Cellular Expression of α7 Nicotinic Acetylcholine Receptor Protein in the Temporal Cortex in Alzheimer's and Parkinson's Disease— A Stereological Approach

Banerjee, Carolin; Nyengaard, Jens Randel; Wevers, Andrea; Vos, Rob A. I. de; Steur, Ernst N.H. Jansen; Lindstrom, Jon; Pilz, Kirsten; Nowacki, Sonja; Bloch, Wilhelm; Schröder, Hannsjörg

doi:10.1006/nbdi.2000.0317

Cited by 86 publications

(35 citation statements)

References 16 publications

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“…Proteins from the soluble fraction (see above) were loaded directly onto ELISA plates, and formic acid fractions were diluted 1:20 in neutralization buffer (1 M Tris base͞0.5 M NaH 2 PO dibasic) before loading. Maxisorp immunoplates (Nalge Nunc) were coated with monoclonal antibody 20.1, a specific antibody against A␤ [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16] (from William E. Van Nostrand, Stony Brook University, Stony Brook, NY) in coating buffer (0.1 M NaCO 3, pH 9.6), and blocked with 3% BSA. Synthetic A␤ standards (Bachem) were defibrillated by dissolving in hexafluoroisopropanol (HFIP) at 1 mg͞ml, and the HFIP evaporated with a stream of N 2 .…”

Section: Methodsmentioning

confidence: 99%

“…In the human AD brain, ␣7nAChRs are also diminished (8,9,30); thus, the 3xTg-AD mice mimic another important molecular phenotypic feature of AD neuropathology. In the transgenic brain, we find that the loss of ␣7nAChRs is preceded by intracellular A␤ accumulation and is restricted to brain regions that develop A␤ pathology, particularly the hippocampus and the cortex.…”

Section: Figmentioning

confidence: 99%

“…Several studies have shown that nAChRs are selectively reduced in the AD brain, particularly in regions harboring plaques and neurofibrillary tangles, suggesting a potential relationship between nicotinic receptors and AD neuropathology (5,(7)(8)(9). Notably, chronic nicotine treatment has also been shown to reduce the plaque burden in amyloid-␤ precursor protein (APP) transgenic mice, although the steady-state levels of soluble A␤ and A␤ remained unaltered (10,11).…”

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confidence: 99%

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Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Oddo

Caccamo

Green

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

189

130

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The association between nicotinic acetylcholine receptor (nAChR) dysfunction and cognitive decline in Alzheimer's disease (AD) has been widely exploited for its therapeutic potential. The effects of chronic nicotine exposure on A␤ accumulation have been studied in both humans and animal models, but its therapeutic efficacy for AD neuropathology is still unresolved. To date, no in vivo studies have addressed the consequences of activating nAChRs on tau pathology. To determine the effects of chronic nicotine administration on A␤ and tau pathology, we chronically administrated nicotine to a transgenic model of AD (3xTg-AD) in their drinking water. Here, we show that chronic nicotine intake causes an up-regulation of nicotinic receptors, which correlated with a marked increase in the aggregation and phosphorylation state of tau. These data show that nicotine exacerbates tau pathology in vivo. The increase in tau phosphorylation appears to be due to the activation of p38-mitogen-activated protein kinase, which is known to phosphorylate tau in vivo and in vitro. We also show that the 3xTg-AD mice have an age-dependent reduction of ␣7nAChRs compared with age-matched nontransgenic mice in specific brain regions. The reduction of ␣7nAChRs is first apparent at 6 months of age and is restricted to brain regions that show intraneuronal A␤42 accumulation. Finally, this study highlights the importance of testing compounds designed to ameliorate AD pathology in a model with both neuropathological lesions because of the differential effects it can have on either A␤ or tau.T he loss of cholinergic neurons is a critical event in the pathogenesis of Alzheimer's disease (AD) (1, 2). Acetylcholine (ACh) is a key neuromodulator in the synaptic mechanisms involved with learning and memory (3) and acts through two major receptor subtypes: nicotinic acetylcholine receptors (nAChRs) and muscarinic acetylcholine receptors (mAChRs). Whereas mAChRs are metabotropic, nAChRs are ligand-gated ion channels formed by a combination of five subunits (␣, ␤, ␥, ␦, and ), each encoded by a member of a gene superfamily (4). The ␣7 and ␣4␤2 are two of the major nicotinic receptors subtypes present in the brain (4, 5). For the past several years, a mainstay of AD therapy has been aimed at inhibiting acetylcholinesterase, the enzyme responsible for degrading ACh in the synaptic cleft, and thereby increasing ACh levels in the brain (6). These compounds slow the phenotypical memory impairments; however, their effectiveness is diminished over time.The AD brain is characterized by two pathological hallmarks: amyloid plaques, which are mainly composed of the A␤ peptide, and neurofibrillary tangles (NFTs), which consist of hyperphosphorylated tau protein. Several studies have shown that nAChRs are selectively reduced in the AD brain, particularly in regions harboring plaques and neurofibrillary tangles, suggesting a potential relationship between nicotinic receptors and AD neuropathology (5, 7-9). Notably, chronic nicotine treatment has also been shown to redu...

