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Extracellular chaperones prevent Aβ42-induced toxicity in rat brains

Journal Article


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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.

Authors


  •   Cascella, Roberta (external author)
  •   Conti, Simona (external author)
  •   Tatini, Francesca (external author)
  •   Evangelisti, Elisa (external author)
  •   Scartabelli, Tania (external author)
  •   Casamenti, Fiorella (external author)
  •   Mark R Wilson
  •   Chiti, Fabrizio (external author)
  •   Cecchi, Cristina (external author)

Publication Date


  • 2013

Citation


  • Cascella, R., Conti, S., Tatini, F., Evangelisti, E., Scartabelli, T., Casamenti, F., Wilson, M. R., Chiti, F. & Cecchi, C. (2013). Extracellular chaperones prevent Aβ42-induced toxicity in rat brains. Biochimica et Biophysica Acta. Molecular Basis of Disease, 1832 (8), 1217-1226.

Scopus Eid


  • 2-s2.0-84877353475

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1772&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/759

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 1217

End Page


  • 1226

Volume


  • 1832

Issue


  • 8

Place Of Publication


  • Netherlands

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.

Authors


  •   Cascella, Roberta (external author)
  •   Conti, Simona (external author)
  •   Tatini, Francesca (external author)
  •   Evangelisti, Elisa (external author)
  •   Scartabelli, Tania (external author)
  •   Casamenti, Fiorella (external author)
  •   Mark R Wilson
  •   Chiti, Fabrizio (external author)
  •   Cecchi, Cristina (external author)

Publication Date


  • 2013

Citation


  • Cascella, R., Conti, S., Tatini, F., Evangelisti, E., Scartabelli, T., Casamenti, F., Wilson, M. R., Chiti, F. & Cecchi, C. (2013). Extracellular chaperones prevent Aβ42-induced toxicity in rat brains. Biochimica et Biophysica Acta. Molecular Basis of Disease, 1832 (8), 1217-1226.

Scopus Eid


  • 2-s2.0-84877353475

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1772&context=smhpapers

Ro Metadata Url


  • http://ro.uow.edu.au/smhpapers/759

Has Global Citation Frequency


Number Of Pages


  • 9

Start Page


  • 1217

End Page


  • 1226

Volume


  • 1832

Issue


  • 8

Place Of Publication


  • Netherlands