| Abstract No.: | B-C2109 |
| Country: | Canada |
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| Title: | INTRACELLULAR Aβ-OLIGOMERS, INFLAMMATION AND BEHAVIORAL DEFICITS IN A NEW TRANSGENIC MODEL OF THE ALZHEIMER-LIKE AMYLOID PATHOLOGY. |
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| Authors/Affiliations: | 1 Maria Teresa Ferretti*; 1 Martin Alejandro Bruno; 1 Vanessa Partridge; 1 Wanda Leon; 1 Adriana Ducatenzeiler; 1 Dina Arvanitis; 1 Freya G. Vercauteren ; 2 Daniel Houle; 1 Augusto Claudio Cuello;
1 Department of Pharmacology, McGill University; 2 Montreal General Hospital, McGill University; QC, Canada
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| Content: | Objective. Evidence from human material and animal models suggest that soluble, oligomeric forms of amyloid-β peptide (Aβ), rather than amyloid plaques, provoke the neuronal dysfunction characteristic of Alzheimer’s disease (AD). Early events in the AD pathology, from the aggregation of soluble Aβ to the rise of neurotoxicity, are still poorly understood and need to be elucidated.
Materials and Methods. To study this, we generated a new transgenic mouse model of amyloid pathology- the McGill-Thy1APP transgenic mouse- which overexpresses the human amyloid precursor protein (APP) bearing the Swedish and Indiana mutations. Amyloid pathology, cognitive deficits and levels of inflammatory markers were assessed at different age points, using immunohistochemistry, Morris Water Maze and Western Blot, respectively. Results. McGill-Thy1APP mice accumulate Aβ intracellularly in cortex and hippocampus as early as 1 week, and start depositing amyloid plaques at 4 months of age. Behavioral deficits were already observed at 3 months, coinciding with the intracellular accumulation of Aβ in pyramidal neurons of the neocortex and hippocampus. Conformational-specific antibodies (OC, Dr. Glabe) and Aβ oligomer-specific antibodies (Nu1, Dr. Klein) revealed that the intracellular Aβ burden was, at least partially, of oligomeric nature. To investigate the mechanism mediating the neurotoxicity of intracellular Aβ-oligomers, we assessed the levels of various markers of neuroinflammation: major histocompatibility complex class II (MHC-II), inducible nitric oxide synthase (i-NOS) and cyclooxygenase 2 (cox-2, the inducible form of the enzyme specifically expressed by neurons). All three were found to be upregulated at the 3 months age point, prior to amyloid plaque formation.
Conclusions. Our results suggest that an inflammatory response is likely to be one of the earliest neurotoxic consequences of the accumulation of intracellular oligomeric Aβ. Pharmacological modulation of neuroinflammation might therefore represent a valid approach in preventing or delaying the onset of the Aβ-induced Alzheimer’s pathology.
(Supported by CIHR grant #MOP6717)
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