This post was written by our guest blogger Janelle Weaver, Ph.D.
Alzheimer’s disease is a neurodegenerative disorder characterized by damage in brain regions involved in learning and memory. A common feature seen in patients’ brains is the accumulation of certain forms of amyloid-beta (Aβ) peptides, which are thought to disrupt the balance of activity in neuronal networks in part by causing a build-up of harmful molecules in neurons. However, the mechanisms underlying this process have been unclear.
In a recent study published in The Journal of Neuroscience, Sanford-Burnham researchers found that Aβ peptides trigger a dramatic rise in the production of the free radical nitric oxide in neurons, resulting in changes to proteins known to disrupt communication between neurons. “Our study suggests that novel drug interventions aimed at decreasing the build-up of harmful nitric oxide molecules in neurons could reduce neuronal damage and prevent or slow the progression of Alzheimer’s disease,” said senior study author Stuart Lipton, M.D., Ph.D., professor and director in the Neuroscience and Aging Research Center and who is also a practicing clinical neurologist seeing patients with Alzheimer’s.
NMDA leads proteins astray
In the new study, Lipton and his team exposed rat neurons to an assemblage of Aβ peptides, each consisting of 42 amino acids—the peptide length associated with more aggressive forms of Alzheimer’s disease. These Aβ peptides caused a rapid increase in levels of nitric oxide—a molecule that can interfere with crucial neuronal functions by chemically reacting with and modifying proteins through a process called S-nitrosylation, which was previously discovered by Lipton and his colleagues. Researchers have known that nitric-oxide production requires an enzyme called neuronal nitric oxide synthase (nNOS). Because nNOS depends on calcium to produce nitric oxide, and calcium flows into neurons through NMDA-type glutamate receptors, the researchers explored the role of these receptors in mediating Aβ-dependent nitric-oxide production.
While synaptic NMDA receptors are located at the junctions between neurons, are used for communication betwween the cells, and are involved in protecting these cells from death, extrasynaptic NMDA receptors are found at other locations along neurons and contribute to neuronal death. To tease apart the potential role of these two types of receptors in nitric-oxide production, Lipton and his team exposed neurons to Aβ peptides and a cocktail of drugs that specifically block the function of synaptic vs. extrasynaptic NMDA receptors.
“The findings show that extrasynaptic NMDA receptors are responsible for the vast majority of Aβ-peptide-induced nitric-oxide production in neurons, consistent with previous research implicating these receptors in neuronal damage,” Lipton said. “Considering the pathological role of extrasynaptic NMDA receptors in disease states, we hypothesized that the excessive increase in nitric oxide might affect various proteins crucial for neuronal survival.”
Indeed, the research team found that the resulting nitric oxide reacted with proteins called Drp1 and Cdk5, leading to the build-up of harmful, S-nitrosylated forms of these proteins, which are known to interfere with communication between neurons by disrupting synapses. Taken together, the findings show that exposure of neurons to Aβ peptides causes a rapid surge in nitric-oxide levels in neurons through activation of extrasynaptic NMDA receptors, leading to an increase in toxic molecules that disrupt the function of neuronal networks.
Protecting neurons from nitric oxide
The researchers next tested whether a drug treatment could protect neurons from this destructive process. When they simultaneously exposed neurons to Aβ peptides and memantine—an extrasynaptic NMDA receptor-blocking drug developed by Lipton and his colleagues and approved by the Food and Drug Administration for the treatment of Alzheimer’s disease—nitric-oxide production was significantly reduced. “Our work suggests that drugs that inhibit the activity of extrasynaptic NMDA receptors may decrease Aβ-peptide-induced nitric oxide production and thereby protect neuronal networks from damage caused by Alzheimer’s disease,” Lipton said. “We are currently developing improved therapies that block extrasynaptic NMDA receptors and prevent the toxic reactions of nitric oxide.”