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P3‐461: Anti‐PrP C monoclonal antibody infusion as a novel treatment for Aß oligomer cognitive deficits
Author(s) -
Wisniewski Thomas,
Chung Erika,
Ji Yong,
Sun Yanjie,
Kascsak Richard,
Kascsak Regina,
Strittmatter Stephen M.
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.2004
Subject(s) - genetically modified mouse , hippocampal formation , monoclonal antibody , hippocampus , senile plaques , antibody , chemistry , gene isoform , pathology , pathological , medicine , transgene , neuroscience , microbiology and biotechnology , pharmacology , alzheimer's disease , biochemistry , biology , immunology , disease , gene
Background: Alzheimer’s Disease (AD) is the most common of the conformational neurodegenerative disorders characterized by the conversion of biological protein to the b-sheet-rich pathological Ab isoform. Ab forms toxic oligomers and fibrils which assemble into neuritic plaques. AD pathology also includes the abnormal phosphorylation of tau protein which forms neurofibrillary tangles. A recent study reveals the cellular prion protein, PrP, to be a major receptor for Ab oligomers, considered the most toxic form of Ab. Ab oligomers suppress LTP signal in murine hippocampal slices but activity remains when pretreated with the PrP monoclonal antibody, 6D11, which binds competitively to PrP. Targeting of PrP to prevent Ab oligomer-related cognitive deficits is a potential novel therapeutic target. Methods: APP/PS1 transgenic mice aged 8 months were intraperitoneally (i.p.) injected with 1mg 6D11 daily for 2 weeks (n 1⁄4 10). For controls, APP/PS1 (n 1⁄4 7) and wild-type mice (n 1⁄4 8) were given i.p. control injections. The mice were then subjected to behavioral testing by radial arm maze to assess the effect of 6D11 treatment on cognition. Animals adapted to their environment for 3 days before 7 consecutive days of training sessions. Animals were then tested for 10 days where each of the 8 arms was baited with sugar water. Water-restricted mice were permitted to enter every arm until all 8 rewards were consumed. The number of errors was recorded for each mouse each day. At the conclusion of behavioral testing, animals were sacrificed and brain tissue will be analyzed biochemically and immunohistochemically for the presence of amyloid plaques and Ab oligomers. Results: Behavioral tests show a marked decrease in errors between APP/PS1 treated and non-treated groups (p < 0.0001). Treated APP/PS1 Tg mice behaved the same as wild-type controls indicating a recovery in cognitive learning, even after this short term 6D11 treatment. Brain tissue samples from both treated and non-treated APP/ PS1 groups indicate no significant differences in amyloid plaque burden, suggesting the cognitive effects were due to 6D11-PrP interactions. Conclusions: Monoclonal antibodies such as 6D11 or other compounds with a high affinity for PrP can be used to treat cognitive deficits in aged AD transgenic mice by competitively binding the major Ab oligomer receptor.