7 October 2012. Oxidative stress is increasingly fingered as a potential cause of Alzheimer's disease (AD), and recent studies suggest that dampening reactive oxygen species in neurons improves synaptic transmission and memory in AD mouse models. In the October 3 Journal of Neuroscience, scientists led by Eric Klann, New York University, and Michael Brownlee, Albert Einstein College of Medicine, also in New York, reported that a protein fragment normally found in the human body relieves oxidative stress. The peptide both corrected synaptic problems in an AD mouse model and prevented memory deficits. Though much research remains to be done, the finding could point to a novel pathway for AD therapeutic targets. "This is a naturally occurring peptide, so it could be safer than a synthetic compound," Klann told Alzforum.
The fragment derives from glucagon-like peptide 1 (GLP-1), a hormone released from the small intestine that enhances insulin secretion from the pancreas. Once released, an enzyme cuts the hormone, leaving GLP-1(9-36)amide. Brownlee observed a few years ago, that the peptide lowered production of superoxide (a damaging free radical) in endothelial cell mitochondria. When he read a 2009 paper from the Klann lab reporting that genetically suppressing superoxide generation reduced amyloid plaques and prevented memory problems in Tg2576 mice (see ARF related news story on Massaad et al., 2009), Brownlee proposed a collaboration: Could GLP-1(9-36)amide correct synaptic memory deficits in AD mouse models by quashing superoxide?
To probe the effects on synaptic activity, first author Tao Ma and colleagues treated hippocampal slices from wild-type or APP/PS1 (Jankowsky et al., 2001) mice with GLP-1(9-36)amide, then measured long-term potentiation (LTP) and long-term depression (LTD), which are both important for learning and memory. The treatment reversed LTP impairments in APP/PS1 slices, as well as in those from wild-type mice treated with 0.5 μM Aβ42 reconstituted from a commercially available preparation. The GLP fragment also lowered abnormally high LTD in the Aβ-treated slices. To test the peptide in vivo, the team then treated 10- to 12-month-old APP/PS1 mice with GLP-1(9-36)amide for two weeks through a micro-osmotic pump. These mice performed as well as wild-type controls on the hidden platform version of the Morris water maze, and significantly improved their performance in both contextual and cue fear conditioning relative to untreated transgenic mice. Interestingly, brain levels of amyloid precursor protein (APP), total Aβ, or intraneuronal Aβ were no different in treated or untreated mice.
To figure out how the peptide worked at the molecular level, the researchers looked at its effects on reactive oxygen species and related proteins. GLP-1(9-36)amide lowered superoxide in mitochondria from both Aβ42-treated mouse slices and those from APP/PS1 mice. GSK-3β activity, which regulates synaptic activity and rises in the presence of too much superoxide, decreased as well. Activation of Akt, a serine/threonine kinase that inhibits GSK-3β activity, faltered in APP/PS1 hippocampus slices, but bounced back after GLP-1(9-36)amide treatment. Taken together, the results suggest that GLP-1(9-36)amide restores synaptic activity levels by reducing reactive oxygen species, thereby boosting Akt activity and quieting abnormal GSK-3β action.
GLP-1(9-36)amide seems to be unique from other GLP-1 agonists currently under investigation as potential therapies for Alzheimer’s. "This peptide is not acting through the [GLP-1] receptor; it is likely acting directly on mitochondria," said Klann. "That might get directly at the source of the oxidative stress." In addition, the fact that this truncated form of GLP-1 does not affect insulin secretion may lessen side effects.
"It's an interesting finding," said Christian Hölscher, University of Ulster, Coleraine, U.K., in that it sheds light on a non-GLP-1 receptor-related mechanism the field has not yet studied. He is among the researchers currently investigating diabetes drugs—including liraglutide and exenatide, which are GLP-1 agonists but do not degrade into -1(9-36)amide—for effectiveness in AD. These GLP-1 agonists are known to influence growth factor-related pathways through GLP-1 receptors, rather than targeting reactive oxygen species. Hölscher cautioned that since GLP-1(9-36)amide most likely does not work through those receptors, the peptide's function, and therefore its potency, might be limited, as demonstrated by the lack of effects on amyloid plaque load. Therapeutic strategies aimed at treating complex diseases like AD may require stronger drugs that have a wide range of beneficial effects, he explained. Hölscher has begun a Phase 2 clinical trial of the GLP-1 agonist liraglutide, for AD.—Gwyneth Dickey Zakaib.
Ma T, Du X, Pick JE, Sui G, Brownlee M, Klann E. Glucagon-like peptide-1 cleavage product GLP-1(9-36) amide rescues synaptic plasticity and memory deficits in Alzheimer’s disease model mice. J Neurosci 2012 October 3; 32(40):13701-13708. Abstract