Preventive Treatment with Memantine May Halt Alzheimer’s Progression, Mouse Study Suggests

Approved medication memantine could be used as a preventive treatment to help stop or delay Alzheimer’s disease progression in people at risk, a University of Virginia study suggests.

Memantine, which is already approved by the U.S. Food and Drug Administration and marketed as Namenda by Allergan, is currently used to alleviate Alzheimer’s symptoms. However, researchers now suggest its potential as a preventive treatment for the disease.

“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,” George Bloom, PhD, a professor and chair of the Department of Biology at the University of Virginia and the study’s lead author, said in a press release.

“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,” he said. “Ideally, we would prevent it from starting in the first place.”

The study, “N-methyl-D-aspartate receptor–mediated calcium influx connects amyloid-b oligomers to ectopic neuronal cell cycle reentry in Alzheimer’s disease,” was published in the journal Alzheimer’s & Dementia.

Alzheimer’s disease is linked to old age — those ages 85 or older have a 50 percent chance of developing Alzheimer’s — resulting in severe memory loss and progressive cognitive decline due to significant brain nerve cell death.

However, the molecular mechanisms behind the disease are likely triggered years before the first symptoms appear. Being able to identify these mechanisms would allow researchers to begin potential preventive therapies to stop the disease from progressing.

Previous studies have shown that about 90 percent of brain nerve cell death observed in Alzheimer’s follows an abnormal attempt to divide. This is thought to be a possible way of compensating for neuron death, and represents a rather unusual phenomenon, since most neurons are formed before birth and never divide again.

However, despite their attempt to divide, nerve cells ultimately fail and die as a consequence of the disease.

“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,” Bloom said.

Bloom’s team has found that excess calcium entering nerve cells — through specialized calcium channels present on cells’ surface — is what drives these cells to initiate their division, or cell cycle.

This phenomenon occurs before the accumulation of beta amyloid plaques in the brain — a hallmark event in Alzheimer’s disease. These plaques, or toxic forms of the amyloid protein, are called amyloid beta oligomers.

Amyloid beta oligomers, in turn, stimulate the opening of the calcium channel N-methyl-D-aspartate receptor (NMDAR) which allows excessive levels of calcium to invade nerve cells. Calcium is a crucial signaling messenger in the brain, and as such, its levels are tightly regulated within neurons.

One of the few FDA-approved treatments to alleviate the symptoms of moderate to severe Alzheimer’s disease is memantine.

Researchers found that, by closing NMDA channels, memantine stops excessive calcium from entering nerve cells, blocking them from re-entering the cell cycle.

The team treated mouse nerve cells with amyloid beta oligomers for 18 hours before treating them with an intracellular calcium chelator called BAPTA — an agent that “grabs” calcium and protects cells against toxic calcium overload.

Treatment with BAPTA prevented mouse nerve cells from re-entering the cell cycle, as did treatment with memantine. NMDAR’s role in this process was further confirmed when researchers removed a key subunit of the channel and saw that it also prevented cell cycle re-entry.

Researchers then used one of the most well-characterized and widely used mouse models of Alzheimer’s disease, which is designed to accumulate high levels of amyloid beta in the brain, eventually leading to the formation of amyloid plaques.

Mice were treated with memantine from the time they were weaned at 3 weeks until 2 months of age, i.e., before they developed symptoms. This preventive treatment blocked nerve cells’ re-entry into the cell cycle.

“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.”

Screening strategies for Alzheimer’s biomarkers would allow researchers to identify people at risk, who would then be able to receive preventive treatment with memantine to prevent them developing symptoms or halt the disease’s progression altogether.

“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.”

The team, together with colleagues at the UVA School of Medicine, are currently designing a clinical trial to test the potential of memantine as an early intervention strategy.