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Liu Q, Huang Y, Xue F, Simard A, Dechon J, Li G, Zhang J, Lucero L, Wang M, Sierks M, Hu G, Chang Y, Lukas RJ, Wu J. 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.
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University of California, San Diego
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.
View all comments by Darwin K. Bergretired from IIBR
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:
Sadot E, Gurwitz D, Barg J, Behar L, Ginzburg I, Fisher A. Activation of m1 muscarinic acetylcholine receptor regulates tau phosphorylation in transfected PC12 cells. J Neurochem. 1996 Feb;66(2):877-80. PubMed.
View all comments by Abraham FisherKarolinska Institutet
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:
Teaktong T, Graham A, Court J, Perry R, Jaros E, Johnson M, Hall R, Perry E. 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.
Yu WF, Guan ZZ, Bogdanovic N, Nordberg A. 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.
Snyder EM, Nong Y, Almeida CG, Paul S, Moran T, Choi EY, Nairn AC, Salter MW, Lombroso PJ, Gouras GK, Greengard P. Regulation of NMDA receptor trafficking by amyloid-beta. Nat Neurosci. 2005 Aug;8(8):1051-8. PubMed.
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