In Vivo Application of beta Amyloid Oligomers: A Simple Tool to Evaluate Mechanisms of Action and New Therapeutic Approaches

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cerebral accumulation of extracellular amyloid beta (A beta) and neurofibrillary tangles made of hyperphosphorylated tau protein, two main lesions which appear sequentially during the disease progression. In the last decade numerous studies have proposed small soluble aggregates of A beta, known as oligomers, as the species responsible for synaptic dysfunction, memory loss and neurodegeneration typical of AD. In vitro and in vivo experiments have identified A beta oligomers as the elements that can alter synaptic function by a reversible mechanism, which gradually becomes permanent when exposure is continuous. Here we show that intracerebroventricular (ICV) injection in mice of a solution containing specifically A beta(1-42) oligomers substantially affects their memory when tested in the novel object recognition task. This acute mouse model enabled us to distinguish whether oligomers were affecting specific phases of the memory processing. A single injection of A beta(1-42) oligomers before memory consolidation abolished information processing, leading to memory impairment, whereas no such effects were observed when the injection was done once the information had been processed, indicating that the oligomers affect memory consolidation rather than retrieval. Beside A beta(1-42), A beta(1-40) oligomers also impaired memory, and both isoforms were antagonized by the anti-A beta 4G8 monoclonal antibody. This simple and reliable paradigm is useful to investigate the mechanisms through which A beta oligomers interfere with neuronal processes and to test the efficacy of new therapeutic approaches specifically against these species. We tested several molecules by direct co-incubation with A beta oligomers, ICV injections preceding A beta oligomers, and the systemic treatment with drugs that cross the blood brain barrier. We also examined the proposed involvement of cellular prion protein as a mediator of the oligomer-induced memory impairment.