Understanding the Susceptibility of Glutamatergic Neural Circuits to Alzheimer’s Disease: Clinical and Basic Studies

Lay Summary

Pilot clinical testing of Riluzole to treat cognitive decline: can and how does it work in the brain?

Researchers will expand their Dana-supported pilot clinical trial to gain an initial indication of whether the drug riluzole can improve functioning in adults with age-related cognitive problems and those with mild cognitive impairment (MCI). Concurrently they will continue to characterize the drug’s actions in the brain in animal models. Together, these studies are anticipated to identify a possible target for riluzole and similar treatments to arrest cognitive decline related to aging and progression from MCI to Alzheimer’s disease (AD).

The potential target relates both to age-related memory problems and AD because the same neural circuits are affected. Cells in these circuits use the neurotransmitter glutamate to pass messages from one to another at synapses. Affected circuits are within the brain’s hippocampus (involved in memory) and those that connect the hippocampus with cortical areas (involved in “executive” functions of judgment, decision-making). The difference: in aging, synaptic changes occur with minimal cell death while in AD the changes are accompanied by substantial cell death.

The researchers’ animal model studies suggest that a cascade of events may occur in AD. The trigger is a decrease in an amino acid called GLT-1, which both transports and regulates glutamate. Essentially, GLT-1 production is disrupted when the abnormal protein “amyloid” accumulates in between brain cells. Amyloid also decreases receptors on brain cells that receive glutamate from a neighboring cell. With too little GLT-1 available to regulate glutamate and too few glutamate receptors, excess excitatory transmitter is released at synapses and this “extracellular” glutamate is not taken back up by cells. Excessive excitatory glutamate leads to build-up of the abnormal protein tau within brain cells. Tau then triggers increased amyloid and cycle starts anew.

The investigators’ groundbreaking animal model studies demonstrate that the drug riluzole: 1) rescues GLT-1 production: and 2) decreases extracellular glutamate by clustering many cells’ “dendritic spines,” which receive glutamate signals. This strengthens glutamate reception and decreases extracellular glutamate. Additionally, the investigators have found that riluzole rescues certain gene changes and molecular pathways in the hippocampus that are altered in aging and AD. In aggregate, the findings indicate that the GLT-1 glutamate transporter may be a therapeutic target for arresting cognitive decline; and that riluzole—and perhaps other drugs that act on GLT-1—may effectively act on this target.

Riluzole is FDA-approved for use in patients with the deadly neurodegenerative disease ALS (amyotrophic lateral sclerosis) and is credited with increasing mean survival time. But its actions on glutamate had not been well understood and its effectiveness in improving cognitive impairment had not been assessed. The Rockefeller investigators’ studies are the first to do so.

The pilot randomized double-blind clinical study is comparing the effects of riluzole versus placebo on cognitive performance and brain changes in cognitively healthy adults who report memory problems and in adults who meet the criteria for mild cognitive impairment (MCI). Finding adults who meet the strict criteria has been difficult. A total of 17 adults has been enrolled and studied to date. Participants are assessed prior to and at three and six months during treatment with riluzole or a placebo. Assessments include cognitive performance related to memory, judgment and decision-making. MRS imaging measures glutamate metabolites and MRI-ASL measures of blood circulation to the hippocampus and frontal areas. It is early in the study, and the investigators are ‘blinded’ to treatment and placebo groups, but they report that brain imaging in some participants is encouraging.

During this next phase, the investigators will: 1) expand their pilot clinical study collaborations to enroll more participants who meet the study criteria to obtain preliminary data on the potential effectiveness of riluzole; 2) delineate the biology of GLT-1 at molecular and functional levels; and 3) use new models deficient in GLT-1 to validate that it is a therapeutic target for improving cognitive impairment by using drugs that ensure its availability.

Significance: These combined clinical and animal model studies may identify an important target for arresting cognitive decline and degenerative brain changes, and lead to larger-scale testing of riluzole and other drugs that may act on this newly identified target.