Cross-Talk Between Oxidative Stress and Modifications of Cholinergic and Glutaminergic Receptors in the Pathogenesis of Alzheimer's Disease1
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Acta Pharmacol Sin 2008 Jul; 29 (7): 773–780 Invited review Cross-talk between oxidative stress and modifications of cholinergic and glutaminergic receptors in the pathogenesis of Alzheimer's disease1 Zhi-zhong GUAN2 Department of Molecular Biology and Pathology, Guiyang Medical University, Guiyang 550004, China Key words Abstract Alzheimer's disease; oxidative stress; nicotinic Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and its receptor; muscarinic receptor; N-methyl-D- pathogenesis is likely to be associated with multiple etiologies and mechanisms in aspartate receptor which oxidative stress and deficits of neurotransmitter receptors may play impor- 1This work was supported financially by grants tant roles. It has been indicated that a high level of free radicals can influence the from the Foundation of Ministry of Science expressions of nicotinic receptors (nAChRs), muscarinic receptors (mAChRs), and and Technology of China (No 2004DFB02800 and 2006DFA33530), the Chinese National N-methyl-D-aspartate (NMDA) receptors, exhibiting disturbances of cellular mem- Natural Science Foundation (No 30460045), brane by lipid peroxidation, damages of the protein receptors by protein oxidation, and the Foundation of Guizhou Province of and possible modified gene expressions of these receptors by DNA oxidation. China (No [2006] 400107, [2006] 52, and [2006] 6015). nAChRs have shown an antioxidative effect by a direct or an indirect pathway; 2Correspondence to Prof Zhi-zhong GUAN. mAChR stimulation may generate reactive oxygen species, which might be a physi- Phn 86-851-690-9566. ological compensative reaction, or improve oxidative stress; and high stimulation E-mail [email protected] to NMDA receptors can increase the sensitivity of oxidative stress of neurons. Received 2008-04-06 This review may provide complemental information for understanding the correla- Accepted 2008-05-05 tion between oxidative stress and changed cholinergic and glutaminergic recep- tors in AD processing, and for revealing the underlying molecular mechanisms of doi: 10.1111/j.1745-7254.2008.00819.x these factors in the multiple etiologies and pathophysiology of the disorder. Introduction ways of neuronal damage, including genetic deficit, oxida- tive stress, impaired neurotransmitter receptors, and other Alzheimer’s disease (AD) is the most common neuro- biological or biochemical abnormalities (Figure 1). Since the degenerative disorder of the elderly. The disease occurs both pathogenesis of AD remains elusive, there is no efficient in sporadic and hereditary forms, and the main clinical fea- cure of the disorder, and targeting the disruption of neu- tures of this disease are progressive memory loss, decline in rotransmission is the most viable therapeutic strategy at language skills, and other cognitive impairments[1]. The major present[4]. pathological hallmarks in AD are senile plaques (SP) and neu- rofibrillary tangles (NFT), which have for the most part been Oxidative stress in AD regarded as central mediators of neuronal cell death leading to cognitive decline and eventual demise[2,3]. The core of SP is Oxidative stress, defined as a disturbance in the balance abundantly deposited with β-amyloid peptides (Aβ), a 39– between the production of free radicals and antioxidative 43 amino acid peptide, which is the result of proteolytic cleav- defense, may play an important role in several pathological age of the transmembrane amyloid precursor protein (APP). conditions of the central nervous system (CNS)[5,6]. There is The NFT contain paired helical filaments that are mostly com- a great deal of evidence to suggest that the damage induced posed of a hyperphosphorylated form of the microtubule-as- by free radicals may be an important pathogenesis in AD[7]. sociated tau protein. Free radicals, such as superoxide, hydroxyl ions, and nitric Although the initiating causes leading to AD are oxide, cause cell injury by damaging lipids, protein, and DNA unknown, it is clear that its pathophysiology is complex and when they are generated in excess or antioxidative defense most likely involves multiple distinct and overlapping path- is impaired[8]. The brain is more vulnerable to oxyradical- ©2008 CPS and SIMM 773 Guan ZZ Acta Pharmacologica Sinica ISSN 1671-4083 Figure 1. Etiology and pathogenesis of AD. Arrow with double directions means both agents can be initiating reason or secondary result. mediated injury because its cellular membranes are preferen- els of the disease have shed light on the central issue of tially enriched in oxyradical-sensitive polyunsaturated fatty whether oxidative stress is a result of the pathology of AD acids that