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P2‐523: Therapeutic Monoclonal Antibodies against Abeta oligomers for Treatment of Alzheimer's disease
Author(s) -
Zhang Ying
Publication year - 2011
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.2011.05.1392
Subject(s) - monoclonal antibody , immunogen , epitope , antibody , western blot , immunization , immunotherapy , medicine , active immunization , immunology , pharmacology , biology , immune system , biochemistry , gene
metabolism both in amyloidogenesis and tau alterations, the two major hallmarks of Alzheimer’s Disease (AD), due to changes in methylation and oxidation reactions. Previous data obtained in our laboratory, using a nutritional B vitamin deficiency model, already showed that two genes involved in amyloid processing (PSEN1 and BACE1) were modulated by onecarbon metabolism alterations. In particular, PSEN1 is modulated by DNA methylation whereas the mechanisms responsible for BACE1 modulation are probably dealing with oxidation. As a consequence of these two genes modulation,production of amyloid peptides was increased. We also demonstrated that S-adenosylmethionine (SAM) supplementation was able to contrast the AD-like features induced by B vitamin deficiency. In the present study we investigated the effect of a combination of SAM and SOD (Superoxide-dismutase), using the samemodel.Methods: TgCRND8mice (carrying a double Indiana/Swedish mutated APP transgene) were feeded either with control or vitamin B deficient diet, with or without oral supplementation of combined SAM+SOD (SAM400mg + SOD 5U perday) or SAM and SOD alone. We measured: i) methylation metabolites by HPLC; ii) oxidative stress by lipid peroxidation assay; iii) PSEN1 and BACE expression by Real-Time PCR and western blotting; iv) amyloid deposition by ELISA tests and immunohistochemistry. Results: SAM+SOD is able to revert (or prevent) the observed exacerbation of Alzheimer-like features induced by B vitamin deficiency in TgCRND8mice, namely: SAM/SAH ratio decrease, increased lipid peroxidation, PSEN1 and BACE over-expression, increased amyloid processing and deposition. SAM and SOD combination shows a synergic effect compared to the effect of the two single molecules. Conclusions: These findings evidence the beneficial effects of the combined administration of SAM and SOD in AD transgenic mice. Interestingly, SAM+SOD are able to contrast also the amyloid deposition normally observed in these mice in control diet conditions. Although molecular mechanisms of SOD activity in this specific system remains to be elucidated, our preclinical data pinpoint the relevance of a clinical trial using SAM+SOD in order to evaluate its efficacy in AD treatment or prevention, alone or as coadjuvant of current therapies.