Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation

White, Anthony R., Maher, Fran, Brazier, Marcus W., Jobling, Michael F., Thyer, James, Stewart, Leanne R., Thompson, Andrew, Gibson, Riki, Masters, Colin L., Multhaup, Gerd, Beyreuther, Konrad, Barrow, Colin J., Collins, Steven J. and Cappai, Roberto 2003, Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation, Brain Research, vol. 966, no. 2, pp. 231-244.

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Title Diverse fibrillar peptides directly bind the Alzheimer’s amyloid precursor protein and amyloid precursor-like protein 2 resulting in cellular accumulation
Author(s) White, Anthony R.
Maher, Fran
Brazier, Marcus W.
Jobling, Michael F.
Thyer, James
Stewart, Leanne R.
Thompson, Andrew
Gibson, Riki
Masters, Colin L.
Multhaup, Gerd
Beyreuther, Konrad
Barrow, Colin J.
Collins, Steven J.
Cappai, Roberto
Journal name Brain Research
Volume number 966
Issue number 2
Start page 231
End page 244
Total pages 13
Publisher Elsevier
Place of publication Amsterdam, Netherlands
Publication date 2003-03
ISSN 0006-8993
1872-6240
Summary The Alzheimer’s disease Aβ peptide can increase the levels of cell-associated amyloid precursor protein (APP) in vitro. To determine the specificity of this response for Aβ and whether it is related to cytotoxicity, we tested a diverse range of fibrillar peptides including amyloid-β (Aβ), the fibrillar prion peptides PrP106–126 and PrP178–193 and human islet-cell amylin. All these peptides increased the levels of APP and amyloid precursor-like protein 2 (APLP2) in primary cultures of astrocytes and neurons. Specificity was shown by a lack of change to amyloid precursor-like protein 1, τ-1 and cellular prion protein (PrPc) levels. APP and APLP2 levels were elevated only in cultures exposed to fibrillar peptides as assessed by electron microscopy and not in cultures treated with non-fibrillogenic peptide variants or aggregated lipoprotein. We found that PrP106–126 and the non-toxic but fibril-forming PrP178–193 increased APP levels in cultures derived from both wild-type and PrPc-deficient mice indicating that fibrillar peptides up-regulate APP through a non-cytotoxic mechanism and irrespective of parental protein expression. Fibrillar PrP106–126 and Aβ peptides bound recombinant APP and APLP2 suggesting the accumulation of these proteins was mediated by direct binding to the fibrillated peptide. This was supported by decreased APP accumulation following extensive washing of the cultures to remove fibrillar aggregates. Pre-incubation of fibrillar peptide with recombinant APP18–146, the putative fibril binding site, also abrogated the accumulation of APP. These findings show that diverse fibrillogenic peptides can induce accumulation of APP and APLP2 and this mechanism could contribute to pathogenesis in neurodegenerative disorders.
Language eng
Field of Research 110999 Neurosciences not elsewhere classified
Socio Economic Objective 970111 Expanding Knowledge in the Medical and Health Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2003, Elsevier
Persistent URL http://hdl.handle.net/10536/DRO/DU:30023814

Document type: Journal Article
Collection: School of Life and Environmental Sciences
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