“This work is illuminating, and supports the idea that overactivity of brain networks is driving the disease, rather than the other way around,” Michela Gallagher told Alzforum (see full comment below). Gallagher, who works at Johns Hopkins University, Baltimore, Maryland, led the group that conducted the recent study of levetiracetam in MCI (see ARF related news story).

The finding comes after years of work in the Mucke lab studying overactive brain networks in mouse models of AD. Mucke told Alzforum that, while the field focused on synaptic suppression driven by amyloid-β (Aβ), his group found something more complex, specifically, that there were indications of hyperactivity in mice that produce abundant brain Aβ. First, the researchers found loss of the calcium-binding protein calbindin in the dentate gyrus of the hippocampus, a sign of excessive calcium influx into neurons (see ARF related news story). Four years later, they reported that subclinical, non-convulsive epileptic activity hampers the J20 mouse model (see ARF related news story). The hippocampus is hyperactive in people at risk for Alzheimer’s, including those with MCI (see Dickerson et al., 2005) and those carrying ApoE4 (see ARF related news story), the strongest genetic risk factor for sporadic AD. One interpretation of the human findings posits that this uptick in activation compensates for cognitive deficits, but the recent work from Gallagher’s group, and now this finding from Mucke’s lab, suggest that hyperactivation may be part of the problem, not a response to it.

First author Pascal Sanchez and colleagues tested a variety of approved anti-epileptic drugs in four- to six-month-old J20 mice. They found that only levetiracetam, both acute and chronic dosing, reduced aberrant firing seen in electroencephalograms. The longer, 28-day treatment also reversed behavioral problems, including hyperactivity in the open field and in the open arms of an elevated maze. Chronic levetiracetam corrected deficits in spatial- and context-dependent tests of learning and memory compared to a saline placebo. Interestingly, 14 days after chronic treatment ended, abnormal spike activity returned, and 21 days after that, the mice were back to behaving abnormally.

How does the anti-epileptic restore learning and memory? In the J20 mice, the observed hyperactivity is, in fact, a highly synchronous activity; it sets off a cascade of compensatory changes that leads to synaptic remodeling in the hippocampus, explained Mucke. This remodeling includes loss of calbindin, increased expression of neuropeptide Y—which has antiepileptic activity—and suppression of the transcription factor Fos. The changes culminate in loss of synaptic function. Levetiracetam normalized these molecular players, and restored long-term potentiation, a measure of synaptic plasticity. The drug reversed these molecular and behavioral changes without affecting APP processing or Aβ deposition.

Gallagher pointed out that a strength of the study is that it contains detailed physiological experiments that cannot be done in humans. “In both cases, preclinical and clinical, targeting overactivity was an effective treatment,” wrote Gallagher, adding “such translation across a preclinical AD model and clinical patients is rare, if not unprecedented, in the AD field.” However, she cautioned that the condition of hyperactivity in amnestic MCI might be much more subtle than in the J20 mice. Their abnormal physiology may represent one end of a spectrum of changes that happen between normal aging and the emergence of AD pathology (see comment below). In fact, Gallagher suggested that aging itself may be conducive to overactivity, and that this activity may permit pathology to take root. Mucke sees the relationship slightly differently. “We picture levetiracetam acting downstream of Aβ because, at least in our model, everything starts with elevated Aβ and the drug blocks the overexcitation of the network that ensues,” he said. His group plans to examine the effect of levetiracetam in J20 mice of different ages to determine if the beneficial effects depend on disease stage.

Why the other anti-epileptic drugs did not have the same effect is unclear. Levetiracetam is often described as an atypical anti-epileptic because of its broad effects. It is the only one of the drugs tested that binds to the synaptic vesicle protein SV2A. “Either through SV2A, or other actions on glutamate transporters, it probably downregulates the amount of glutamate around the synaptic cleft,” suggested Mucke.

Brad Hyman, Massachusetts General Hospital, Charlestown, told Alzforum that the potential differential efficacy of levetiracetam and other anti-epileptic agents generates the intriguing possibility that anti-seizure properties per se are not the critical issue for the effect. He suggested that subtle changes in excitatory/inhibitory balance might contribute to some neural system dysfunction in the J20 model. Other models, including APP23 and APP/PS1 mice, and certain strains of Tg2576 APP mice, also exhibit epileptic-like seizures (see Lalonde et al., 2005; Minkeviciene et al., 2009).

What do these new findings mean for the clinic? “These results, in conjunction with a series of other findings in the field (most importantly, Bakker et al., 2012), make a strong case for the need for further studies of physiologic neural network-level abnormalities in AD and related disorders, and also for the targeting of these abnormalities for novel approaches to treatment,” wrote Brad Dickerson, who also works at MGH (see full comment below). Mucke and Gallagher are pursuing the idea of using levetiracetam in clinical trials.—Tom Fagan.

Reference:
Sanchez PE, Zhu L, Verret L, Vossel KA, Orr AG, Cirrito JR, Devidze N, Ho K, Yu G-Q, Palop JJ, Mucke L. Levetiracetam suppresses neuron network dysfunction and reverses synaptic and cognitive deficits in an Alzheimer’s disease model. Proc Natl Acad Sci U S A. 2012 Aug 6. Abstract