Alpha7-nicotinic acetylcholine receptors mediate an Abeta(1-42)-induced increase in the level of acetylcholinesterase in primary cortical neurones

The beta-amyloid protein (Abeta) is the major protein component of amyloid plaques found in the Alzheimer brain. Although there is a loss of acetylcholinesterase (AChE) from both cholinergic and non-cholinergic neurones in the brain of Alzheimer patients, the level of AChE is increased around amyloid plaques. Previous studies using P19 cells in culture and transgenic mice which overexpress human Abeta have suggested that this increase may be due to a direct action of Abeta on AChE expression in cells adjacent to amyloid plaques. The aim of the present study was to examine the mechanism by which Abeta increases levels of AChE in primary cortical neurones. Abeta1-42 was more potent than Abeta1-40 in its ability to increase AChE in primary cortical neurones. The increase in AChE was unrelated to the toxic effects of the Abeta peptides. The effect of Abeta1-42 on AChE was blocked by inhibitors of alpha7 nicotinic acetylcholine receptors (alpha7 nAChRs) as well as by inhibitors of L- or N-type voltage-dependent calcium channels (VDCCs), whereas agonists of alpha7 nAChRs (choline, nicotine) increased the level of AChE. The results demonstrate that the effect of Abeta1-42 on AChE is due to an agonist effect of Abeta1-42 on the alpha7 nAChR.     

Non-neuronal nicotinic acetylcholine receptors: Cholinergic regulation of the immune processes

Nicotinic acetylcholine receptors (nAChRs) were initially discovered and studied as mediators of fast synaptic transmission in neuromuscular junctions and autonomic ganglia. Later on, they were found in the brain and in many nonexcitable tissues where they regulate vital cellular functions and the activity of other receptors. Primary immune organs, the bone marrow and thymus, are innervated with cholinergic nerves, which mediate the control of lymphopoiesis provided by the autonomic nervous system. In addition, lymphocytes are able to produce endogenous acetylcholine that can regulate the immune processes in an auto/paracrine way. Correspondingly, both T and B lymphocytes express functional nAChRs involved in the regulation of development and activation of these cells. This review describes the structure and roles of nAChRs in the immune system with regard to its potential regulation by the autonomic nervous system, as well as by self sources of endogenous agonists. Neirofiziologiya/Neurophysiology, Vol. 39, Nos. 4/5, pp. 307–314, July–October, 2007.     

In Vivo Regulation of [3H]Acetylcholine Recognition Sites in Brain by Nicotinic Cholinergic Drugs

The in vivo regulation of [3H]acetylcholine [( 3H]ACh) recognition sites on nicotinic receptors in rat brain was examined by administering drugs that increase stimulation of nicotinic cholinergic receptors, either directly or indirectly. After 10 days of treatment with the cholinesterase inhibitor diisopropyl fluorophosphate, [3H]ACh binding in the cortex, thalamus, striatum, and hypothalamus was decreased. Scatchard analyses indicated that the decrease in binding in the cortex was due to a reduction in the apparent density of [3H]ACh recognition sites. In contrast, after repeated administration of nicotine (5-21 days), the number of [3H]ACh recognition sites was increased in the cortex, thalamus, striatum, and hypothalamus. Similar effects were observed in the cortex and thalamus following repeated administration of the nicotinic agonist cytisin. The nicotinic antagonists mecamylamine and dihydro-beta-erythroidine did not alter [3H]ACh binding following 10-14 days of administration. Further, concurrent treatment with these antagonists and nicotine did not prevent the nicotine-induced increase in these binding sites. The data indicate that [3H]ACh recognition sites on nicotinic receptors are subject to up- and down-regulation, and that repeated administration of nicotine results in a signal for up-regulation, probably through protracted desensitization at the recognition site.     

