Active and passive immunization strategies based on the SDPM1 peptide demonstrate pre-clinical efficacy in the APPswePSEN1dE9 mouse model for Alzheimer's disease

NEUROBIOLOGY OF DISEASE

卷:62

Article

Camboni, Marybeth¹  Wang, Chiou-Miin¹  Miranda, Carlos¹  Yoon, Jung Hae¹  Xu, Rui¹  Zygmunt, Deborah¹  Kaspar, Brian K.^1,2,4  Martin, Paul T.^1,2,3 

[1] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH 43205 USA

[2] Ohio State Univ, Dept Pediat, Columbus, OH 43210 USA

[3] Ohio State Univ, Dept Physiol & Cell Biol, Columbus, OH 43210 USA

[4] Ohio State Univ, Dept Neurosci, Columbus, OH 43210 USA

关键词: Alzheimer's disease;    Vaccine;    Peptide mimotope;    Amyloid;    Neurodegeneration;    Learning;    Memory;    Synaptophysin;    PSD95;    Synapse;   

DOI  :  10.1016/j.nbd.2013.09.001

来源: Elsevier

【 摘 要 】

Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting A beta amyloid may have clinical benefit in Alzheimer's disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native A beta amyloid-specific binding peptide,lowers brain A beta amyloid plaque burden and brain A beta 1-40 and A beta 1-42 peptide levels, improves cognitive learning and memory in Morris water maze tests and increases the expression of synaptic brain proteins. This was the case in young mice immunized prior to development of significant brain amyloid burden, and in older mice, where brain amyloid was already present. Active immunization was optimized using ALUM as an adjuvant to stimulate production of anti-SDPM1 and anti-A amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited A beta amyloid-mediated toxicity in cultured neuronal cells. The protein sequence of the variable domain within the P4D6 heavy chain was found to mimic a multimer of the SDPM1 peptide motif. These data demonstrate the efficacy of active and passive vaccine strategies to target A beta amyloid oligomers using an engineered peptide-mimotope strategy. (C) 2013 Elsevier Inc. All rights reserved.

【 授权许可】

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