Allosteric modulation of nicotinic acetylcholine receptors as a treatment strategy for Alzheimer's disease
Introduction
A large body of evidence, including autoradiographic and histochemical studies of autopsy brain tissue Nordberg and Winblad, 1986, Whitehouse et al., 1986, Schröder et al., 1991, Perry et al., 1995, and brain imaging studies of patients (Nordberg et al., 1995), identifies the selective loss of nicotinic acetylcholine receptors as the biochemical parameter most closely associated with the severeness of the disease. In the upper cortical layers of the frontal cortex and in the temporal cortex, the loss of nicotinic acetylcholine receptors appears to concern predominantly an α4 subunit-bearing subtype rather than the α7 nicotinic acetylcholine receptor, as is suggested by histochemical studies Martin-Ruiz et al., 1999, Wevers et al., 1999 and radioligand binding (Potter et al., 1999).
Of the many nicotinic acetylcholine receptor subtypes that are expressed in the mammalian brain, the α4β2 and the α7 subtype are the most prominent ones. They are both found in postsynaptic as well as in presynaptic and perisynaptic locations Albuquerque et al., 1996a, Alkondon et al., 1999b. The α7 nicotinic receptor displays functional properties quite different from those of the α4β2 nicotinic receptor, among which are a much higher Ca2+ permeability, very fast desensitization and different pharmacology, including activation by choline and blockade by α-bungarotoxin Castro and Albuquerque, 1995, Albuquerque et al., 1996b, Alkondon et al., 1997, Alkondon et al., 1999b. Due to its sensitivity to choline, the α7 nicotinic receptor can be chemically excited even after the natural transmitter has been enzymatically cleaved. α7 Nicotinic acetylcholine receptor therefore can respond not only to synaptic events of acetylcholine release but also to volume changes in acetylcholine/choline concentration. (Rapid desensitization of α7 nicotinic acetylcholine receptor and an appropriate refractory period may be prerequisites for the latter response mode.) Due to its Ca2+ permeability, α7 nicotinic receptor activation can produce metabotropic responses in the excited cell, including Ca2+-controlled transmitter release and stimulation of gene transcription and protein biosynthesis. Very recently, the first electrophysiological studies of human cerebral cortical interneurons have been reported (Alkondon et al., 1999a). These studies established that both α4β2 and α7 nicotinic acetylcholine receptors are located on the somatodendritic regions of human interneurons, and as demonstrated by their ability to modulate GABA release, could be involved in inhibitory and disinhibitory mechanisms in the human cortex. The inhibitory action could enhance the signal-to-noise ratio of neuronal circuitry, whereas the disinhibitory action could lead to synaptic strengthening which is an essential element of the learning paradigm long-term potentiation (LTP) (Alkondon et al., 1999a).
Three major strategies have so far been applied to balance nicotinic cholinergic deficits, stimulation of acetylcholine synthesis, inhibition of acetylcholine degradation, and administration of nicotinic receptor agonists. Practically no therapeutic effects have been achieved by the administration of acetylcholine precursors (Feldman and Gracon, 1996). Administration of choline esterase inhibitors presently is the most commonly applied therapeutic approach. These inhibitors have proven albeit limited therapeutic value (Nordberg and Svensson, 1998), and most of them do not prevent progression of the disease to any significant extend Rogers et al., 1998, Flicker, 1999. A number of nicotinic receptor agonists are presently in preclinical and clinical testings Bjugstad et al., 1996, Menzaghi et al., 1997, Francis et al., 1999, even though they are difficult to dose, as higher levels may cause desensitization rather than increased activation of nicotinic receptors (Maelicke and Albuquerque, 1996). Other unsolved problems are drug transport to the targeted nicotinic receptor(s) in the brain and target selectivity (receptor subtype).
A novel approach to drug treatment in Alzheimer's disease is the application of allosteric modulators of nicotinic receptors Maelicke and Albuquerque, 1996, Maelicke et al., 1995. Allosteric modulators are compounds that interact with the receptor via binding sites that are distinct from those for acetylcholine and nicotinic receptor agonists and antagonists. Consequently, modulators are not directly involved in the neurotransmission process they affect, and hence, usually do not induce compensatory processes, as agonists and antagonists may do (e.g., receptor desensitization, down-regulation of expression). Because Alzheimer's disease is associated with a deficit in nicotinic neurotransmission, allosteric modulators are needed to up-modulate (potentiate) the channel activity of nicotinic receptors in response to acetylcholine. Such properties are displayed by a novel class of nicotinic receptor ligands, named “allosterically potentiating ligands” (APLs) Maelicke and Albuquerque, 1996, Schrattenholz et al., 1996.
Allosteric modulation of receptor activity is a quite common mechanism in neurotransmission. Arguably, the most prominent example is the benzodiazepines which positively modulate (potentiate) the activity of the GABAA receptor by facilitating opening of the receptor-integral Cl− channel (increase in the probability of channel opening at given concentrations of GABA). This effect is the underlying principle of the anxiolytic action of benzodiazepines (McDonald and Twyman, 1992).
Section snippets
Results
In Fig. 1A, a representative example of allosteric potentiation of nicotinic responses is shown. Using 3-day old PC 12 cells of bipolar morphology, the response to 100 μM acetylcholine, in the absence of 1-methyl-galanthamine (me-Gal, first trace), was nearly doubled in peak amplitude when acetylcholine was applied together with 0.4 μM N-methyl-galanthamine (second trace). At the same concentration, N-methyl-galanthamine alone did not induce a significant whole-cell current (third trace). The
Discussion
The key feature of Alzheimer's disease is a loss in cognitive function which includes loss of (short-term) memory and learning ability, impaired attention associated with relentlessness, disturbances of language, and emotional instability. All these functional deficits are the result of impaired neurotransmission in the central nervous system and probably involve several transmitter systems. Interestingly, the biochemical parameter best correlated with the severeness of Alzheimer's disease is a
Acknowledgements
This work was supported by grants from the Deutsche Forschungsgemeinschaft, the Janssen Research Foundation, and the German Fonds der Chemischen Industrie.
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