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Neurobiol Dis. 2014 Feb;62:31-43. doi: 10.1016/j.nbd.2013.09.001. Epub 2013 Sep 8.

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

Author information

1
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA.
2
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA; Department of Pediatrics, The Ohio State University, USA; Department of Neuroscience, The Ohio State University, USA.
3
Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, USA; Department of Pediatrics, The Ohio State University, USA; Department of Physiology and Cell Biology, The Ohio State University, USA. Electronic address: Paul.Martin@nationwidechildrens.org.

Abstract

Recent clinical and pre-clinical studies suggest that both active and passive immunization strategies targeting Aβ amyloid may have clinical benefit in Alzheimer's disease. Here, we demonstrate that vaccination of APPswePSEN1dE9 mice with SDPM1, an engineered non-native Aβ amyloid-specific binding peptide, lowers brain Aβ amyloid plaque burden and brain Aβ1-40 and Aβ1-42 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-Aβ amyloid antibodies. Intracerebral injection of P4D6, an SDPM1 peptide-mimotope antibody, also lowered brain amyloid plaque burden in APPswePSEN1dE9 mice. Additionally, P4D6 inhibited Aβ 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 Aβ amyloid oligomers using an engineered peptide-mimotope strategy.

KEYWORDS:

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

PMID:
24021662
PMCID:
PMC3881373
DOI:
10.1016/j.nbd.2013.09.001
[Indexed for MEDLINE]
Free PMC Article

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