Alzheimer Disease: Albuquerque EX

Albuquerque EX, Pereira EF, Alkondon M, Rogers SW. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, MD, USA. · Physiol Rev. · Pubmed #19126755 links to  free full text

Abstract: The classical studies of nicotine by Langley at the turn of the 20th century introduced the concept of a "receptive substance," from which the idea of a "receptor" came to light. Subsequent studies aided by the Torpedo electric organ, a rich source of muscle-type nicotinic receptors (nAChRs), and the discovery of alpha-bungarotoxin, a snake toxin that binds pseudo-irreversibly to the muscle nAChR, resulted in the muscle nAChR being the best characterized ligand-gated ion channel hitherto. With the advancement of functional and genetic studies in the late 1980s, the existence of nAChRs in the mammalian brain was confirmed and the realization that the numerous nAChR subtypes contribute to the psychoactive properties of nicotine and other drugs of abuse and to the neuropathology of various diseases, including Alzheimer's, Parkinson's, and schizophrenia, has since emerged. This review provides a comprehensive overview of these findings and the more recent revelations of the impact that the rich diversity in function and expression of this receptor family has on neuronal and nonneuronal cells throughout the body. Despite these numerous developments, our understanding of the contributions of specific neuronal nAChR subtypes to the many facets of physiology throughout the body remains in its infancy.

Maelicke A, Samochocki M, Jostock R, Fehrenbacher A, Ludwig J, Albuquerque EX, Zerlin M. · Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, Mainz, Germany. · Biol Psychiatry. · Pubmed #11230879 No free full text.

Abstract: Cholinesterase inhibitors are the only approved drug treatment for patients with mild to moderately severe Alzheimer's disease. Interestingly, the clinical potency of these drugs does not correlate well with their activity as cholinesterase inhibitors, nor is their action as short lived as would be expected from purely symptomatic treatment. A few cholinesterase inhibitors, including galantamine, produce beneficial effects even after drug treatment has been terminated. These effects assume modes of action other than mere esterase inhibition and are capable of inducing systemic changes. We have recently discovered a mechanism that could account, at least in part, for the above-mentioned unexpected properties of some cholinesterase inhibitors. We have found that a subgroup of cholinesterase inhibitors, including galantamine but excluding tacrine, directly interacts with nicotinic acetylcholine receptors. These compounds, named allosterically potentiating ligands, sensitize nicotinic receptors by increasing the probability of channel opening induced by acetylcholine and nicotinic agonists and by slowing down receptor desensitization. The allosterically potentiating ligand action, which is not necessarily associated with cholinesterase inhibition, has been demonstrated by whole-cell patch-clamp recordings to occur in natural murine and human neurons and in murine and human cell lines expressing various subtypes of neuronal nicotinic acetylcholine receptors.

Maelicke A, Schrattenholz A, Samochocki M, Radina M, Albuquerque EX. · Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, Mainz, Germany. · Behav Brain Res. · Pubmed #10942046 No free full text.

Abstract: One of the most prominent cholinergic deficit in Alzheimer's disease (AD) is the reduced number of nicotinic acetylcholine receptors (nAChR) in the hippocampus and cortex of AD patients, as compared to age-matched controls. This deficit results in reduced nicotinic cholinergic excitation which may not only impair postsynaptic depolarization but also presynaptic neurotransmitter release and Ca2+-dependent intracellular signaling, including transcriptional activity. Presently, the most common approach to correct the nicotinic cholinergic deficit in AD is the application of cholinesterase inhibitors. Due to the resulting increase in synaptic acetylcholine levels, both in concentration and time, additional nAChR molecules, e.g. those more distant from the ACh release sites, could be activated. As an obvious disadvantage, this approach affects cholinergic neurotransmission as a whole, including muscarinic neurotransmission. As a novel and alternative approach, a treatment strategy which exclusively targets nicotinic receptors is suggested. The strategy is based on a group of modulating ligands of nicotinic receptors, named allosterically potentiating ligands (APL), which increase the probability of channel opening induced by ACh and nicotinic agonists, and in addition decrease receptor desensitization. The action of APL on nicotinic receptors is reminiscent of that of benzodiazepines on GABA(A) receptors and of that of glycine on the NMDA-subtype of glutamate receptor. Representative nicotinic APL are the plant alkaloids physostigmine, galanthamine and codeine, and the neurotransmitter serotonin (5HT). The potentiating effect of APL on nicotinic neurotransmission has been shown by whole-cell patch-clamp studies in natural murine and human neurons, and in murine and human cell lines expressing various subtypes of neuronal nAChR.