Changes in Nicotinic and Muscarinic Cholinergic Receptors in Alzheimer-Type Dementia

Nicotinic and muscarinic cholinergic receptors were studied in autopsied brains from four histologically normal controls and five histopathologically verified cases of Alzheimer-type dementia (ATD), using ligand binding techniques. Nicotinic and muscarinic cholinergic receptors were assessed by (-)-[3H]nicotine and [3H]quinuclidinyl benzilate [( 3H]QNB), respectively. Compared with the controls, (-)-[3H]nicotine binding sites in the ATD brain regions examined were significantly reduced in the putamen and the nucleus basalis of Meynert (NbM). [3H]QNB binding was significantly reduced in the hippocampus and NbM. These findings suggest that there are significant changes of nicotinic and muscarinic cholinergic receptors in selected regions of ATD brains.     

Desensitization of central cholinergic mechanisms and neuroadaptation to nicotine

This review focuses on neuroadaptation to nicotine. The first part of the paper delineates some possible general mechanisms subserving neuroadaptation to commonly abused drugs. The postulated role of the mesocorticolimbic neuroanatomical pathway and drug-receptor desensitization mechanisms in the establishment of tolerance to, dependence on, and withdrawal from psychoactive drugs are discussed. The second part of the review deals with the pharmacological effects of nicotine at both pre- and postsynaptic locations within the central nervous system, and the still-perplexing upregulation of brain nicotine-binding sites seen after chronic nicotine administration. A special emphasis has been put on desensitization of presynaptic cholinergic mechanisms, and postsynaptic neuronal nicotinic-receptor function and its modulation by endogenous substances. A comparison with the inactivation process occuring at peripheral nicotinic receptors is also included. Finally, a hypothesis on the possible connections between desensitization of central cholinergic mechanisms and neuroadaptation to nicotine is advanced. A brief comment on the necessity of fully understanding the effects of nicotine on the developing nervous system closes this work.     

Why do young women smoke? V. Role of direct and interactive effects of nicotinic cholinergic receptor gene variation on neurocognitive function

Previous work suggests that young women who smoke cigarettes regularly, or did so in the past, manifest a neurocognitive profile that is characterized by small but significant impairments of response inhibition and attention. The present study sought to determine whether variation in nicotinic cholinergic receptor (nAchR) genes impacts upon cognitive function in these domains by overall or differential effects on the performance of current, former and non-smokers. The study sample consisted of 100 female college students, current or past smokers, and 144 who had never smoked. All performed a computerized neurocognitive test battery and were genotyped for 39 single nucleotide polymorphisms in 11 nAchR genes. The results, derived from linear or logistic regression, show significant direct and interactive relationships between single nucleotide polymorphisms and haplotypes in several nAchR genes and performance on the Matching Familiar Figures Test (MFFT) Stroop test, Continuous Performance Task (CPT) and Tower of London (TOL) test. Response inhibition (MFFT, Stroop, CPT Loading Phase, TOL) was associated with variants in CHRNA2, CHRNA4, CHRNA5, CHRNA7, CHRNA9, CHRNA10, CHRNB2 and CHRNB3. Selective attention (Stroop) was associated with CHRNA4, CHRNA5, CHRNA9 and CHRNB2. Sustained attention (CPT Boring Phase) was associated with CHRNA4, CHRNA5, CHRNA7, CHRNA10 and CHRNB3. Up to 37% of the variance among the smokers and up to 47% of the variance among the non-smokers on the test measures was explained. Differences between smokers and non-smokers in neurocognitive function, putatively implicated in susceptibility to nicotine dependence, may be modulated by variants in nAchR genes, with potential implications for prevention and treatment.     

