Browsing by Author "Chacón, MA"

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    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.
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    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.
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    The N-terminal copper-binding domain of the amyloid precursor protein protects against Cu2+ neurotoxicity in vivo
    (2004) Cerpa, WF; Barría, MI; Chacón, MA; Suazo, M; González, M; Opazo, C; Bush, AI; Inestrosa, NC
    The amyloid precursor protein (APP) contains a Cu binding domain (CuBD) localized between amino acids 135 and 156 (APP(135-156)), which can reduce Cu2+ to Cu1+ in vitro. The physiological function of this APP domain has not yet being established; nevertheless several studies support the notion that the CuBD of APP is involved in Cu homeostasis. We used APP synthetic peptides to evaluate their protective properties against Cu2+ neurotoxicity in a bilateral intra-hippocampal injection model. We found that human APP135-156 protects against Cu2+-induced neurotoxic effects, such as, impairment of spatial memory, neuronal cell loss, and astrogliosis. APP135-156 lacking two histidine residues showed protection against Cu2+; however, APP135-156 mutated in cysteine 144, a key residue in the reduction of Cu2+ to Cu1+, did not protect against Cu2+ neurotoxicity. In accordance with recent reports, the CuBD of the Caenorhabditis elegans, APL-1 protected against Cu2+ neurotoxicity in vivo. We also found that Cu2+ neurotoxicity is associated with an increase in nitrotyrosine immunofluorescence as well as with a decrease in Cu2+ uptake. The CuBD of APP therefore may play a role in the detoxification of brain Cu.
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    Wnt signaling involvement in β-amyloid-dependent neurodegeneration
    (2002) Inestrosa, NC; De Ferrari, GV; Garrido, JL; Alvarez, A; Olivares, GH; Barría, MI; Bronfman, M; Chacón, MA
    Alzheimer's disease (AD) is a progressive dementia paralleled by selective neuronal death, which is probably caused by the cytotoxic effects of the amyloid-p peptide (Abeta). We have observed that Abeta-dependent neurotoxicity induces a loss of function of Wnt signaling components and that activation of this signaling cascade prevent such cytotoxic effects. Therefore we propose that compounds which mimic this signaling cascade may be candidates for therapeutic intervention in Alzheimer's patients. (C) 2002 Elsevier Science Ltd. All rights reserved.