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Browsing by Author "Inestrosa, NC"

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A major portion of synaptic basal lamina acetylcholinesterase is detached by high salt- and heparin-containing buffers from rat diaphragm muscle and Torpedo electric organ
(1998) Casanueva, OI; García-Huidobro, T; Campos, EO; Aldunate, R; Garrido, J; Inestrosa, NC
Collagen-tailed asymmetric acetylcholinesterase (AChE) forms are believed to be anchored to the synaptic basal lamina via electrostatic: interactions involving proteoglycans. However, it was recently found that in avian and rat muscles, high ionic strength or polyanionic buffers could not detach AChE: from cell-surface clusters and that these buffers solubilized intracellular non-junctional asymmetric AChE rather than synaptic: forms of the enzyme. In the present study, asymmetric AChE forms were specifically solubilized by ionic buffers from sg synaptic basal! lamina-enriched fractions, largely devoid of intracellular material, obtained from the electric organ of Torpedo californica and the end plate regions of rat diaphragm muscle, Furthermore, foci of AChE activity were seen to diminish in size, number, and staining intensity when the rat synaptic basal lamina-enriched preparations were treated with the extraction buffers, Pn the case of Torpedo, almost all the AChE activity was removed from the pure basal lamina sheets. We therefore conclude that a major portion of extracellular collagen-tailed AChE is extractable from rat and Torpedo synaptic basal lamina by high ionic strength and heparin buffers,;although some non-extractable AChE activity remains associated with the junctional regions.
Acetylcholinesterase is a senile plaque component that promotes assembly of amyloid beta-peptide into Alzheimer's filaments
(1996) Inestrosa, NC; Alvarez, A; Calderon, F
Acetylcholinesterase promotes the aggregation of amyloid-beta-peptide fragments by forming a complex with the growing fibrils
(1997) Alvarez, A; Opazo, C; Alarcon, R; Garrido, J; Inestrosa, NC
Acetylcholinesterase (AChE), an enzyme involved in the hydrolysis of the neurotransmitter acetylcholine, consistently colocalizes with the amyloid deposits characteristic of Alzheimer's disease and may contribute to the generation of amyloid proteins and/or physically affect fibril assembly. Ln order to identify the structural domains of the amyloid-beta-peptide (A beta) involved in the aggregation induced by AChE, we have studied the effect of this cholinergic enzyme on A beta peptide fragments of different sizes. AChE enhanced the aggregation of the A beta(12-28) and A beta(25-35) peptides but not of the A beta(1-16) fragment. The inductive effect of AChE on the aggregation of A beta(12-28) was abolished by the presence of either A beta(1-16) or A beta(9-21). The effect of the enzyme was also analysed using two different mutant fragments, possessing a low and the other a high capacity for fibrillogenesis. The fragments used were A beta(12-28)(Val18-->Ala) and A beta(12-28)(Glu22-->Gln), respectively. AChE was able to promote the aggregation of these fragments in a very specific way and both mutant peptides were able to form amyloid fibrils, as revealed by negative staining under the electron microscope. Binding assays indicated that AChE was bound to A beta(12-28), as well as to the A beta(1-16) peptide. AChE was seen to form strong complexes with the A beta(12-28) fibrils as such complexes stained positively for both thioflavine-T and AChE activity, were resistant to high ionic strength treatment, and were partially sensitive to detergents, suggesting that hydrophobic interactions may play a role in the stabilization of the AChE-A beta complex. Our results suggest that such amyloid-AChE complexes are formed when AChE interacts with the growing amyloid fibrils and accelerates the assembly of A beta peptides. This is consistent with the fact that AChE is known to be present within A beta deposits including the pre-amyloid diffuse and mature senile plaques found in Alzheimer's brain. (C) 1997 Academic Press Limited.
Acetylcholinesterase, a senile plaque component, affects the fibrillogenesis of amyloid-beta-peptides
(1995) Alvarez, A; Bronfman, F; Perez, CA; Vicente, M; Garrido, J; Inestrosa, NC
Acetylcholinesterase (AChE) colocalizes with amyloid-beta peptide (A beta) deposits present in the brain of Alzheimer's patients. Recent studies showed that A beta(1-40) Can adopt two different conformational states in solution (an amyloidogenic conformer, A beta ac, and a non-amyloidogenic conformer, A beta nac) which have distinct abilities to form amyloid fibrils. We report here that AChE binds A beta nac and accelerates amyloid formation by the same peptide. No such effect was observed with A beta ac, the amyloidogenic conformer, suggesting that AChE acts as a 'pathological chaperone' inducing a conformational transition from A beta nac into A beta ac in vitro.
