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

Background: Alzheimer's disease (AD) is characterized by a decline in cognitive function and accumulation of amyloid-beta peptide (A beta) in extracellular plaques. Mutations in amyloid precursor protein (APP) and presenilins alter APP metabolism resulting in accumulation of A beta 42, a peptide essential for the formation of amyloid deposits and proposed to initiate the cascade leading to AD. However, the role of A beta 40, the more prevalent A beta peptide secreted by cells and a major component of cerebral A beta deposits, is less clear. In this study, virally-mediated gene transfer was used to selectively increase hippocampal levels of human A beta 42 and A beta 40 in adult Wistar rats, allowing examination of the contribution of each to the cognitive deficits and pathology seen in AD. Results: Adeno-associated viral (AAV) vectors encoding BRI-A beta cDNAs were generated resulting in high-level hippocampal expression and secretion of the specific encoded A beta 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 beta 40 and AAV-BRI-A beta 42. Brain tissue was analyzed by ELISA and immunohistochemistry to quantify levels of detergent soluble and insoluble A beta peptides. BRI-A beta 42 and the combination of BRI-A beta 40+42 overexpression resulted in elevated levels of detergent-insoluble A beta. No significant increase in detergent-insoluble A beta was seen in the rats expressing APPsw or BRI-A beta 40. No pathological features were noted in any rats, except the AAV-BRI-A beta 42 rats which showed focal, amorphous, Thioflavin-negative A beta 42 deposits. Conclusion: 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 beta 42 alone is sufficient to initiate A beta deposition, both A beta 40 and A beta 42 may contribute to cognitive deficits.