Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8260897 | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease | 2013 | 10 Pages |
Abstract
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, formation of the extracellular amyloid β (Aβ42) plaques, neuronal and synapse loss, and activated microglia and astrocytes. Extracellular chaperones, which are known to inhibit amyloid fibril formation and promote clearance of misfolded aggregates, have recently been shown to reduce efficiently the toxicity of HypF-N misfolded oligomers to immortalised cell lines, by binding and clustering them into large species. However, the role of extracellular chaperones on Aβ oligomer toxicity remains unclear, with reports often appearing contradictory. In this study we microinjected into the hippocampus of rat brains Aβ42 oligomers pre-incubated for 1 h with two extracellular chaperones, namely clusterin and α2-macroglobulin. The chaperones were found to prevent Aβ42-induced learning and memory impairments, as assessed by the Morris Water Maze test, and reduce Aβ42-induced glia inflammation and neuronal degeneration in rat brains, as probed by fluorescent immunohistochemical analyses. Moreover, the chaperones were able to prevent Aβ42 colocalisation with PSD-95 at post-synaptic terminals of rat primary neurons, suppressing oligomer cytotoxicity. All such effects were not effective by adding pre-formed oligomers and chaperones without preincubation. Molecular chaperones have therefore the potential to prevent the early symptoms of AD, not just by inhibiting Aβ42 aggregation, as previously demonstrated, but also by suppressing the toxicity of Aβ42 oligomers after they are formed. These findings elect them as novel neuroprotectors against amyloid-induced injury and excellent candidates for the design of therapeutic strategies against AD.
Keywords
PSD-95HypF-NCLUCM-H2DCFDAD-PBSMWMNBMPMSFAβEGTADTTGFAPFBSNGS2′,7′-dichlorodihydrofluorescein diacetate3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromideα2MBSADMSOIba-1MTTα2-macroglobulinHippocampal injurybovine serum albuminEDTAethylene diamine tetraacetic acidethylene glycol tetraacetic acidLearning impairmentAlzheimer's diseaseMorris water maze testclusterinCNSdithiothreitolDimethylsulfoxideembryonic dayfetal bovine serumnormal goat serumcentral nervous systemDulbecco's phosphate-buffered salinephenylmethylsulfonyl fluorideneurobasal mediumHaptoglobinneuronal nucleiGlial fibrillary acidic proteinpostsynaptic density protein 95amyloid-beta peptide
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Authors
Roberta Cascella, Simona Conti, Francesca Tatini, Elisa Evangelisti, Tania Scartabelli, Fiorella Casamenti, Mark R. Wilson, Fabrizio Chiti, Cristina Cecchi,