Acetylcholinesterase-Aβ complexes are more toxic than Aβ fibrils in rat hippocampus -: Effect on rat β-amyloid aggregation, laminin expression, reactive astrocytosis, and neuronal cell loss
(2004) Reyes, AE; Chacón, MA; Dinamarca, MC; Cerpa, W; Morgan, C; Inestrosa, NC
Neuropathological changes generated by human amyloid-beta peptide (Abeta) fibrils and Abeta-acetylcholinesterase (Abeta-AChE) complexes were compared in rat hippocampus in vivo. Results showed that Abeta-AChE complexes trigger a more dramatic response in situ than Abeta fibrils alone as characterized by the following features observed 8 weeks after treatment: 1) amyloid deposits were larger than those produced in the absence of AChE. In fact, AChE strongly stimulates rat Abeta aggregation in vitro as shown by turbidity measurements, Congo Red binding, as well as electron microscopy, suggesting that Abeta-AChE deposits observed in vivo probably recruited endogenous Abeta peptide; 2) the appearance of laminin expressing neurons surrounding Abeta-AChE deposits (such deposits are resistant to disaggregation by laminin in vitro); 3) an extensive astrocytosis revealed by both glial fibrillary acidic protein immunoreactivity and number counting of reactive hypertrophic astrocytes; and 4) a stronger neuronal cell loss in comparison with Abeta-injected animals. We conclude that the hippocampal injection of Abeta-AChE complexes results in the appearance of some features reminiscent of Alzheimer-like lesions in rat brain. Our studies are consistent with the notion that Abeta-AChE complexes are more toxic than Abeta fibrils and that AChE triggered some of the neurodegenerative changes observed in Alzheimer's disease brains.
Amyloid precursor protein fragment and acetylcholinesterase increase with cell confluence and differentiation in a neuronal cell line
(1996) Bronfman, FC; Fernandez, HL; Inestrosa, NC
This study addresses the developmental regulation of amyloid precursor protein (APP) fragments comprising the amyloid-beta peptide (A beta) and the amyloid-promoting factor acetylcholinesterase (AChE) in a mouse neuronal cell line (Neuro-2a). Results indicate that a 35-kDa amyloidogenic fragment of APP and the major molecular forms of AChE (G(1) and G(4)) in Neuro-2a cells significantly increase with increasing levels of cell confluence. The foregoing molecules undergo further increases when neuroblastoma cells differentiate in the presence of dibutyryl cAMP. In contrast, a 17-kDa fragment of APP and butyrylcholinesterase mere not affected by cell confluence or differentiation. These findings are the first to indicate that a selective A beta-containing fragment of APP is subject to developmental regulation. Moreover, our data show that the 35-kDa fragment and AChE forms respond in parallel to the same developmental stimuli, i.e., cell confluence and differentiation. This points to the existence of a functional relationship between both molecules, a notion that is consistent with the potential role that has been ascribed to AChE in both APP processing and the formation of amyloid deposits in Alzheimer's brains. (C) 1996 Academic Press, Inc.
Amyloid-β-peptide reduces copper(II) to copper(I) independent of its aggregation state
(2000) Opazo, C; Ruiz, FH; Inestrosa, NC
Alzheimer's disease (AD) is characterized by the deposition of amyloid beta -peptide (A beta) and neuronal degeneration in brain regions involved in learning and memory. One of the leading etiologic hypotheses regarding AD is the involvement of free radical-mediated oxidative stress in neuronal degeneration. Recent evidence suggests that metals concentrated in amyloid deposits may contribute to the oxidative insults observed in AD-affected brains. We hypothesized that A beta peptide in the presence of copper enhances its neurotoxicity generating free radicals via copper reduction. In the present study, we have examined the effect of the aggregation state of amyloid-beta -peptide on copper reduction. In independent experiments we measured the copper-reducing ability of soluble and fibrillar A beta (1-40) forms by bathocuproine assays. As it was previously observed for the amyloid precursor protein (APP), the A beta peptide showed copper-reducing ability. The capacity of A beta to reduce copper was independent of the aggregation state. Finally, the A beta peptide derived from the human sequence has a greater effect than the A beta peptide derived from the rat sequence, suggesting that histidine 13 may play a role in copper reduction. In agreement with this possibility, the A beta peptide reduces less copper in the presence of exogenous histidine.