are the substrates of lipid peroxidation, and dam- or whether it is an initiator of pathological damage. From aged adult neurons cannot be replaced. our studies relating to oxidative stress in AD, we have Multiple lines of evidence link oxidative stress and AD. In shown decreased cellular membrane phospholipids and brain tissues from AD, carbonyls derived from protein oxida- polyunsaturated fatty acids in the AD brain, in which these tion were increased in the neuronal cytoplasm and nuclei of specific lipid modifications strongly support the involve- neurons and glial cells[9]. Moreover, NFT were strongly la- ment of free radicals in the pathogenesis of AD[16]. A closed beled by carbonyls. Transgenic animals with Aβ overexpression correlation has been found between the high level of lipid show the same type of oxidative damage found in AD, and peroxidation and the decreased number of nicotinic recep- this damage directly correlates with the presence of Aβ de- tors in the AD brain[17]. We have suggested that oxidative posits[10]. To diagnose AD in clinical examinations, oxidative stress is an early event in AD and is likely to play a more stress markers, such as 3-nitrotyrosine, 8-hydroxy-2'- active role in the pathogenesis than previously hypoth- deoxyguanosine, and isoprostanes, are found to be increased esized[18]. The mechanisms of oxidative stress in AD are in cerebrospinal fluid in AD patients[11]. Interestingly, the shown in Figure 2. elevation of lipid peroxidation in transgenic mice with APP Aggregated Aβ is toxic in a variety of neuronal cell mutations has been observed to precede the surge in the Aβ preparations, and the overexpression of Aβ in transgenic level and amyloid plaque formation[12,13]. mice leads to increased neuronal oxidative stress. Reduced glucose metabolism and mitochondrial abnor- Interestingly, recent evidence, however, has revealed that malities are associated with AD, as mitochondrial abnor- Aβ and NTF might have a compensatory response induced malities are considered to be the source of oxidative stress by reactive oxygen species (ROS) and have neurotrophic in AD[14]. Mitochondrial abnormalities have been associ- and potentially cytoprotective properties[19]. ated with deficiencies in enzyme activities, specifically the α-keto-glutarate dehydrogenase complex, pyruvate dehy- Changed cholinergic and glutaminergic drogenase complex, and cytochrome oxidase in AD neurons. receptors in AD Oxidative phosphorylation produces superoxide radicals There is a great deal of evidence that suggests that in the as a byproduct associated with electron transport. Height- AD brain, a number of neurotransmitter receptor systems ened superoxide radical formation in AD also correlates are defective. Such abnormalities include cholinergic-, with heightened superoxide dismutase levels that may al- glutaminergic-, dopaminergic-, and γ-amino butyric acid-re- low the release of H2O2 from the mitochondria to the cyto- ceptor (GABA) systems. Of all the neurotransmitter sys- [15] plasm . tems studied, cholinergic and glutaminergic receptors are Recent studies of living patients and transgenic mod- 774 Http://www.chinaphar.com Guan ZZ Figure 2. Mechanism of oxidative stress in AD. Arrow with double directions means both agents can be initiating reason or secondary result. more noticeably involved in the pathogenesis of AD. model provoked interest in developing therapeutic agonists for specific nAChR subtypes. In a recent study, we found Neuronal nicotinic acetylcholine receptors in that suppressed gene expression of nAChRs resulted from [25] AD treatment by nanomolar Aβ25–35 and Aβ40 in PC12 cells . In cholinergic transmission, neuronal nicotinic acetyl- The α7 nAChR is of importance in an AD study due to its [26] choline receptors (nAChRs) have been extensively investi- neuroprotective function . The α7 nAChR is highly ex- gated during the progress of AD. The nAChRs belong to a pressed on neurons of the hippocampus and cholinergic pro- gene super family of homologous receptors, including jection neurons from the basal forebrain. A number of recent nicotinic, GABA, glycine, serotonin, and glutamate recep- studies have convincingly demonstrated an interaction be- tors[20]. The nAChRs in the brain are composed of 2 types of tween the α7 nAChR and Aβ in vitro and on neurons. For subunits, α and β. The gene family for neuronal nAChRs instance, it was shown that Aβ1–42 co-immunoprecipitates contains at least 9 α subunits (α2–α10) and 3 β subunits with the α7 nAChR in the samples from a postmortem AD [27] (β2–β4). Like the muscle type of nAChRs, the agonist rec- hippocampus, and Aβ can activate α7 nAChR . A recent ognition site of the neuronal nAChRs is on the interface study has shown a selective increased α7 nAChR in APPSWE between the α and β subunits. The expression of combina- transgenic mice,