The α7 nicotinic acetylcholine receptor (α7nAChR) binds the amyloid-β peptide (Aβ) with high affinity (Wang et al., 2000), and has been implicated in Aβ internalization, stimulation of tau phosphorylation (see ARF related news story on Wang et al., 2003), and downregulation of synaptic glutamate receptors in response to Aβ (see ARF related news story on Snyder et al., 2005). Adding to these in vitro studies, new in vivo data from Steve Heinemann’s lab at the Salk Institute in La Jolla, California, published in the July 8 issue of the Journal of Neuroscience, puts the α7 receptor on the pathway to neuronal dysfunction and memory problems in response to Aβ in a mouse model of AD. By crossing α7nAChR knockout mice with animals expressing mutated human amyloid precursor protein (APP), the researchers found that lack of α7 protects the mice from synaptic loss, restores normal long-term potentiation, and improves their performance in the Morris water maze, all without affecting Aβ levels.

The results support the idea that α7nAChR (α7) is a key mediator of Aβ action, and suggest that receptor could be a good drug target. Many pharma companies are working on α7 agonists that would act as cognitive enhancers by augmenting acetylcholine signaling, but the current study offers an alternative therapeutic path that would involve interrupting α7 signaling, or at least blocking access of the receptors to Aβ.

In the study, first author Gustavo Dziewczapolski found that deletion of the α7 gene in the background of APP overexpression (the PDAPP J9 mouse) improved the performance of adult animals in the Morris water maze. While 13- to 16-month-old APP mice did poorly in the memory test, age-matched APP/ α7 KO mice performed more like normal animals. When Dziewczapolski looked at brain tissue, he found that older PDAPP mice showed approximately a 20 percent reduction in the synaptic marker synaptophysin or the dendritic marker MAP2 in frontal cortex and hippocampus, but both markers were preserved in the α7 KO/APP mice. An increase in glial fibrillary acidic protein, a marker of inflammation, in the cortex of APP mice was also reduced in the α7 knockout mice. The effects carried over to neuron function as well. Defects in long-term potentiation measured in hippocampal slices from the APP mice were gone in the APP/α7 knockouts.

The effects were not due to changes in Aβ or plaque load: Expression of amyloid precursor protein and Aβ peptide levels were no different between the strains. The results indicate that without α7, the mice are resistant to Aβ-induced synaptic loss and behavioral changes.

How might this happen? The paper does not settle the question of mechanism, but one possibility is decreased internalization of Aβ (Nagele et al., 2002), which could prevent any toxic actions of intracellular Aβ. “We all think of extracellular Aβ, but intracellular Aβ could be important too,” Dziewczapolski told ARF. “Measuring intracellular Aβ is technically difficult, but we are trying to develop a way to do this. Our next step is to see if we have less intracellular Aβ.”

Alternatively, the α7 receptor has been shown to play a role in the downregulation of NMDA receptors at synapses in response to Aβ. The investigators did measure overall levels of NMDA receptor in brain tissue, and saw no change. That does not rule out changes in cell surface receptor levels, another parameter the researchers are planning to look at.

The idea of using an α7 antagonist in AD seems to run counter to the current interest in α7 agonists for neuroprotection and cognitive enhancement in AD and other diseases. In addition, recent findings showed that low concentrations of Aβ enhance LTP via the α7 receptor (see ARF related news story on Puzzo et al., 2008). However, the authors suggest that positive interactions under normal conditions may turn to pathological effects under conditions where Aβ is elevated. “This is probably the most controversial part of the paper,” Dziewczapolski said, “But we think that in cases where Aβ42 is high, it will be important to block the α7 receptor with an antagonist.” In addition, it is possible that even an agonist could act to antagonize the effects of Aβ, Dziewczapolski explained, if the compound blocks Aβ binding or stimulates receptor internalization.

In favor of the α7 receptor as a target, recent work identified a novel α7β2 nACh receptor dimer that was especially sensitive to Aβ (see ARF related news story). Another recent report provided evidence that receptor levels hold steady in the course of AD (see ARF related news story on Ikonomovic et al., 2009), in contrast to previous reports that α7 receptors were lost.

The caveat to the study, Dziewczapolski cautions, is that the α7/APP animals lack the α7 receptor from birth, so the researchers cannot rule out developmental effects. The more definitive experiment will be to do conditional knockouts, and to assess the results of silencing the receptor after AD pathology has commenced.—Pat McCaffrey.

