Potential amyloid plaque-specific peptides for the diagnosis of Alzheimer's disease

Amyloid plaques (AP) represent one of the main molecular hallmarks of Alzheimer's disease (AD). In order to develop new AP-specific contrast agents for AD molecular imaging, the phage display technology was used to identify peptides specific to amyloid-beta (A beta(42)). A random disulfide constrained heptapeptide phage display library was screened against A beta(42). After biopanning, 72 phage clones were isolated and their binding affinity to A beta(42) was evaluated by enzyme-linked immunosorbent assay (ELISA). The final library was enriched in two peptide sequences. The K(d) of candidate phage clones for binding to A beta(42) are in the picomolar range. The binding affinity for A beta(42) of two selected peptides was confirmed by ELISA, and the specific interaction with AP was validated by immunohistochemistry on brain sections. The preliminary MRI in vivo study, which was performed with a peptide functionalized contrast agent on AD transgenic mouse, showed encouraging results. To conclude, low molecular weight peptides presenting a specific affinity for A beta(42) were identified by phage display. As specific carriers, they have a real potential for molecular imaging of AD thanks to AP binding.

[1]  L. Iversen,et al.  The toxicity in vitro of beta-amyloid protein. , 1995, The Biochemical journal.

[3]  Thomas Wisniewski,et al.  A non-toxic ligand for voxel-based MRI analysis of plaques in AD transgenic mice , 2008, Neurobiology of Aging.

[4]  Ralph Weissleder,et al.  Differential conjugation of tat peptide to superparamagnetic nanoparticles and its effect on cellular uptake. , 2002, Bioconjugate chemistry.

[5]  S. Laurent,et al.  From phage display to magnetophage, a new tool for magnetic resonance molecular imaging. , 2007, Bioconjugate chemistry.

[6]  Nobuhisa Iwata,et al.  19F and 1H MRI detection of amyloid β plaques in vivo , 2005, Nature Neuroscience.

[7]  C. DeCarli,et al.  What does fluorodeoxyglucose PET imaging add to a clinical diagnosis of dementia? , 2007, Neurology.

[8]  M. Rapoport,et al.  PD98059 Prevents Neurite Degeneration Induced by Fibrillar β‐Amyloid in Mature Hippocampal Neurons , 2000, Journal of neurochemistry.

[9]  Xudong Huang,et al.  The A beta peptide of Alzheimer's disease directly produces hydrogen peroxide through metal ion reduction. , 1999, Biochemistry.

[10]  Bettina Schmitt,et al.  Selection of D‐Amino‐Acid Peptides That Bind to Alzheimer's Disease Amyloid Peptide Aβ1–42 by Mirror Image Phage Display , 2003, Chembiochem : a European journal of chemical biology.

[11]  Rohit Bakshi,et al.  Magnetic Resonance Imaging of Iron Deposition in Neurological Disorders , 2006, Topics in magnetic resonance imaging : TMRI.

[12]  G. Curran,et al.  Design and chemical synthesis of a magnetic resonance contrast agent with enhanced in vitro binding, high blood-brain barrier permeability, and in vivo targeting to Alzheimer's disease amyloid plaques. , 2004, Biochemistry.

[13]  Thomas Wisniewski,et al.  Detection of Alzheimer's amyloid in transgenic mice using magnetic resonance microimaging , 2003, Magnetic resonance in medicine.

[14]  T. Clackson,et al.  Phage display : a practical approach , 2004 .

[15]  C. Kang,et al.  Identification of peptides that specifically bind Aβ1–40 amyloid in vitro and amyloid plaques in Alzheimer's disease brain using phage display , 2003, Neurobiology of Disease.

[16]  M. Zwick,et al.  Phage-displayed peptide libraries. , 1998, Current opinion in biotechnology.

[17]  J. Kreuter,et al.  Nanoparticulate systems for brain delivery of drugs. , 2001, Advanced drug delivery reviews.

[18]  L. Lue,et al.  Microglial chemotaxis, activation, and phagocytosis of amyloid β-peptide as linked phenomena in Alzheimer's disease , 2001, Neurochemistry International.

[19]  Michael Garwood,et al.  In vivo visualization of Alzheimer's amyloid plaques by magnetic resonance imaging in transgenic mice without a contrast agent , 2004, Magnetic resonance in medicine.

[20]  J. Kreuter,et al.  Nanoparticulate systems for brain delivery of drugs. , 2001 .

[21]  G A Johnson,et al.  Detection of neuritic plaques in Alzheimer's disease by magnetic resonance microscopy. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[22]  J. Sipe Amyloid proteins : the beta sheet conformation and disease , 2005 .

[23]  Marc Dhenain,et al.  Characterization of in vivo MRI detectable thalamic amyloid plaques from APP/PS1 mice , 2009, Neurobiology of Aging.

[24]  C. Masters,et al.  Distinct sites of intracellular production for Alzheimer's disease Aβ40/42 amyloid peptides , 1997, Nature Medicine.

[25]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[26]  A. Rehemtulla,et al.  Molecular Imaging , 2009, Methods in Molecular Biology.

[27]  P. Butler,et al.  Islet amyloid in type 2 diabetes, and the toxic oligomer hypothesis. , 2008, Endocrine reviews.

[28]  J A Frank,et al.  Synthesis and relaxometry of high‐generation (G = 5, 7, 9, and 10) PAMAM dendrimer‐DOTA‐gadolinium chelates , 1999, Journal of magnetic resonance imaging : JMRI.

[29]  M. F. Falangola,et al.  Visualization of β‐amyloid plaques in a transgenic mouse model of Alzheimer's disease using MR microscopy without contrast reagents , 2004, Magnetic resonance in medicine.

[30]  D. Willbold,et al.  Selection of D‐Amino‐Acid Peptides that Bind to Alzheimer′s Disease Amyloid Peptide Aβ1‐42 by Mirror Image Phage Display. , 2003 .

[31]  Andrew J Wheaton,et al.  In vivo measurement of plaque burden in a mouse model of Alzheimer's disease , 2006, Journal of magnetic resonance imaging : JMRI.

[32]  A. Nordberg Amyloid plaque imaging in vivo: current achievement and future prospects , 2008, European Journal of Nuclear Medicine and Molecular Imaging.

[33]  Alfons Verbruggen,et al.  Molecular imaging of alpha v beta3 integrin expression in atherosclerotic plaques with a mimetic of RGD peptide grafted to Gd-DTPA. , 2008, Cardiovascular research.

[34]  A Van der Linden,et al.  Noninvasive in vivo MRI detection of neuritic plaques associated with iron in APP[V717I] transgenic mice, a model for Alzheimer's disease , 2005, Magnetic resonance in medicine.

[35]  L. Kiessling,et al.  Phage display affords peptides that modulate beta-amyloid aggregation. , 2006, Journal of the American Chemical Society.

[36]  Sophie Laurent,et al.  Magnetic resonance imaging of inflammation with a specific selectin‐targeted contrast agent , 2005, Magnetic resonance in medicine.

[37]  H. Vanderstichele,et al.  Prominent Cerebral Amyloid Angiopathy in Transgenic Mice Overexpressing the London Mutant of Human APP in Neurons , 2000 .