At least two receptors of asymmetric acetylcholinesterase are present at the synaptic basal lamina of Torpedo electric organ
(1998) Casanueva, OI; Deprez, P; García-Huidobro, T; Inestrosa, NC
Asymmetric acetylcholinesterase (AChE) is anchored to the basal lamina (BL) of cholinergic synapses via its collagenic tail, yet the complement of matrix receptors involved in its attachment remains unknown. The development of a novel overlay technique has allowed us to identify two Torpedo BL components that bind asymmetric AChE: a polypeptide of similar to 140kDa and a doublet of 195-215kDa. These were found to stain metachromatically with Coomassie blue R-250, mere solubilized by acetic acid, and were sensitive to collagenase treatment. Upon sequence analysis, the 140kDa polypeptide yielded a characteristic collagenous motif. Another AChE-binding BL constituent, identified by overlay, corresponded to a heparan sulfate proteoglycan. Lastly, we established that this proteoglycan, but not the collagenous proteins, interacted with at least one heparin binding domain of the collagenic tail of AChE. Our results indicate that at least two BL receptors are likely to exist for asymmetric AChE in Torpedo electric organ. (C) 1998 Academic Press.
Crosslinking of amyloid-β peptide to brain acetylcholinesterase
(1998) Opazo, C; Inestrosa, NC
Acetylcholinesterase (AChE) is the enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine in the central nervous system. Recently, we have found that AChE promotes the assembly of amyloid-beta peptides (A beta) into Alzheimer fibrils. The action of AChE on the state of aggregation of the A beta peptide supposes a near neighbor relationship between these two molecules. In the present work, we have studied A beta-AChE interactions using the crosslinker reagent disuccinimidyl suberate (DSS), in the presence of [I-125]-A beta peptide The A beta-AChE complexes formed by crosslinking were then analyzed by SDS-PAGE and autoradiography. We observed the formation of [I-125] A beta-labeled complexes of 70, 160, 250, and 300 kDa corresponding to monomers, dimers, tetramers, and oligomers of AChE, respectively crosslinked with the A beta peptide. Our results suggest that AChE and the A beta peptide may be involved in physiologically relevant interactions, related to the pathogenesis of Alzheimer disease (AD).
Cysteine 144 is a key residue in the copper reduction by the β-amyloid precursor protein
(1999) Ruiz, FH; González, Y; Bodini, M; Opazo, C; Inestrosa, NC
The beta-amyloid precursor protein (beta-APP) contains a copper-binding site localized between amino acids 135 and 156 (beta-APP(135-156)). We have employed synthetic beta-APP peptides to characterize their capacities to reduce Cu(II) to Cu(I). Analogues of the wild-type beta-APP(135-156) peptide, containing specific amino acid substitutions, were used to establish which residues are specifically involved in the reduction of copper by beta-APP(135-156). We report here that beta-APP's copper-binding domain reduced Cu(II) to Cu(I). The single-mutant beta-APP(His147-->Ala) and the double-mutant beta-APP(His147-->Ala/His149-->Ala) showed a small decrease in copper reduction in relation to the wild-type peptide and the beta-APP(Cys144-->Ser) mutation abolished it, suggesting that Cys144 is the key amino acid in the oxidoreduction reaction. Our results confirm that soluble beta-APP is involved in the reduction of Cu(II) to Cu(I).
Ethanol specifically decreases peroxisome proliferator activated receptor β in B12 oligodendrocyte-like cells
(2003) Leisewitz, AV; Jung, JE; Perez-Alzola, P; Fuenzalida, KM; Roth, A; Inestrosa, NC; Bronfman, M
Peroxisome proliferator activated receptors (PPARs) are nuclear receptors that control important genes involved in lipid metabolism. Their role in nerve cells is uncertain, although anomalous myelination of the corpus callosum has been described in the PPARbeta-null mouse, and abnormalities of this tissue have been documented in fetal alcohol syndrome in humans. We report here that ethanol treatment of B12 oligodendrocyte-like cells induces a concentration- and time-dependent decrease in the mRNA and protein levels of PPARbeta, with no effect on PPARalpha or PPARgamma. The effect on PPARbeta is seen as an increase in mRNA degradation, as assessed by run-off assays, due to a significant decrease in PPARbeta mRNA half-life, with no observed changes in intracellular localization. Our results suggest a possible link between PPARbeta function and ethanol-induced abnormal myelination in oligodendrocytes.
