alzheimer’s, Multiple Sclerosis, Parkinson’s, and many other neurodegenerative diseases.

In the lab studies, brain cells received diazoxide treatment. Diazoxide is a drug investigated for use in ischemic heart disease as well as strokes.

Pretreatment before the cells were exposed to PAF prevented beading within the dendrites and helped to preserve synaptic functions. When cells are stressed with small amounts of diazoxide, protective genes could be triggered to induce adaptations that will help the dendrites withstand insults.

Researchers do recognize that diazoxide is not the only possible effective drug. Memantine is a drug that blocks glutamate receptors and is often used in Alzheimer’s treatment.

Chemical preconditioning would be a possible way to represent an alternate or complementary strategy.

Preconditioning to protect the synapse is likely going to be more important in the earlier phases in neurodegenerative diseases than simply the preservation of the cell body.

Lewis can be reached at slewis@campustimes.org.



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