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Section: Methodsmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Oddo

Caccamo

Green

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

189

130

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“…It can be hypothesized that inhibition of ␣7 nAChRs by increased levels of KYNA contributes to the cognitive deficits in patients with AD and DS (see Court et al, 1999). It is also conceivable that reduced levels of KYNA in the brain of patients with PD (Ogawa et al, 1992) contribute to decreased ␣4␤2 nAChR expression, which correlates well with the severity of motor dysfunctions in this disease (Banerjee et al, 2000;Perry et al, 2000). Moreover, the lower incidence of PD among cigarette smokers compared to nonsmokers (Fratiglioni and Wang, 2000) could be explained at least in part by nicotine-induced increased levels of KYNA leading to higher expression of ␣4␤2 nAChRs.…”

Section: Kynurenic Acid (Kyna)mentioning

confidence: 99%

Unconventional ligands and modulators of nicotinic receptors

et al. 2002

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ABSTRACT:Evidence gathered from epidemiologic and behavioral studies have indicated that neuronal nicotinic receptors (nAChRs) are intimately involved in the pathogenesis of a number of neurologic disorders, including Alzheimer's disease, Parkinson's disease, and schizophrenia. In the mammalian brain, neuronal nAChRs, in addition to mediating fast synaptic transmission, modulate fast synaptic transmission mediated by the major excitatory and inhibitory neurotransmitters glutamate and GABA, respectively. Of major interest, however, is the fact that the activity of the different subtypes of neuronal nAChR is also subject to modulation by substances of endogenous origin such as choline, the tryptophan metabolite kynurenic acid, neurosteroids, and ␤-amyloid peptides and by exogenous substances, including the so-called nicotinic allosteric potentiating ligands, of which galantamine is the prototype, and psychotomimetic drugs such as phencyclidine and ketamine. The present article reviews and discusses the effects of unconventional ligands on nAChR activity and briefly describes the potential benefits of using some of these compounds in the treatment of neuropathologic conditions in which nAChR function/expression is known to be altered.

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“…In heterologous expression systems, including the Xenopus oocyte, the ␣7-subunit forms functional homomeric AcChoRs that show an unusually fast desensitization and high permeability to Ca 2ϩ (4)(5)(6)(7)(8). Even though it is not yet clear to what extent the ␣7 homomeric composition also applies in vivo, we and others have found it of interest to investigate the functional profile of homomeric ␣7 receptors, because they may be involved in the pathogenesis of many neurological disorders (9)(10)(11)(12)(13)(14)(15)(16).…”

mentioning

confidence: 99%

Some properties of human neuronal α7 nicotinic acetylcholine receptors fused to the green fluorescent protein

Palma

Mileo²,

Martı́nez-Torres

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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The functional properties and cellular localization of the human neuronal ␣7 nicotinic acetylcholine (AcCho) receptor (␣7 AcChoR) and its L248T mutated (mut) form were investigated by expressing them alone or as gene fusions with the enhanced version of the green fluorescent protein (GFP). Xenopus oocytes injected with wild-type (wt), mut␣7, or the chimeric subunit cDNAs expressed receptors that gated membrane currents when exposed to AcCho. As already known, AcCho currents generated by wt␣7 receptors decay much faster than those elicited by the mut␣7 receptors. Unexpectedly, the fusion of GFP to the wt and mutated ␣7 receptors led to opposite results: the AcCho-current decay of the wt receptors became slower, whereas that of the mutated receptors was accelerated. Furthermore, repetitive applications of AcCho led to a considerable ''run-down'' of the AcCho currents generated by mut␣7-GFP receptors, whereas those of the wt␣7-GFP receptors remained stable or increased in amplitude. The AcCho-current run-down of mut␣7-GFP oocytes was accompanied by a marked decrease of ␣-bungarotoxin binding activity. Fluorescence, caused by the chimeric receptors expressed, was seen over the whole oocyte surface but was more intense and abundant in the animal hemisphere, whereas it was much weaker in the vegetal hemisphere. We conclude that fusion of GFP to wt␣7 and mut␣7 receptors provides powerful tools to study the distribution and function of ␣7 receptors. We also conclude that fused genes do not necessarily recapitulate all of the properties of the original receptors. This fact must be borne close in mind whenever reporter genes are attached to proteins. F luorescent tagging of cellular proteins is a very useful, and aesthetically pleasant, method for studying the intracellular traffic and distribution of many proteins, including neurotransmitter receptors. It is commonly assumed that the tagged proteins function in exactly the same way as the native nontagged proteins. To determine whether that is the case for neurotransmitter receptors, we chose to study two human receptors that are homomeric: the GABA1 (1) and now the ␣7 nicotinic receptors.The neuronal ␣7 nicotinic acetylcholine receptor (␣7-AcChoR) is widely expressed in the central nervous system and, being located mainly at nerve terminals, it is believed to be involved in regulating the neurotransmitter release that mediates fast cholinergic neurotransmission (2, 3). In heterologous expression systems, including the Xenopus oocyte, the ␣7-subunit forms functional homomeric AcChoRs that show an unusually fast desensitization and high permeability to Ca 2ϩ (4-8). Even though it is not yet clear to what extent the ␣7 homomeric composition also applies in vivo, we and others have found it of interest to investigate the functional profile of homomeric ␣7 receptors, because they may be involved in the pathogenesis of many neurological disorders (9-16).For this study we constructed a chimera in which the enhanced form of the green fluorescent protein (GFP) was fused to the C...

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Cellular Expression of α7 Nicotinic Acetylcholine Receptor Protein in the Temporal Cortex in Alzheimer's and Parkinson's Disease— A Stereological Approach

Cited by 86 publications

References 16 publications

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Chronic nicotine administration exacerbates tau pathology in a transgenic model of Alzheimer's disease

Unconventional ligands and modulators of nicotinic receptors

Some properties of human neuronal α7 nicotinic acetylcholine receptors fused to the green fluorescent protein

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