There’s a new player in town or, to be precise, in the rat brain. Based on a report in yesterday’s Journal of Neuroscience, scientists can now add the α7β2 heteromeric nicotinic acetylcholine receptor (nAChR) to the α7 homomeric receptors already known to exist in the basal forebrain—a site of cholinergic neuron loss in early Alzheimer disease (AD). “We think that, at least in the basal forebrain, the majority of nicotinic receptors are heteromeric α7β2, though there are also some homomeric α7s,” said principal investigator Jie Wu, from the Barrow Neurological Institute in Phoenix, Arizona. More importantly for Alzheimer researchers, these heteromeric receptors appear to be much more sensitive than their known cousins to blockage by oligomers of amyloid-β (Aβ), raising questions about what role these novel receptors may play in the human disease.

“Nicotinic acetylcholine receptors are perhaps the most complex neurotransmitter receptors in the brain,” Wu told ARF. The pentameric structures can form from various combinations of 16 different subunits, which can sometimes make data difficult to interpret. While homomeric α7 receptors have been seen as the predominant nicotinic receptor in the basal forebrain, recent evidence showed that β2 subunits are highly expressed in that region, as well. This is the first data showing that α7 and β2 subunits form a complex and are functional in the basal forebrain, said Wu.

First author Qiang Liu and colleagues used a mixture of electrophysiology, pharmacology, cell biology, and genetics to confirm the presence of the heteromeric receptor in rat basal forebrain. The researchers discovered that nicotinic receptors in acutely isolated cholinergic neurons from the medial septum/diagonal band (MS/DB) of the forebrain have different properties than the α7 homomeric receptors in dopaminergic neurons from the ventral tegmental area (VTA). In the latter neurons, the transmitter choline elicited the rapid induction of current indicative of α7 homomeric stimulation, whereas in MS/DB neurons the kinetics were significantly slower, suggesting the receptors were not identical. Moreover, receptors on MS/DB neurons were much more susceptible to blockage by the β2-selective antagonist dihydro-β-erythroidine (DHβE), suggesting the β2 subunit may be modulating choline responses. Finally, the researchers found that α7 and β2 subunits co-immunoprecipitate from basal forebrain neurons but not VTA neurons. “These results are consistent with the hypothesis that functional α7-nAChRs on MS/DB cholinergic neurons also contain DHβE-sensitive β2 subunits,” write the authors. They found similar kinetics and pharmacological responses in Xenopus oocytes co-expressing α7 and β2 subunits, but not in neurons from β2 subunit knockout mice. This further supports the hypothesis that α7β2 receptors assemble and function in forebrain neurons. (Due to questionable antibody specificity, immunoprecipitation experiments with nAChRs can be difficult to interpret, hence multiple lines of evidence are needed).

Nicotinic ACh receptors are intimately tied into the pathophysiology of AD. These receptors disappear from the cortex and hippocampus during the course of the disease (see Burghaus et al., 2000). Four of the five AD drugs approved by the U.S. Food and Drug Administration are cholinesterase inhibitors, which boost acetylcholine levels. There are also indications that cholinergic stimulation attenuates Aβ production (see Mousavi et al., 2008) and that Aβ can bind to ACh receptors and spur phosphorylation of tau, the major component of neurofibrillary tangles (see ARF related news story). Nicotinic agonists are among the more commonly pursued drug candidates in the pharma industry’s pipeline for AD and even schizophrenia.

To test how α7β2 receptors might fit into the larger cholinergic picture, Liu and colleagues tested their response to Aβ42. Aβ oligomers inhibited the response to choline of MS/DB neurons (but not of VTA neurons) even at concentrations as low as 1 nM. “That’s a more physiological level of Aβ, which is usually about 5 nM in the AD brain, or at least lower than 10 nM,” said Wu—100nM Aβ is typically used to block α7 homomeric receptors. The authors confirmed Aβ oligomer toxicity in oocytes expressing the two receptor subunits, and also found that forebrain neurons from β2 subunit knockout mice were unaffected by 1 nM Aβ42. “Based on the current findings, we suggest that selective, high-affinity effects of oligomeric Aβ1-42 on basal forebrain, cholinergic neuronal α7β2-nAChRs could acutely contribute to disruption of cholinergic signaling and diminished learning and memory abilities,” wrote the authors.

Wu said it is unclear why these receptors should be more sensitive to Aβ. He noted that adding the β2 subunit seems to increase the receptor’s affinity for nicotine dramatically, so it somehow changes the properties of the receptor. Whether the heteromeric receptors are expressed and functional in the human basal forebrain is a question Wu plans to investigate next.—Tom Fagan

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  1. Cholinergic transmission is an early and major casualty of Alzheimer disease. Recent evidence implicates nicotinic cholinergic signaling as likely to be a critical part of the deficit. Activation of nicotinic acetylcholine receptors (nAChRs) by the endogenous neurotransmitter acetylcholine contributes importantly to attention, learning, and memory, and other higher order functions of the nervous system. β amyloid peptide (Aβ), which accumulates early in Alzheimer disease, specifically blocks nAChRs. It has also been reported at low concentrations to act as an agonist for some nAChRs and possibly to be internalized with the receptors where it exerts intracellular effects as well, but these latter actions remain controversial.