Expression of α₂-macroglobulin receptor/low density lipoprotein receptor-related protein (LRP) in rat microglial cells
(2000) Marzolo, MP; von Bernhardi, R; Bu, GJ; Inestrosa, NC
Low density lipoprotein receptor-related protein (LRP) participates in the uptake and degradation of several ligands implicated in neuronal pathophysiology including apolipoprotein E (apoE), activated alpha(2)-macroglobulin (alpha(2)M*) and beta-amyloid precursor protein (APP). The receptor is expressed in a variety of tissues. in the brain LRP is present in pyramidal-type neurons in cortical and hippocampal regions and in astrocytes that are activated as a result of injury or neoplasmic transformation. As LRP is expressed in the monocyte/macrophage cell system, we were interested in examining whether LRP is expressed in microglia. We isolated glial cells from the brain of neonatal rats and LRP was immunodetected both in microglial cells and in astrocytes expressing glial fibrillar acidic protein (GFAP). Microglial cells were able to bind and internalize LRP-specific ligand, alpha(2)M*. The internalization was inhibitable by RAP, with a Kd of 1.7 nM. The expression of LRP was upregulated by dexamethasone, and down-regulated by lipopolysaccharide (LPS), gamma interferon (IFN-gamma) or a combination of both. LRP was less sensitive to dexamethasone in activated astrocytes than in microglia. We provided the first analysis of LRP expression and regulation in microglia. Our results open the possibility that microglial cells could be related to the participation of LRP and its ligands in different pathophysiological states in brain. (C) 2000 Wiley-Liss, Inc.
Extracellular matrix regulates the amount of the beta-amyloid precursor protein and its amyloidogenic fragments
(1996) Bronfman, FC; Soto, C; Tapia, L; Tapia, V; Inestrosa, NC
We have studied the influence of the extracellular matrix (ECM) on the amount of beta-amyloid precursor protein (APP) and C-terminal amyloid-bearing fragments in 3T3 fibroblasts. After incubation with ECM components, the cellular APP content of 3T3 cells changed. Besides, different substrata including collagen, fibronectin, laminin, vitronectin, and heparin, determined changes in the amount of a C-terminal 22 kDa-fragment. The regulation of amyloidogenic fragments by the ECM was transient; in fact, when 3T3 cells were plated on tissue culture dishes coated with collagen or vitronectin, maximal levels of the 22 kDa fragment were observed 12 h after plating; in the presence of fibronectin, the maximum level of the amyloidogenic fragment was obtained 36 h after plating. These results indicate that the ECM modulates in a transient way the generation of APP-derived polypeptides containing the amyloid-beta-peptide (A beta). The ECM does not have a generalized effect on 3T3 fibroblasts, because no significant differences in cell attachment, growth rate, whole-cell polypeptide pattern, beta(1) integrin and a-tubulin levels were observed on cells grown on various matrix proteins. Laminin, collagen, and heparin also influence the level of an amyloidogenic fragment of 35 kDa in Neuro 2A neuronal cells, without a significant change in the neuronal marker acetylcholinesterase. In this case, however, a long-lasting response to ECM molecules was observed. These observations provide evidence that ECM molecules influence APP biogenesis, including the generation of amyloidogenic fragments containing the A beta peptide. Our studies might prove significant to understand the localized increment of beta-amyloid deposition in selected areas of the brain of Alzheimer's patients. (C) 1996 Wiley-Liss, Inc.
