Hazy memories. Foggy thoughts. Clouded judgments. They all become more common as we age, even if we are spared the ravages of neurodegenerative disorders such as Alzheimer’s. If only we could disperse the gathering mists of ordinary dementia.

What we experience as fogginess is actually something else in the aging brain. There, cognitive decline manifests as lost and altered connections between neurons, particularly in the hippocampus and prefrontal cortex. Some of this degradation may be reversible.

According to researchers at The Rockefeller University and The Icahn School of Medicine at Mount Sinai, synaptic damage that has been associated with excess glutamate, a chemical signal, may be prevented if an existing drug, riluzole, is administered. Riliuzole is already on the market as a treatment for ALS. In experiments with rats, it also seems to improve connections between certain neurons. These changes, moreover, appear to slow age-related cognitive decline.

The researchers described their experiments December 15 in the online version of the Proceedings of the National Academy of Sciences, in an article entitled, “Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering.”

In this article, the researchers set about to understand the synaptic susceptibilities of the glutamatergic neural circuits. If glutamate is too abundant, excess can spill out and excite connecting neurons in the wrong places. In the case of age-related cognitive decline, this process damages synapses. In neurodegenerative disorders, such as Alzheimer's disease, it contributes to the death of neurons.

Used to slow the progress of another neurodegenerative condition, ALS (also known as Lou Gehrig's disease), riluzole was an obvious choice as a potential treatment, because it works by helping to control glutamate release and uptake, preventing harmful spillover. The researchers began giving riluzole to rats once they reached 10 months old, the rat equivalent of middle age, when their cognitive decline typically begins.

“Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals,” wrote the authors. “Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1.”

The kind of clustering observed by the researchers increases synaptic plasticity, and it is thought to allow nonlinear summation of synaptic strength. And so it may serve as a kind of compensation mechanism against age-related cognitive decline. It is possible that this form of compensation could be enhanced through the action of riluzole.

“The fact that riluzole increased the clustering of only the thin, most plastic spines, suggests that its enhancement of memory results from both an increase in synaptic strength and synaptic plasticity, which might explain its therapeutic effectiveness,” said John Morrison, professor of neuroscience and the Friedman Brain Institute and dean of basic sciences and the Graduate School of Biomedical Sciences at Mount Sinai. Thin spines, which are rapidly adaptable, clustered more in the riluzole-treated animals than in the young animals and the untreated, older animals.

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