    A number of nAChR subtypes have been identified in brain, but two major classes are most abundant: a homopentameric receptor composed of α7 subunits and a heteropentameric receptor containing β2 subunit(s) in conjunction with others. Both are inhibited by Aβ. The paper by Liu et al. in the January 28 issue of the Journal of Neuroscience reports an interesting and unexpected finding. They provided evidence for a novel nAChR—one that contains both α7 and β2 subunits co-assembled—and demonstrate that it has unusually high sensitivity to blockade by Aβ. Though the receptor is a minor species, it is expressed in critical forebrain regions where it is positioned to influence cholinergic function and cognitive processes.

    Previous studies had demonstrated that α7 and β2 subunits could co-assemble when co-expressed in heterologous cells, but a native receptor of this composition had eluded investigators. Liu et al. combine biochemical and electrophysiological approaches to identify the receptor, define its properties, and distinguish it from the relatively abundant α7 homo- and β2 heteropentamers. Though most α7-containing nAChRs are known to desensitize quickly, they have a relatively high permeability to calcium and can be concentrated on presynaptic terminals. As a result, they can have dramatic effects on transmitter release and on mechanisms shaping synaptic plasticity, including those thought to underlie learning and memory. Interestingly, the α7/β2 heteromeric nAChR described here by Liu et al. is slow to desensitize. If it is permeable to calcium, its position on cholinergic neurons of the basal forebrain could have a major impact on acetylcholine release. Inhibition of such receptors by Aβ could markedly accentuate the cholinergic deficit encountered in Alzheimer’s patients. The unique pharmacological and physiological properties of these newly described receptors recommend them as an interesting candidate target for therapeutic intervention.

  2. In this study, Liu et al. demonstrate the co-assembly of α7 nicotinic receptors and β2 subunits. The increasing knowledge of the functional role of α7 nicotinic receptors in brain is fascinating. It appears more relevant that the α7 nicotinic receptors also may colocalize with β2 subunits, similar to the other forms of nicotinic subunits expressed in brain, rather than solely existing in monomeric forms.

    Interestingly enough, Liu et al. observed that it was the oligomeric form of Aβ, in such low concentrations as 1 nM, that inhibited the α7β2 nicotinic receptors in rodent brain. An important question is how relevant these observations are for the Alzheimer brain. Earlier studies have demonstrated a decrease in α7 nicotinic receptors in the neurons but an increase in α7 nicotinic receptors in the astrocytes (Teaktong et al., 2003; Yu et al., 2005). The increase of α7 nicotinic receptors was especially high in Alzheimer patients with APPswe mutations compared to patients with sporadic Alzheimer’s disease (Yu et al., 2005). Do the heteromeric forms of α7 receptors exist in Alzheimer brains?

    Is there a different distribution of monomeric and heteromeric α7 nicotinic receptors in neurons versus astrocytes? The α7 nicotinic receptors have also been suggested to be required for Aβ-promoted NMDA endocytosis (Snyder et al., 2005). Thus, several independent studies support an important link between α7 nicotinic receptors and Aβ, both regarding toxicity as well as neuroprotective mechanisms. The search for selective α7 nicotinic receptor as new drug targets in Alzheimer disease might be very rewarding.

    References:

    . Alzheimer's disease is associated with a selective increase in alpha7 nicotinic acetylcholine receptor immunoreactivity in astrocytes. Glia. 2003 Jan 15;41(2):207-11. PubMed.

    . High selective expression of alpha7 nicotinic receptors on astrocytes in the brains of patients with sporadic Alzheimer's disease and patients carrying Swedish APP 670/671 mutation: a possible association with neuritic plaques. Exp Neurol. 2005 Mar;192(1):215-25. PubMed.

    . Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.

    View all comments by Agneta Nordberg
  3. This is a very interesting paper. It would be very important to know whether this receptor also mediates tau hyperphosphorylation as shown for the α7 nicotinic receptors in some, but not in all, papers that tested the correlation. I’d like to clarify that we (Sadot et al., 1996) did not test the nicotinic receptor as the authors suggest, but the m1 muscarinic receptor.

    References:

    . Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem. 1996 Feb;66(2):877-80. PubMed.

References

News Citations

  1. Nicotine and β Amyloid—Smoking Guns?

Paper Citations

  1. . Quantitative assessment of nicotinic acetylcholine receptor proteins in the cerebral cortex of Alzheimer patients. Brain Res Mol Brain Res. 2000 Mar 29;76(2):385-8. PubMed.
  2. . Nicotinic receptor agonists and antagonists increase sAPPalpha secretion and decrease Abeta levels in vitro. Neurochem Int. 2009 Mar-Apr;54(3-4):237-44. PubMed.

Further Reading

Primary Papers

  1. . A novel nicotinic acetylcholine receptor subtype in basal forebrain cholinergic neurons with high sensitivity to amyloid peptides. J Neurosci. 2009 Jan 28;29(4):918-29. PubMed.