Human-like rodent amyloid-β-peptide determines Alzheimer pathology in aged wild-type Octodon degu
(2005) Inestrosa, NC; Reyes, AE; Chacón, MA; Cerpa, W; Villalón, A; Montiel, J; Merabachvili, G; Aldunate, R; Bozinovic, F; Aboitiz, F
It is generally accepted that human Alzheimer's disease (AD) neuropathology markers are completely absent in rodent brains. We report here that an aged wild-type South American rodent, Octodon degu, expresses neuronal beta-amyloid precursor protein (beta-APP695) displaying both intracellular and extracellular deposits of amyloid-beta-peptide (A beta), intracellular accumulations of tau-protein and ubiquitin, a strong astrocytic response and acetylcholinesterase (AChE)-rich pyramidal neurons. The high amino acid homology (97.5%) between deguA beta and humanA beta sequences is probably a major factor in the appearance of AD markers in this aged rodent. Our results indicate that aged 0. degu constitutes the first wild-type rodent model for neurodegenerative processes associated to AD. (c) 2004 Elsevier Inc. All rights reserved.
Interaction of the collagen-like tail of asymmetric acetylcholinesterase with heparin depends on triple-helical conformation, sequence and stability
(2000) Deprez, P; Doss-Pepe, E; Brodsky, B; Inestrosa, NC
The collagen-like tail of asymmetric acetylcholinesterase (AChE) contains two heparin-binding domains (HBDs) that interact with heparan sulphate proteoglycans, determining the anchoring of the enzyme at the basal lamina and its specific Localization at the neuromuscular junction. Both HBDs are characterized by a cluster of basic residues containing a core with the BBXB consensus sequence (where B represents a basic residue and X a non-basic residue). To study the interaction of such HBDs with heparin we have used synthetic peptides to model the N-terminal and C-terminal sites. CD spectroscopy showed that all peptides are triple-helical at low temperatures, and undergo trimer-to-monomer transitions. Displacement assays of asymmetric AChE bound to heparin were performed using the peptides in both monomeric and triple-helical states. In the monomeric con- formation, all the peptides were able to displace low levels of AChE depending on the basic charge content. In the triplehelical conformation, peptides containing the consensus sequence showed a large increase in the ability to displace bound AChE. Results suggest that the specific binding of the collagen-like-tail peptides to heparin depends both on the presence of the core sequence and on the triple-helical conformation. Moreover, BBXB-containing peptides that are less stable are more effective in displacing AChE, suggesting that the interaction region needs a significant amount of structural flexibility to better accommodate the ligand.
Laminin affects polymerization, depolymerization and neurotoxicity of Aβ peptide
(2002) Morgan, C; Bugueño, MP; Garrido, J; Inestrosa, NC
Amyloid deposition in Alzheimer fibrils forms neurotoxic senile plaques in a process that may be modulated by associated proteins. In this work we demonstrate the ability of laminin-1 and laminin-2 to inhibit fibril formation and toxicity on cultured rat hippocampal neurons. We confirm that the laminin-1-derived peptide YFQRYL1 inhibits efficiently both fibril formation and neurotoxicity and show that the IKVAV peptide inhibits amyloid neurotoxicity despite its slight inhibition of fibril formation. On other hand, laminin-1 induces disaggregation of preformed fibrils in vitro, characterized as a progressive disassembly of fibrils into protofibrils and further clearance of these latter species, leading to a continual inhibition of amyloid neurotoxicity. (C) 2002 Published by Elsevier Science Inc.
Laminin blocks the assembly of wild type Aβ and the Dutch variant peptide into Alzheimer's fibrils
(1998) Bronfman, FC; Alvarez, A; Morgan, C; Inestrosa, NC
Amyloid fibril formation is believed to be a nucleation-dependent polymerization process which may be influenced by various other factors with important consequences for the development, prevention or treatment of amyloidosis. We have previously shown that laminin inhibits A beta peptide fibril formation in vitro. Here we present a kinetic study that indicates laminin to be a potent anti-amyloidosis factor, as it not only inhibited alpha beta(1-40) fibril aggregation, but also inhibited the aggregation of the Dutch A beta(1-40) variant, a peptide with a higher capacity to aggregate than the wild-type A beta(1-40). The inhibitory effect of laminin on amyloid fibril formation was not overcome by the addition of pre-formed A beta fibrils, suggesting that laminin inhibits the fibril elongation process. At the present time, however, we cannot rule out the possibility that laminin also affects the initial nucleation process of A beta fibril formation. On other hand, laminin was not able to counteract the amyloid fibril formation promoted by acetylcholinesterase (AChE), another component of the amyloid deposits found in AD brains. The effect of laminin may bet important as an inhibitor of A beta amyloidogenesis in vivo, specifically at the level of cerebral blood vessels.
