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Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal Aβ levels

DOI: 10.1186/1750-1326-2-11

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Adeno-associated viral (AAV) vectors encoding BRI-Aβ cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded Aβ peptide. As a comparison the effect of AAV-mediated overexpression of APPsw was also examined. Animals were tested for development of learning and memory deficits (open field, Morris water maze, passive avoidance, novel object recognition) three months after infusion of AAV. A range of impairments was found, with the most pronounced deficits observed in animals co-injected with both AAV-BRI-Aβ40 and AAV-BRI-Aβ42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble Aβ peptides. BRI-Aβ42 and the combination of BRI-Aβ40+42 overexpression resulted in elevated levels of detergent-insoluble Aβ. No significant increase in detergent-insoluble Aβ was seen in the rats expressing APPsw or BRI-Aβ40. No pathological features were noted in any rats, except the AAV-BRI-Aβ42 rats which showed focal, amorphous, Thioflavin-negative Aβ42 deposits.The results show that AAV-mediated gene transfer is a valuable tool to model aspects of AD pathology in vivo, and demonstrate that whilst expression of Aβ42 alone is sufficient to initiate Aβ deposition, both Aβ40 and Aβ42 may contribute to cognitive deficits.Alzheimer's disease (AD) is a prevalent neurodegenerative disorder characterized by a decline in cognitive function, accumulation of extracellular amyloid-β peptides (Aβ) and intracellular neurofibrillary tangles, and neuronal loss. Numerous AD-linked mutations in amyloid precursor protein (APP) and presenilins (PS) [1-3] alter APP metabolism resulting in accumulation of Aβ42, a 42-amino acid product essential for the formation of parenchymal and vascular amyloid deposits [4], and proposed to initiate the cascade leading to AD [3]. However, the role of Aβ40, the more prevalent Aβ peptide secreted by cells and a major component of deposits in the cerebral vasculature o

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