Reference:
Dziewczapolski G, Glogowski CM, Masliah E, Heinemann SF. Deletion of the alpha7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-1. Abstract

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  1. This is a very interesting finding, a remarkable result with real therapeutic potential. Previous studies had suggested that the β amyloid peptide can interact with α7-containing nicotinic receptors and that it may hijack signaling through the receptor to exert negative effects on neurons. How this occurs and what significance it might have for Alzheimer disease have been matters of some contention. Using genetically engineered mice that produce a precursor protein (APP) of the β amyloid peptide, Dziewczapolski et al. clearly show that the α7-receptor gene product is necessary for the mice to display key behavioral deficits reminiscent of Alzheimer disease. Deleting the α7 gene enables the mice to behave nearly the same as wild-type (control) mice in the assays. In addition to providing strong evidence for a physiologically relevant pathway, the results are exciting because they identify a possible target for drug intervention. Specific antagonists that inhibit only α7-containing nicotinic receptors may have substantial benefit for slowing progression of the disease. Partial agonists may offer a different strategy, given the desensitization features of the receptor. Such compounds already exist, but designing variants that are effective, specific, and able to cross the blood-brain barrier will pose challenges for the future. A different, but also interesting challenge, will be the elucidation of how α7-containing receptors enable APP products to exert their behavioral effects.

    View all comments by Darwin K. Berg
  2. This very interesting paper by Dziewczapolski et al. provides further evidence for the involvement of α7 nicotinic acetylcholine receptors in either mediating or contributing to the pathogenesis of Aβ-induced biochemical and behavioral pathology. The paper shows that knockout of the α7 nicotinic receptor mitigates biochemical pathology and the cognitive and LTP deficits in APP transgenic mice. The study, therefore, provides further support for the view that selective inhibitors of the α7 nicotinic receptor may have value in the treatment of Alzheimer disease.

    The precise mechanism that causes the amelioration of Aβ's effects is less certain. One possibility is that Aβ binds to the α7 nicotinic receptor, which, in turn, directly causes the neurotoxic effects (Wang et al., 2000; Wang et al., 2000; Wang et al., 2003). There are several studies which support this notion. The observations of Dineley et al. (2001), and Snyder et al. (2005) are consistent with this hypothesis. Our own work (Fodero et al., 2004) found that α7 nicotinic receptors are needed for an Aβ-induced increase in a minor glycoform of acetylcholinesterase that is selectively elevated in Alzheimer disease brain. However, in our own studies, we were unable to reach the conclusion of Wang et al. that Aβ binds directly to the α7 nicotinic receptor, despite having tested this idea repeatedly in a variety of experimental paradigms (brain homogenate and tissue slice binding assays, Xenopus oocyte expression system, functional assays) (Small et al., 2007).

    Another possibility that deserves serious consideration is the idea that the α7 nicotinic receptor may facilitate Aβ's effects, without being a direct mediator. Aβ is known to increase calcium permeability of the plasma membrane and the α7 receptor is also permeable to calcium. Thus, activation of the α7 receptor may contribute synergistically to calcium-induced neurotoxicity and dysfunction. This concept is elaborated in a recent article (Small, 2008), in which it is speculated that the α7 nicotinic acetylcholine receptor contributes to the progression of Alzheimer disease through a mechanism involving synaptic scaling. Changes in the level of α7 receptor may be due to altered activity of neural networks, rather than to any direct effect of Aβ on the receptor itself.

    Whatever the mechanism involved, this paper by Dziewczapolski et al. strengthens the case for considering α7 nicotinic acetylcholine receptors as an important target for Alzheimer disease therapeutics. Whether such a strategy will be free of unwanted side effects is unclear. However, as α7 receptors are neuromodulatory and function more in the regulation of synaptic plasticity than in direct neurotransmission, this possibility seems increasingly likely.

    View all comments by David Small

References

News Citations

  1. Nicotine and β Amyloid—Smoking Guns?
  2. Amyloid-β Zaps Synapses by Downregulating Glutamate Receptors
  3. Aβ Boosts Memory; Mint/X11 Proteins Boost Aβ?
  4. New Kid on the Block: Nicotinic Receptor Sensitive to Aβ
  5. Smoke Screen—Plaque Pathology May Blur α7 Nicotinic Receptor Changes

Paper Citations

  1. . Amyloid peptide Abeta(1-42) binds selectively and with picomolar affinity to alpha7 nicotinic acetylcholine receptors. J Neurochem. 2000 Sep;75(3):1155-61. PubMed.
  2. . Alpha 7 nicotinic acetylcholine receptors mediate beta-amyloid peptide-induced tau protein phosphorylation. J Biol Chem. 2003 Aug 22;278(34):31547-53. PubMed.
  3. . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
  4. . Intracellular accumulation of beta-amyloid(1-42) in neurons is facilitated by the alpha 7 nicotinic acetylcholine receptor in Alzheimer's disease. Neuroscience. 2002 Jan;110(2):199-211.
  5. . Picomolar amyloid-beta positively modulates synaptic plasticity and memory in hippocampus. J Neurosci. 2008 Dec 31;28(53):14537-45. PubMed.
  6. . Cortical alpha7 nicotinic acetylcholine receptor and beta-amyloid levels in early Alzheimer disease. Arch Neurol. 2009 May;66(5):646-51. PubMed.
  7. . Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-15. PubMed.

Further Reading

Papers

  1. . Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-15. PubMed.

Primary Papers

  1. . Deletion of the alpha 7 nicotinic acetylcholine receptor gene improves cognitive deficits and synaptic pathology in a mouse model of Alzheimer's disease. J Neurosci. 2009 Jul 8;29(27):8805-15. PubMed.