%0 Journal Article
%T Novel rat Alzheimer's disease models based on AAV-mediated gene transfer to selectively increase hippocampal A¦Â levels
%A Patricia A Lawlor
%A Ross J Bland
%A Pritam Das
%A Robert W Price
%A Vallie Holloway
%A Lisa Smithson
%A Bridget L Dicker
%A Matthew J During
%A Deborah Young
%A Todd E Golde
%J Molecular Neurodegeneration
%D 2007
%I BioMed Central
%R 10.1186/1750-1326-2-11
%X Adeno-associated viral (AAV) vectors encoding BRI-A¦Â cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded A¦Â 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-A¦Â40 and AAV-BRI-A¦Â42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble A¦Â peptides. BRI-A¦Â42 and the combination of BRI-A¦Â40+42 overexpression resulted in elevated levels of detergent-insoluble A¦Â. No significant increase in detergent-insoluble A¦Â was seen in the rats expressing APPsw or BRI-A¦Â40. No pathological features were noted in any rats, except the AAV-BRI-A¦Â42 rats which showed focal, amorphous, Thioflavin-negative A¦Â42 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 A¦Â42 alone is sufficient to initiate A¦Â deposition, both A¦Â40 and A¦Â42 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-¦Â peptides (A¦Â) 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 A¦Â42, 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 A¦Â40, the more prevalent A¦Â peptide secreted by cells and a major component of deposits in the cerebral vasculature o
%U http://www.molecularneurodegeneration.com/content/2/1/11