Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer's disease.
Vaccination has become an important therapeutic approach to the treatment of Alzheimer's disease (AD), however, immunization with Abeta amyloid can have unwanted, potentially lethal, side effects. Here we demonstrate an alternative peptide-mimotope vaccine strategy using the SDPM1 peptide. SDPM1 is a 20 amino acid peptide bounded by cysteines that binds tetramer forms of Abeta(1-40)- and Abeta(1-42)-amyloids and blocks subsequent Abeta amyloid aggregation. Immunization of mice with SDPM1 induced peptide-mimotope antibodies with the same biological activity as the SDPM1 peptide. When done prior to the onset of amyloid plaque formation, SDPM1 vaccination of APPswePSEN1(A246E) transgenic mice reduced amyloid plaque burden and Abeta(1-40) and Abeta(1-42) levels in the brain, improved cognitive performance in Morris water maze tests, and resulted in no increased T cell responses to immunogenic or Abeta peptides or brain inflammation. When done after plaque burden was already significant, SDPM1 immunization still significantly reduced amyloid plaque burden and Abeta(1-40/1-42) peptide levels in APPswePSEN1(A246E) brain without inducing encephalitogenic T cell responses or brain inflammation, but treatment at this stage did not improve cognitive function. These experiments demonstrate the efficacy of a novel vaccine approach for Alzheimer's disease where immunization with an Abeta(1-40/1-42) amyloid-specific binding and blocking peptide is used to inhibit the development of neuropathology and cognitive dysfunction.
Wang
Chiou-Miin
CM
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Ohio State University College of Medicine, Columbus, OH 43205, USA.
Devries
Sarah
S
Camboni
Marybeth
M
Glass
Matthew
M
Martin
Paul T
PT
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D023582:Alzheimer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D016229:Amyloid beta-Peptides; D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D003071:Cognition / Q000187:drug effects*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D018782:Maze Learning / Q000187:drug effects*; D051379:Mice; D008822:Mice, Transgenic; D010446:Peptide Fragments; D058225:Plaque, Amyloid / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D014611:Vaccination
D023582:Alzheimer Vaccines; D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)