Laminin inhibits amyloid-beta-peptide fibrillation
(1996) Bronfman, FC; Garrido, J; Alvarez, A; Morgan, C; Inestrosa, NC
Laminin, an important extracellular matrix component is induced by brain injury and colocalizes with amyloid-beta-peptide (A beta) deposits in Alzheimer brains. We report here that laminin inhibits amyloid fibril formation as determined by thioflavin T fluorescence spectroscopy and electron microscopic examination. The inhibition of amyloid formation by laminin was concentration dependent and was observed at a laminin concentration of 300 nM, corresponding to a laminin/A beta protein molar ratio of 1:800. The potential effect of laminin, may prove important to inhibit AP fibrillogenesis in vivo, specifically at the level of cerebral blood vessels.
Molecular modeling of the amyloid-β-peptide using the homology to a fragment of triosephosphate isomerase that forms amyloid in vitro
(1999) Contreras, CF; Canales, MA; Alvarez, A; De Ferrari, GV; Inestrosa, NC
The main component of the amyloid senile plaques found in Alzheimer's brain is the amyloid-beta-peptide (A beta), a proteolytic product of a membrane precursor protein. Previous structural studies have found different conformations for the A beta peptide depending on the solvent and pH used. In general, they have suggested an alpha-helix conformation at the N-terminal domain and a beta-sheet conformation for the C-terminal domain. The structure of the complete A beta peptide (residues 1-40) solved by NMR has revealed that only helical structure is present in A beta. However, this result cannot explain the large beta-sheet A beta aggregates known to form amyloid under physiological conditions. Therefore, we investigated the structure of A beta by molecular modeling based on extensive homology using the Smith and Waterman algorithm implemented in the MPsrch program (Blitz server). The results showed a mean value of 23 % identity with selected sequences. Since these values do not allow a clear homology to be established with a reference structure in order to perform molecular modeling studies, we searched for detailed homology, A 28% identity with an alpha/beta segment of a triosephosphate isomerase (TIM) from Culex tarralis with an unsolved three-dimensional structure was obtained. Then, multiple sequence alignment was performed considering A beta, TIM from C.tarralis and another five TIM sequences with known three-dimensional structures. We found a TIM segment with secondary structure elements in agreement with previous experimental data for A beta. Moreover, when a synthetic peptide from this TIM segment was studied in vitro, it was able to aggregate and to form amyloid fibrils, as established by Congo red binding and electron microscopy, The A beta model obtained was optimized by molecular dynamics considering ionizable side chains in order to simulate A beta in a neutral pH environment. We report here the structural implications of this study.
Neurotoxicity of acetylcholinesterase amyloid β-peptide aggregates is dependent on the type of Aβ peptide and the AChE concentration present in the complexes
(1999) Muñoz, FJ; Inestrosa, NC
Alzheimer's disease (AD) is a neurodegenerative disorder whose hallmark is the presence of senile plaques and neurofibrillary tangles, Senile plaques are mainly composed of amyloid beta-peptide (A beta) fibrils and several proteins including acetylcholinesterase (AChE), AChE has been previously shown to stimulate the aggregation of A beta(1-40) into amyloid fibrils, In the present work, the neurotoxicity of different amyloid aggregates formed in the absence or presence of AChE was evaluated in rat pheochromocytoma PC12 cells. Stable AChE-A beta complexes were found to be more toxic than those formed without the enzyme, for A beta(1-40) and A beta(1-42), but not for amyloid fibrils formed with A beta(Val18-->Ala), a synthetic variant of the A beta(1-40) peptide. Of all the AChE-A beta complexes tested the one containing the A beta(1-40) peptide was the most toxic, When increasing concentrations of AChE were used to aggregate the A beta(1-40) peptide, the neurotoxicity of the complexes increased as a function of the amount of enzyme bound to each complex. Our results shea that AChE-A beta(1-40) aggregates are more toxic than those of AChE-A beta(1-42) and that the neurotoxicity depends on the amount of AChE bound to the complexes, suggesting that AChE may play a key role in the neurodegeneration observed in Alzheimer brain. (C) 1999 Federation of European Biochemical Societies.

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