Immunization with the SDPM1 peptide lowers amyloid plaque burden and improves cognitive function in the APPswePSEN1(A246E) transgenic mouse model of Alzheimer’s disease

摘要

Vaccination has become an important therapeutic approach to the treatment of Alzheimer’s disease (AD), however, immunization with Aβ 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 Aβ1–40- and Aβ1–42-amyloid and blocks subsequent Aβ 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 Aβ1–40 and Aβ1–42 levels in the brain, improved cognitive performance in Morris water maze tests, and resulted in no increased T cell responses to immunogenic or Aβ peptides or brain inflammation. When done after plaque burden was already significant, SDPM1 immunization still significantly reduced amyloid plaque burden and Aβ1–40/1–42 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 Aβ1–40/1–42 amyloid-specific binding and blocking peptide is used to inhibit the development of neuropathology and cognitive dysfunction.