On Memory-Impaired Mice, and Properties of Memantine and Melatonin

Miriam Vale
Bachelor of Journalism

The latest, and, perhaps, most newsworthy advances in Alzheimer's research were presented at the popular hot topics session on July 13. The topics that were presented ranged from a discussion of age-related memory deficits in transgenic mice, to use of the drug memantine for the treatment of moderately severe to severe AD.

Dr. David Morgan of the University of South Florida's College of Medicine presented data showing that Ab vaccination blocked cognitive deficits in double transgenic mice carrying mutant amyloid precursor protein (APP) and mutant presenilin 1 (PS1).

The development of transgenic mice models with age-related deficits in learning and memory are quite useful for testing whether therapeutic approaches to AD could potentially reduce or prevent dementia. Using these double transgenic mice, the group found that they could detect the presence of a working memory deficit in mice doing the six-arm radial water maze task. According to Morgan, this test is similar to the registration and recall components of the clinical examination for dementia.

The underwater maze resembles a wheel with six spokes. In this test, the mice must find a hidden underwater platform in one of six channels joined at a central area. The mice must learn the location of the platform over four consecutive learning trials; they are then tested for retention 30 minutes after the last learning trial. The cycle is repeated everyday with only the location of the platform altered so that the mice cannot use reference memory to find it.

The researchers found that 12-month-old and 15-month old mice that had received a course of vaccinations from 4-months of age onwards performed as well as wild-type mice (control mice), in that they learned to navigate the maze with few errors. By contrast, age-matched, non-immunized, transgenic mice were unable to learn the task. The researchers also found that15-month old mice that received a shorter course of the vaccination reached almost the same performance level as the controls. However, the 'short-term' vaccination mice had almost no reduction in their Ab burden when compared to nonimmunized mice, suggesting that the plaques were not responsible per se for the observed cognitive deficits. The radial arm water maze is a sensitive measure of changes in working memory performance because it separates working memory from reference memory. Morgan expects that it may be effective in longitudinal studies

Dr. Barry Reisberg of New York University's School of Medicine, presented his findings from a placebo-controlled six-month trial of the drug memantine for the treatment of patients with moderately severe to severe AD. Memantine is a fast, voltage-dependent NMDA-receptor antagonist. It blocks the NMDA receptor in the presence of the sustained release of low glutamate concentrations and thereby attenuates the function of the NMDA receptor. The presentation only included phase III of the trial, which evaluated the efficacy and tolerability of memantine. The drug, which is already in use in Germany, may also be useful for the treatment of advanced dementia. Pre-clinical data suggest that the drug has symptomatic and neuroprotective properties. The 28-week double-blind trial tested the efficacy of the drug in 32 American centres. The eligibility of patients for the trial was based on their having been diagnosed with AD with a severity rating of five or six on the Global Deterioration Scale. Patients received either 10mg memantine or placebo. Though both treatment groups worsened over the trial period, overall the decline was smaller for the memantine treatment group. It produced statistically significant improvements in clinical global changes, function and cognition. Memantine also appeared to be safe and well tolerated by the study participants. According to Reisberg, "Neuroprotective properties of memantine, in addition to the symptomatic treatment effects reported, may have contributed to these results."