24 Aug 2003

In this week's Nature Medicine, researchers reveal that glucagon-like peptide-1 (GLP-1), a product of proglucagon processing, may have an important role in learning and neuroprotection.

The peptide, first found in intestinal L cells of the gut, is also expressed in the brain, along with its receptor (GLP-1R). This prompted principal investigator Colin Haile, Jefferson Medical College, Philadelphia, to investigate the role of GLP-1 in neurons. Working with an international group of collaborators, Haile and first author Matthew During looked for potential neurologic roles for the peptide. When they administered it to rats, the authors found that the animals performed better than controls in a variety of learning tasks. In the Morris water maze, for example, rats directly injected in the brain with 0.1 micrograms of GLP-1 traveled much shorter distances (about two meters on average) than untreated littermates (about 10 meters) in search of the hidden platform.

To further investigate the role of the peptide, During and colleagues used a strain of mice deficient in the peptide receptor (GLP-1R). These animals showed deficits in learning, as judged by their relative haste in re-exposing themselves to a negative stimulus-wild-type animals took on average three times as long before re-exposure. When During transfected the GLP-1R-negative mice with adeno-associated virus carrying the receptor, however, their responses improved. In a similar experiment, During induced overexpression of the receptor in the hippocampus of otherwise normal rats. These animals outperformed controls in a variety of tests including the water maze, where their traveling distance to the platform was half the norm.

The latter experiment suggests that GLP-1 may play a role in the hippocampus. Previous experiments have also indicated that the peptide may be neuroprotective (see Perry et al., 2002). To test this hypothesis, During and colleagues examined the effect of kainic acid on normal and GLP-1R negative mice-the acid is known to induce excitotoxic neuronal damage in the hippocampus. The authors found that the homozygous null mice succumbed to seizure much faster (after about 1,600 seconds) than did wild type animals (typically after 2,400 seconds). The results were statistically significant.

How the peptide works is uncertain, but as the receptor is coupled to multiple G-proteins, it could activate one or more signaling pathways. In support of this, the authors found that the first nine amino acids of the GLP-1 analog Ser(2) exendin-which also improves learning when administered intranasally to rats-leads to a significant increase in phosphorylation of MAP kinase in rat hippocampuses. MAP kinase may thus mediate the improvement in learning. During's experiments supports this, as Ser(2) exendin (1-9)-mediated learning improvements were blocked by PD98059, an inhibitor of the MAP kinase pathway. The authors conclude that "GLP-1R may be a promising target for therapeutic strategies directed towards neurodegenerative and cognitive disorders."—Tom Fagan