Summary: Researchers report memantine, an FDA approved drug, may not only alleviate symptoms of mild Alzheimer’s disease, but could also prevent progression of the disease if used before symptoms appear.
Source: University of Virginia.
About 50 percent of people who reach the age of 85 will develop Alzheimer’s disease. Most will die within about five years of exhibiting the hallmark symptoms of the disease – severe memory loss and a precipitous decline in cognitive function.
But the molecular processes that lead to the disease will have begun years earlier.
Currently, there are no known ways to prevent the disease or to stop its progression once it has begun. But research at the University of Virginia offers new understanding of how the disease develops at the molecular level, long before extensive neuronal damage occurs and symptoms show up.
Additionally, the researchers have found that an FDA-approved drug, memantine, currently used only for alleviating the symptoms of moderate-to-severe Alzheimer’s disease, might be used to prevent or slow the progression of the disease if used before symptoms appear. The research also offers, based on extensive experimentation, a hypothesis as to why this might work.
The findings are published currently online in the journal Alzheimer’s & Dementia.
“Based on what we’ve learned so far, it is my opinion that we will never be able to cure Alzheimer’s disease by treating patients once they become symptomatic,” said George Bloom, a UVA professor and chair of the Department of Biology, who oversaw the study in his lab. “The best hope for conquering this disease is to first recognize patients who are at risk, and begin treating them prophylactically with new drugs and perhaps lifestyle adjustments that would reduce the rate at which the silent phase of the disease progresses.
“Ideally, we would prevent it from starting in the first place.”
As Alzheimer’s disease begins, there is a lengthy period of time, perhaps a decade or longer, when brain neurons affected by the disease attempt to divide, possibly as a way to compensate for the death of neurons. This is unusual in that most neurons develop prenatally and then never divide again. But in Alzheimer’s the cells make the attempt, and then die.
“It’s been estimated that as much as 90 percent of neuron death that occurs in the Alzheimer’s brain follows this cell cycle reentry process, which is an abnormal attempt to divide,” Bloom said. “By the end of the course of the disease, the patient will have lost about 30 percent of the neurons in the frontal lobes of the brain.”
Erin Kodis, a former Ph.D. student in Bloom’s lab and now a scientific editor at AlphaBioCom, hypothesized that excess calcium entering neurons through calcium channels on their surface drive those neurons back into the cell cycle. This occurs before a chain of events that ultimately produce the plaques found in the Alzheimer’s brain. Several experiments by Kodis ultimately proved her theory correct.
The building blocks of the plaques are a protein called amyloid beta oligomers. Kodis found that when neurons are exposed to toxic amyloid oligomers, the channel, called the NMDA receptor, opens, thus allowing the calcium flow that drives neurons back into the cell cycle.
Memantine blocks cell cycle reentry by closing the NMDA receptor, Kodis found.
“The experiments suggest that memantine might have potent disease-modifying properties if it could be administered to patients long before they have become symptomatic and diagnosed with Alzheimer’s disease,” Bloom said. “Perhaps this could prevent the disease or slow its progression long enough that the average age of symptom onset could be significantly later, if it happens at all.”
Side effects of the drug appear to be infrequent and modest.
Bloom said potential patients would need to be screened for Alzheimer’s biomarkers years before symptoms appear. Selected patients then would need to be treated with memantine, possibly for life, in hopes of stopping the disease from ever developing, or further developing.
“I don’t want to raise false hopes,” Bloom said, but “if this idea of using memantine as a prophylactic pans out, it will be because we now understand that calcium is one of the agents that gets the disease started, and we may be able to stop or slow the process if done very early.”
Bloom currently is working with colleagues at the UVA School of Medicine to design a clinical trial to investigate the feasibility of using memantine as an early intervention.
About this neuroscience research article
Source: Fariss Samarrai – University of Virginia Publisher: Organized by NeuroscienceNews.com. Image Source: NeuroscienceNews.com image is credited to Erin Kodis and George Bloom. Original Research:Abstract for “N-methyl-D-aspartate receptor–mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer’s disease” by Erin J. Kodis, Sophie Choi, Eric Swanson, Gonzalo Ferreira, George S. Bloom in Alzheimer’s & Dementia. Published July 4 2018. doi:10.1016/j.jalz.2018.05.017
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[cbtabs][cbtab title=”MLA”]University of Virginia”Alzheimer’s Drug May Stop Disease If Used Before Symptoms Appear.” NeuroscienceNews. NeuroscienceNews, 1 August 2018. <https://neurosciencenews.com/alzheimers-prevention-drug-9641/>.[/cbtab][cbtab title=”APA”]University of Virginia(2018, August 1). Alzheimer’s Drug May Stop Disease If Used Before Symptoms Appear. NeuroscienceNews. Retrieved August 1, 2018 from https://neurosciencenews.com/alzheimers-prevention-drug-9641/[/cbtab][cbtab title=”Chicago”]University of Virginia”Alzheimer’s Drug May Stop Disease If Used Before Symptoms Appear.” https://neurosciencenews.com/alzheimers-prevention-drug-9641/ (accessed August 1, 2018).[/cbtab][/cbtabs]
N-methyl-D-aspartate receptor–mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer’s disease
Introduction Alzheimer’s disease (AD) symptoms reflect synaptic dysfunction and neuron death. Amyloid-β oligomers (AβOs) induce excess calcium entry into neurons via N-methyl-D-aspartate receptors (NMDARs), contributing to synaptic dysfunction. The study described here tested the hypothesis that AβO-stimulated calcium entry also drives neuronal cell cycle reentry (CCR), a prelude to neuron death in AD.
Methods Pharmacologic modulators of calcium entry and gene expression knockdown were used in cultured neurons and AD model mice.
Results In cultured neurons, AβO-stimulated CCR was blocked by NMDAR antagonists, total calcium chelation with 1,2-Bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), or knockdown of the NMDAR subunit, NR1. NMDAR antagonists also blocked the activation of calcium-calmodulin-dependent protein kinase II and treatment of Tg2576 AD model mice with the NMDAR antagonist, memantine, prevented CCR.
Discussion This study demonstrates a role for AβO-stimulated calcium influx via NMDAR and CCR in AD and suggests the use of memantine as a disease-modifying therapy for presymptomatic AD.