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How Cognitive Stimulation Might Protect Against Aβ Oligomers
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Cognitive stimulation has been shown to lower the risk of Alzheimer’s disease, but what actually happens in the brain to confer protection? In the March 6 Neuron, researchers led by Dennis Selkoe report that β2-adrenergic signaling plays a key role. Wild-type mice that explored different objects every day had greater synaptic plasticity in the hippocampus, and better resisted the toxic effects of Aβ oligomers, compared to mice in standard cages. Blocking the β2-adrenergic pathway abolished this protection. By contrast, stimulating the pathway provided the same benefit as environmental enrichment. Intriguingly, β-adrenergic signaling has been shown to fade in AD brains. The results offer a molecular underpinning for the environmental enrichment phenomenon. They suggest therapeutic possibilities while raising questions about β-blocker drugs used in humans.
Alzforum held a Webinar in which Dennis Selkoe, Brigham and Women’s Hospital, was joined for a panel discussion by Michael Heneka from the University of Bonn, Germany; Joanna Jankowsky from Baylor College of Medicine, Houston, Texas; and Orly Lazarov from the University of Illinois at Chicago. Selkoe presented his findings and the panel discussed their implications.
We thank Neuron for giving Alzforum readers temporary free access to this paper:
Li S, Jin M, Zhang D, Yang T, Koeglsperger T, Fu H, Selkoe DJ. Environmental novelty activates b2-adrenergic signaling to prevent the impairment of hippocampal LTP by Ab oligomers. Neuron. 2013 Mar 6.
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 Listen to the Webinar
Dennis Selkoe's Presentation
Michael Heneka's Presentation
Joanna Jankowsky's Presentation
Orly Lazarov's Presentation
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Background Text
by Madolyn Bowman Rogers
Numerous epidemiological studies suggest that cognitive and social stimulation can ward off Alzheimer’s disease (see, e.g., ARF news story; ARF related news story). Likewise, AD model mice housed in enriched environments—cages containing toys and exercise wheels—stay smarter than their counterparts in normal cages and seem to accumulate less amyloid in the brain (see ARF related news story; Arendash et al., 2004; Jankowsky et al., 2005; Berardi et al., 2007; Costa et al., 2007; Hu et al., 2010). How much of the effect comes from exercise, which has been shown to boost cognition in both animals and people (see ARF related news story; ARF
news story; ARF
news story; and ARF
news story), and how much from mental stimulation? Exactly how environmental enrichment (EE) protects against AD remains a mystery.
In the March 6 Neuron, researchers led by Dennis Selkoe at Brigham and Women’s Hospital, Boston, pinpointed β2-adrenergic signaling as a key factor in defending synapses from oligomeric Aβ. First the researchers treated young or middle-aged wild-type mice to an enriched environment for several weeks. Hippocampal slices from these animals showed greater long-term potentiation (LTP) compared to those from control mice. When the researchers added Aβ oligomers from several sources, including human brain and synthetic preparations, EE slices maintained normal synaptic plasticity at Aβ doses that wiped out LTP in control slices. Adding a β2-adrenergic antagonist to these slices abolished the protection, while pharmacologically stimulating the pathway in control slices provided as much benefit as EE. The researchers saw the same effects when they fed agonists and antagonists to the mice and then examined LTP in slices.
An enriched environment (left) versus a standard cage.
The β2-adrenergic receptor responds to norepinephrine. In the brain, this neurotransmitter is made by noradrenergic neurons in the locus ceruleus. These cells degenerate in AD. Some studies suggest that their loss hastens amyloid deposition and worsens cognition, and that boosting noradrenaline levels in mice can slow disease (see ARF Webinar; ARF related news story; ARF news story).
To dissect the role of exercise, the authors gave some mice only exercise wheels and others only toys. Slices from the exercise group succumbed to Aβ toxicity, while those from the toy group resisted. The findings imply that exercise and EE act through different pathways to confer cognitive benefits. Intriguingly, a recent study found that people benefited more from “exergames” than exercise alone. Exergames use interactive virtual devices to create the illusion that a person riding a stationary bike is racing across mountain terrain, for example (see ARF related news story).
The findings raise many new questions. On the potentially worrisome side, β-adrenergic blockers are used to lower blood pressure in many elderly people; could these drugs be accelerating cognitive decline? Conversely, could stimulating the β2-adrenergic receptor in the brain sharpen cognition? Current β2-adrenergic receptor agonists would not make appropriate AD therapeutics because they also act on the peripheral nervous system to speed up heart rate. If certain selective agonists could be delivered directly to the central nervous system, or be designed to avoid peripheral effects, would they be useful therapeutics? How could the results of this paper, once reproduced, be tested clinically? Short of drug trials, are there public health implications that could be articulated in the short term? Which non-pharmacological interventions get some basic science reinforcement from these data?
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Webinar: A Webinar is a seminar conducted remotely over the Web. Attendees view the slides through their Web browser and hear the presentations over their own telephones. 
