In work that spans molecular to cognitive aspects of Alzheimer's disease, scientists have shown that one of the changes in the brains of mice with Alzheimer's is a reduction in certain types of rhythmic activity that are important for information processing. Increasing levels of one type of sodium channel increased both such rhythmic activity and the animals' learning abilities.

The work identifies both a channel type and a cell population that are important in the development of Alzheimer's – either of which could be targeted therapeutically.

A large chunk of the research and many of the clinical trials on Alzheimer's disease have focused on beta amyloid, the protein that aggregates in Alzheimer's disease. Amyloid plaques are the anatomical calling card of Alzheimer's, and a-beta protein is undoubtedly toxic to neurons at some points in its life cycle.

Still, that focus in one sense ignores the neuronal bottom line.

"At the end of the day, what a neuron does is fire," Jorge Palop told BioWorld Today. And so, honing in on such firing directly is another way to address what goes wrong in Alzheimer's disease. Palop is an investigator at the Gladstone Institutes, and the senior author of the paper detailing the new insights, which was published in the April 27, 2012, edition of Cell.

Neuronal firing is coordinated by different types of membrane channels that open and close in rapid succession during action potentials. In those studies, Palop and his team looked at one particular ion channel, NAV1.1, which allows sodium ions to pass through the membrane.

Palop and his team became interested in the sodium channels because genetic models of Alzheimer's disease have epilepsy. And when such animals, but not their wild-type cousins, are treated with sodium channel blockers, their epilepsy gets worse.

The researchers first looked at the relationship between epileptic fits and another type of rhythmic neuronal firing, the gamma oscillation. Coordinated neural firing needs to strike a fine balance – too much synchronicity leads to an epileptic fit. But some degree of synchronicity provided by the gamma oscillations "is very important to information processing," Palop explained.

The team found that Alzheimer's mice tended to have epileptic fits when gamma activity was weaker. Gamma oscillations are generated by specific groups of interneurons, and so Palop and his team turned their attention to those interneurons. They found that both Alzheimer's mice and brain tissue from people with Alzheimer's disease had lower-than-normal levels of NAV1.1 channels.

When the authors inhibited the sodium channels with such blockers, gamma activity was reduced – and that in turn disrupted the animals' abilities to learn.

Conversely, when the authors increased the levels of NAV1.1 channels in Alzheimer's mice via a transgene, that strengthened their gamma rhythms and improved their memories. Such treatment even increased their life spans, since the epileptic fits of Alzheimer's mice can be fatal.

The best-known central nervous system drugs target the neurotransmitters that are used to chemically couple neurons. Examples include selective serotonin re-uptake inhibitors for depression, and dopamine precursors for Parkinson's disease. But drugs that affect electrically activated channels also exist. Anesthetics and anti-epileptic drugs are sodium channel blockers, and so it might be possible to develop activators of the channels, as well.

Likewise, therapeutic interventions tend to focus on long-range projection neurons that connect different brain regions. But targeting interneurons therapeutically is, in principle, no different from going after such projection neurons.

In fact, Palop said the situation his team has described in the brain has striking similarities to the heart, where electrical coupling allows heart cells to beat in synchrony. A mutation of another kind of sodium channel can lead to heart arrhythmias. Such arrhythmia is exacerbated when people with the condition are treated with sodium channel blockers. "It unmasks the underlying condition," Palop said. "One way to think of Alzheimer's disease is as a sort of brain arrhythmia."

And correcting that brain arrhythmia may also affect the amyloid aggregation that is the focus of so much attention in Alzheimer's disease. Other studies have found that a-beta is released from synapses during neuronal activity.