Lopes C, Pereira EF, Wu HQ, Purushottamachar P, Njar V, Schwarcz R, Albuquerque EX. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA. · J Pharmacol Exp Ther. · Pubmed #17446300 links to  free full text

Abstract: Galantamine, a drug used to treat Alzheimer's disease, is a nicotinic allosteric potentiating ligand, and kynurenic acid (KYNA), a neuroactive metabolite of the kynurenine pathway, is an endogenous noncompetitive inhibitor of alpha7* nicotinic receptors (nAChRs) [the asterisk next to the nAChR subunit is intended to indicate that the exact subunit composition of the receptor is not known (Pharmacol Rev 51:397-401, 1999)]. Here, possible interactions between KYNA and galantamine at alpha7* nAChRs were examined in vitro and in vivo. In the presence of tetrodotoxin (TTX), approximately 85% of cultured hippocampal neurons responded to choline (0.3-30 mM) with alpha7* nAChR-subserved whole-cell (type IA) currents. In the absence of TTX and in the presence of glutamate receptor antagonists, choline triggered inhibitory postsynaptic currents (IPSCs) by activating alpha7* nAChRs on GABAergic neurons synapsing onto the neurons under study. Galantamine (1-10 microM) potentiated, whereas KYNA (10 nM-1 mM) inhibited, choline-triggered responses. Galantamine (1 microM), applied before KYNA, shifted to the right the concentration-response relationship for KYNA to inhibit type IA currents, increasing the IC(50) of KYNA from 13.9 +/- 8.3 to 271 +/- 131 microM. Galantamine, applied before or after KYNA, antagonized inhibition of choline-triggered IPSCs by KYNA. Local infusion of KYNA (100 nM) in the rat striatum reduced extracellular dopamine levels in vivo. This effect resulted from alpha7* nAChR inhibition and was blocked by coapplied galantamine (1-5 microM). It is concluded that galantamine competitively antagonizes the actions of KYNA on alpha7* nAChRs. Reducing alpha7* nAChR inhibition by endogenous KYNA may be an important determinant of the effectiveness of galantamine in neurological and psychiatric disorders associated with decreased alpha7* nAChR activity in the brain.

Albuquerque EX, Santos MD, Alkondon M, Pereira EF, Maelicke A. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA. · Alzheimer Dis Assoc Disord. · Pubmed #11669505 No free full text.

Abstract: Impaired cholinergic function in the central nervous system is an early feature of Alzheimer disease (AD). Currently, cholinergic deficit is usually corrected by increasing the amount of acetylcholine in the synapse by inhibiting acetylcholinesterase (AChE). One of the most consistent cholinergic deficits in AD is the reduced expression of nicotinic acetylcholine receptors (nAChR) in the brain. Since these receptors are essential for learning and memory, restoring nicotinic cholinergic function is a promising approach to treating AD. Allosteric modulation of nAChR is a novel approach, which circumvents development of tolerance through long-term use of conventional nicotinic agonists. Allosteric modulators interact with receptor-binding sites distinct from those capable of recognizing the natural agonist. Positive allosteric modulation of nAChR activity has no effect on conductance of single channels; instead, by facilitating channel opening, it potentiates responses evoked by the interaction of the natural agonist with presynaptic and postsynaptic nAChR. Allosteric modulation of nAChR activity could therefore potentially produce a significant benefit in AD. One such allosteric modulator is galantamine. In addition to increasing nAChR activity, galantamine also inhibits AChE. This novel, dual mechanism of action distinguishes galantamine from many other AChE inhibitors. Galantamine has been shown to improve cognitive and daily function for at least 6 months in placebo-controlled trials, and to maintain these functions at baseline levels for at least 12 months in a 6-month open-label extension study. Galantamine has positive effects on nAChR expression, which are likely to contribute to its sustained efficacy in the treatment of AD patients.

Albuquerque EX, Pereira EF, Mike A, Eisenberg HM, Maelicke A, Alkondon M. · Department of Pharmacology and Experimental Therapeutics, University of Maryland School of Medicine, Baltimore 21201, USA. · Behav Brain Res. · Pubmed #10942040 No free full text.