Structural and functional crosstalk between acetylcholine receptor and its membrane environment

Nicotinic acetylcholine receptor (AChR) is a transmembrane protein belonging to the superfamily of rapid, ligand-operated channels. Theoretical models based on thermodynamic criteria assign portions of the polypeptide chains to the lipid bilayer region. From an experimental point of view, however, the relationship between the two moieties remains largely unexplored. Current studies from our laboratory are aimed at defining the structural, dynamic, and functional relationship between membrane lipids and AChR. We are particularly interested in establishing the characteristics of and differences between the lipids in each leaflet of the bilayer and the belt or “annular” lipids immediately surrounding AChR and the bulk bilayer lipids. We are also interested in determining the possible implications of lipid modifications on AChR channel properties. Toward these ends, fluorescence and other spectroscopic techniques, together with biochemical analyses and patch-clamp studies, are currently being undertaken. Correlations can be established between structural aspects of phospholipid packing in the immediate perimeter of AChR and other properties of these annular lipids revealed by dynamic spectroscopic and molecular modeling techniques. Lipid compositional analyses of the clonal muscle cell line BC3H-1 and chemical modification studies have been carried out by incubation of intact cells in culture and of membrane patches excised therefrom with liposomes of different lipid composition. These studies have been combined with electrophysiological measurements using the patch-clamp technique, with the aim of determining the possible effects of lipids on the channel properties of muscle-type AChR. A variety of experimental conditions, involving polar head and fatty acyl chain substitution of phospholipids and cholesterol incorporation, are being assayed in the BC3H-1 cells. Dedicated to the memory of the late E. De Robertis.     

Role of A β and the α 7 nicotinic acetylcholine receptor in regulating synaptic plasticity in Alzheimer's disease

Alzheimer's disease (AD) is caused by the accumulation of β-amyloid protein (Aβ) in the brain. The aggregation of β-amyloid protein to higher molecular weight fibrillar forms is also considered to be an important step in the pathogenesis of the disease. The memory problems associated with AD are likely to be caused by changes in synaptic plasticity. Recent studies suggest that Aβ binds to the α 7 nicotinic acetylcholine receptor (α 7 nAChR), which plays an important role in synaptic plasticity and memory. A loop domain localized towards the C-terminus of the extracellular region of the receptor has been identified as forming part of a putative Aβ-binding site. In cell culture experiments, the binding of Aβ to the α 7 nAChR has been found to cause an increase in the level of acetylcholinesterase, which is also increased around amyloid plaques in the AD brain. These studies indicate that the Aβ-binding site on the α 7 nAChR receptor is an important new target for therapeutic development in AD.     

Alpha7 nicotinic acetylcholine receptors in lung inflammation and carcinogenesis: Friends or foes?

The lung tissue expresses the cholinergic system including nicotinic acetylcholine receptors (nAChRs) which included in many physiologic and pathologic processes. Mounting evidence revealed that these receptors have important roles in lung carcinogenesis via modulating either stimulatory or inhibitory signaling pathways. Among different members of nicotinic receptors family, alpha7-subtype of nAChR (α7nAChR) is a critical mediator involved in both inflammatory responses and cancers. Several studies have shown that this receptor is the most powerful regulator of responses that stimulate lung cancer processes such as proliferation, angiogenesis, metastasis, and inhibition of apoptosis. Moreover, aside from its roles in the regulation of cancer pathways, there is growing evidence indicating that α7nAChR has profound impacts on lung inflammation through the cholinergic anti-inflammatory pathway. Regarding such diverse effects as well as the critical roles of nicotine as an activator of α7nAChR on lung cancer pathogenesis, its modulation has emerged as a promising target for drug developments. In this review, we aim to highlight the detrimental as well as the possible beneficial influences of α7nAChR downstream signaling cascades in the control of lung inflammation and cancer-associated properties. Consequently, by considering the significant global burden of lung cancer, delineating the complex influences of α7 receptors would be of great interest in designing novel anticancer and anti-inflammatory strategies for the patients suffering from lung cancer.     

