203. Prevention of Alzheimer's-Like Symptoms Using Lentiviral-Mediated Secreted Amyloid Precursor Protein-Alpha Overexpression in a Transgenic Mouse Model

Alzheimer's disease (AD) is a neurodegenerative disease that is associated with memory loss and poor cognition. Pathologically, the disease is characterised by amyloid plaques and neurofibrillary tangles. The abnormally high level of amyloid-β is thought to be due in part to an imbalance in amyloid precursor protein cleavage whereby there is an increase in amyloid-β production concomitant with a decrease in the production of secreted amyloid precursor protein-alpha (sAPPα). sAPPα is neuroprotective, supports neurogenesis and regulates learning and memory. In the current study, a lentiviral vector containing sAPPα and green fluorescent protein (GFP) cDNA, under the control of a synapsin promoter was injected bilaterally into the hippocampus of 4-month old male APPSwe/PS1ΔE9 transgenic mice at four sites per hemisphere. The two control groups consisted of B6/C3 wild-type and transgenic littermates injected with an control vector containing only GFP. At 12 months of age, animals underwent behavioural testing to examine hippocampus-dependent memory performance. There were no significant differences between groups in the open field and elevated plus maze tests of activity and anxiety. During acquisition of spatial memory in a water maze, transgenic controls showed poor learning, as the total distance to the platform (3.0 m±0.7) was significantly higher than that for wild-type controls (1.79 m±0.43). However, this impaired learning effect was prevented in the transgenic sAPPα group (1.38 m±0.18. Transgenic mice injected with control vector performed poorly at water maze probe trials testing spatial memory retention, and had to swim a lot further to reach the target (35.45 m±2.85); however, in transgenic mice treated with sAPPα (26.07 m±1.83) performance was significantly improved (p < 0.05). Moreover, transgenic-sAPPα animals performed similarly to wildtype animals (25.43 m±2.03). There were no significant differences between groups in a dry-land spatial memory task – the Barnes maze, or a contextual fear-conditioning test. These results indicate that the overexpression of sAPPα is persistent for at least up to 8 months, and could prevent Alzheimer's-like behavioural deficits in an animal model.Supported by a grant from the Health Research Council of New Zealand.