Abstract: The present report describes the participation of nicotinic receptors (nAChRs) in controlling the excitability of local neuronal circuitries in the rat hippocampus and in the human cerebral cortex. The patch-clamp technique was used to record responses triggered by the non-selective agonist ACh and the alpha7-nAChR-selective agonist choline in interneurons of human cerebral cortical and rat hippocampal slices. Evidence is provided that functional alpha7- and alpha4beta2-like nAChRs are present on somatodendritic and/or preterminal/terminal regions of interneurons in the CA1 field of the rat hippocampus and in the human cerebral cortex and that activation of the different nAChR subtypes present in the preterminal/terminal areas of the interneurons triggers the tetrodotoxin-sensitive release of GABA. Modulation by nAChRs of GABAergic transmission, which can result either in inhibition or disinhibition of pyramidal neurons, depends both on the receptor subtype present in the interneurons and on the agonist acting upon these receptors. Not only do alpha7 nAChRs desensitize faster than alpha4beta2 nAChRs, but also alpha7 nAChR desensitization induced by ACh lasts longer than that induced by choline. These mechanisms, which appear to be retained across species, might explain the involvement of nAChRs in cognitive functions and in such neurological disorders as Alzheimer's disease and schizophrenia.

Maelicke A, Albuquerque EX. · Laboratory of Molecular Neurobiology, Institute of Physiological Chemistry and Pathobiochemistry, Johannes-Gutenberg University Medical School, 6 Duesbergweg, D-55099, Mainz, Germany. · Eur J Pharmacol. · Pubmed #10771010 No free full text.

Abstract: The basic symptoms of Alzheimer's dementia, i.e., a loss in cognitive function, are due to impaired nicotinic cholinergic neurotransmission. To compensate for this impairment by drug treatment, blockers of the acetylcholine-degrading enzyme acetylcholinesterase are applied, even though this approach obviously is prone to many side-effects, including those of muscarinic nature. We have recently described a novel class of nicotinic acetylcholine receptor ligands which, similar to the action of benzodiazepines on GABA(A) receptors, allosterically potentiate submaximal nicotinic responses. The sensitizing effect is a consequence of facilitated channel opening in the presence of allosterically potentiating ligand (APL). Representative members of this class of ligands are the plant alkaloids physostigmine, galanthamine, and codeine. Because APLs could enhance nicotinic neurotransmission under conditions of reduced secretion and/or increased degradation of acetylcholine or reduced acetylcholine-sensitivity of nicotinic acetylcholine receptors, they could have a preventive and corrective action on impaired but still functioning nicotinic neurotransmission.

Wevers A, Monteggia L, Nowacki S, Bloch W, Schütz U, Lindstrom J, Pereira EF, Eisenberg H, Giacobini E, de Vos RA, Steur EN, Maelicke A, Albuquerque EX, Schröder H. · Department of Anatomy, University of Köln, Joseph-Stelzmann Strasse 9, 50931 Köln, Germany. · Eur J Neurosci. · Pubmed #10383644 No free full text.

Abstract: Impairment of cholinergic transmission and decreased numbers of nicotinic binding sites are well-known features accompanying the cognitive dysfunction seen in Alzheimer's disease (AD). In order to elucidate the underlying cause of this cholinoceptive dysfunction, the expression of two pharmacologically different nicotinic acetylcholine receptor (nAChR) subunits (alpha4, alpha7) was studied in the cerebral cortex of Alzheimer patients as compared to controls. Patch-clamp recordings of 14 dissociated neurons of control cortices showed responses suggesting the existence of alpha4- and alpha7-containing functional nAChRs in the human cortex. In cortices of Alzheimer patients and controls, the pattern of distribution and the number of alpha4 and alpha7 mRNA-expressing neurons were similar, whereas at the protein level a decrease in the density of alpha4- and alpha7-expressing neurons of approximately 30% was observed in Alzheimer patients. The histotopographical correlation of nAChR expression with accompanying pathological changes, e.g. accumulation of hyperphosphorylated-tau (HP-tau) protein and beta-amyloid showed that neurons in the vicinity of beta-amyloid plaques bore both nAChR transcripts. Neurons heavily labelled for HP-tau, however, expressed little or no alpha4 and alpha7 mRNA. These results point to an impaired synthesis of nAChRs on the protein level as a possible cause of the cholinoceptive deficit in AD. Further investigations need to elucidate whether interactions of HP-tau with nAChR mRNA, or alterations in the quality of alpha4 and alpha7 transcripts give rise to decreased protein expression at the level of individual neurons.