Toxicity study in juvenile rats with the α4β2 nicotinic acetylcholine receptor partial agonist CP-601,927

BACKGROUND: CP‐601927 is a selective α₄β₂ nicotinic acetylcholine receptor (nAChR) partial agonist. The objective of this study was to assess the potential effects persisting into adulthood when CP‐601,927 was administered to neonatal/juvenile rats. Since the juvenile toxicity study was being performed early in the development program and this study would represent the longest dosing period yet evaluated, the study design incorporated standard endpoints typically evaluated in a general toxicity screening study. METHODS: CP‐601,927 was administered to Sprague‐Dawley rats from postnatal day (PND) 7–70 by oral gavage at doses of 0.3, 1, or 3 mg/kg. During treatment animals were evaluated for growth, development, and sexual maturation. At the end of the treatment period general toxicity screening endpoints were collected (e.g., organ weights, histology, clinical chemistry). Following a 2‐week latency period, animals were evaluated for CNS function in a comprehensive behavioral training battery consisting of a functional observational battery, motor activity, acoustic startle response, and learning and memory evaluations. Reproductive competency was evaluated by mating treated rats and allowing pregnant dams to deliver and rear their litters until PND 10. RESULTS AND CONCLUSIONS: Treatment‐related findings included the death of 2 males receiving 3 mg/kg CP‐601,927, and transient reductions in body weight for both males and females during the third week of dosing which quickly recovered to control levels. The only treatment‐related alteration in behavior was decreased motor activity, which occurred only in females at the highest dose tested. CP‐601,927 had no effect on acoustic startle response, learning and memory, sexual maturation, reproductive capacity, or general toxicity endpoints. Birth Defects Res (Part B) 92:323–332, 2011. © 2011 Wiley‐Liss, Inc.     

Increased 5-Lipoxygenase Immunoreactivity in the Hippocampus of Patients With Alzheimer's Disease

The proinflammatory enzyme 5-lipoxygenase (5-LOX) is upregulated in Alzheimer''s disease (AD), but its localization and association with the hallmark lesions of the disease, β-amyloid (Aβ) plaques and neurofibrillary tangles (NFTs), is unknown. This study examined the distribution and cellular localization of 5-LOX in the medial temporal lobe from AD and control subjects. The spatial relationship between 5-LOX immunoreactive structures and AD lesions was also examined. We report that, in AD subjects, 5-LOX immunoreactivity is elevated relative to controls, and its localization is dependent on the antibody-targeted portion of the 5-LOX amino acid sequence. Carboxy terminus–directed antibodies detected 5-LOX in glial cells and neurons, but less frequently in neurons with dystrophic (NFT) morphology. In contrast, immunoreactivity observed using 5-LOX amino terminus–directed antibodies was virtually absent in neurons and abundant in NFTs, neuritic plaques, and glia. Double-labeling studies showed a close association of 5-LOX–immunoreactive processes and glial cells with Aβ immunoreactive plaques and vasculature and also detected 5-LOX in tau immunoreactive and amyloid containing NFTs. Different immunolabeling patterns with antibodies against carboxy vs amino terminus of 5-LOX may be caused by post-translational modifications of 5-LOX protein in Aβ plaques and NFTs. The relationship between elevated intracellular 5-LOX and hallmark AD pathological lesions provides further evidence that neuroinflammatory pathways contribute to the pathogenesis of AD. (J Histochem Cytochem 56:1065–1073, 2008)     

The Role of the Amyloid Protein Precursor (APP) in Alzheimer's Disease: Does the Normal Function of APP Explain the Topography of Neurodegeneration?

Alzheimer's disease (AD) is the most common form of dementia in the aged population. Early-onset familial AD (FAD) involves mutations in a gene on chromosome 21 encoding the amyloid protein precursor or on chromosomes 14 or 1 encoding genes known as presenilins. All mutations examined have been found to increase the production of amyloidogenic forms of the amyloid protein (A), a 4 kDa peptide derived from APP. Despite the remarkable progress in elucidating the biochemical mechanisms responsible for AD, little is known about the normal function of APP. A model of how APP and A are involved in pathogenesis is presented. This model may explain why certain neuronal populations are selectively vulnerable in AD. It is suggested that those neurons which more readily undergo neuritic sprouting and synaptic remodelling are more vulnerable to A neurotoxicity.