Expression of nicotinic acetylcholine receptors in Alzheimer’s disease: postmortem investigations and experimental approaches

Wevers, Andrea; Burghaus, Lothar; Moser, Natasha; Witter, Brigitte; Steinlein, Ortrud K.; Schütz, Ulrich; Achnitz, Bernd; Krempel, Udo; Nowacki, Sonja; Pilz, Kirsten; Stoodt, Jens; Lindstrom, Jon; Vos, Rob A. I. de; Steur, Ernst N.H. Jansen; Schröder, Hannsjörg

doi:10.1016/s0166-4328(00)00215-1

Cited by 72 publications

(66 citation statements)

References 33 publications

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“…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%

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.

191

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: Figmentioning

confidence: 99%

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.

191

130

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“…A major neuropathological feature of most patients with clinical AD is the loss of cholinergic neurons in the basal forebrain (Schliebs and Arendt 2006;Geula et al 2008), and several groups have reported a selective loss of different subtypes of acetylcholine receptors (AChRs) in AD brains (Wevers et al 2000;Teaktong et al 2004). By modulating activity-dependent events, AChRs participate in fundamental aspects of synaptic plasticity (Albuquerque et al 1997;Ge and Dani 2005).…”

Section: Cholinergic Mechanismsmentioning

confidence: 99%

Alzheimer’s Disease Amyloid β-Protein and Synaptic Function

et al. 2009

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Alzheimer's disease (AD) is characterized neuropathologically by the deposition of different forms of amyloid beta-protein (A beta) including variable amounts of soluble species that correlate with severity of dementia. The extent of synaptic loss in the brain provides the best morphological correlate of cognitive impairment in clinical AD. Animal research on the pathophysiology of AD has therefore focussed on how soluble A beta disrupts synaptic mechanisms in vulnerable brain regions such as the hippocampus. Synaptic plasticity in the form of persistent activity-dependent increases or decreases in synaptic strength provide a neurophysiological substrate for hippocampal-dependent learning and memory. Acute treatment with human-derived or chemically prepared soluble A beta that contains certain oligomeric assemblies, potently and selectively disrupts synaptic plasticity causing inhibition of long-term potentiation (LTP) and enhancement of long-term depression (LTD) of glutamatergic transmission. Over time these and related actions of A beta have been implicated in reducing synaptic integrity. This review addresses the involvement of neurotransmitter intercellular signaling in mediating or modulating the synaptic plasticity disrupting actions of soluble A beta, with particular emphasis on the different roles of glutamatergic and cholinergic mechanisms. There is growing evidence to support the view that NMDA and possibly nicotinic receptors are critically involved in mediating the disruptive effect of A beta and that targeting muscarinic receptors can indirectly modulate A beta's actions. Such studies should help inform ongoing and future clinical trials of drugs acting through the glutamatergic and cholinergic systems.

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“…These deficits appear early in the disease and correlate with the progressive loss of cognitive abilities (Nordberg, 1994(Nordberg, , 2001Whitehouse and Kalaria, 1995). In AD patients, the alpha7nAChRs protein levels are reduced in the cortex and hippocampus Guan et al, 2000;Martin-Ruiz et al, 1999;Nordberg, 2001;Wevers et al, 2000). Although the protein loss is evident in AD, reductions in gene expression at the transcriptional level are less clear.…”

Section: Cholinergic Implications In Neurodegenerative Disorders: Fromentioning

confidence: 99%

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

Conejero-Goldberg

Davies

Ulloa

2008

Neuroscience & Biobehavioral Reviews

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Alzheimer's disease (AD) is the leading cause of dementia affecting over 25 million people worldwide. Classical studies focused on the description and characterization of the pathological hallmarks found in AD patients including the neurofibrillary tangles and the amyloid plaques. Current strategies focus on the etiology of these hallmarks and the different mechanisms contributing to neurodegeneration. Among them, recent studies reveal the close interplay between the immunological and the neurodegenerative processes. This article examines the implications of the alpha7 nicotinic acetylcholine receptor (alpha7nAChR) as a critical link between inflammation and neurodegeneration in AD. Alpha7nAChRs are not only expressed in neurons but also in Glia cells where they can modulate the immunological responses contributing to AD. Successful therapeutic strategies against AD should consider the connections between inflammation and neurodegeneration. Among them, alpha7nAChR may represent a pharmacological target to control these two mechanisms during the pathogenesis of neurodegenerative and behavioral disorders.

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Expression of nicotinic acetylcholine receptors in Alzheimer’s disease: postmortem investigations and experimental approaches

Cited by 72 publications

References 33 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

Alzheimer’s Disease Amyloid β-Protein and Synaptic Function

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

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