ABETACOGNITION · The functional significance of soluble amyloid beta (Abeta) oligomers for learning and memory deficits in Alzheimer's disease

Alzheimer’s disease (AD) is characterised by a gradual cognitive decline, which initially affects learning and memory, and gradually impairs other cognitive functions. Despite considerable scientific effort, the cause and pathogenesis of AD is still unknown. Recent in vitro studies suggest that the destruction of synapses by soluble aggregates of amyloid beta (Abeta) might play a role in mediating the progression of the disease. However, what is lacking is an approach that establishes the links between cellular pathology, its causative effect on neuronal network activity in the affected brain areas, and the resulting behavioural impairments. This project aims to address this shortcoming by using a cross-disciplinary design. Core to this project are novel transgenic mice overexpressing soluble (Abeta), which will be tested on object and spatial recognition memory tasks. A novel imaging technique, manganese-enhanced MRI, will be used to establish the effect that soluble (Abeta) has on neuronal activity in the perirhinal cortex and hippocampus, brain areas that are affected early in AD and mediate these types of memory. Lastly, we aim to investigate whether memory deficits in arc(Abeta) mice can be abolished by inhibitors that target elements of (Abeta)-activated signalling cascades recently established in vitro. This will be achieved by direct infusion of drugs into the brain regions of interest in freely behaving arc(Abeta) mice, with the aim of identifying new targets for pharmacotherapeutic intervention. The fellowship at the Max-Planck-Institute for Psychiatry in Munich will enable the applicant, who has received excellent training in the basic field of learning and memory at Oxford and Cambridge, to acquire additional competencies focused on the neuroscience of neuropsychiatric disorders. By moving from the UK to Germany, the fellow will help to circulate scientific knowledge within the European Research Area, towards a common European effort to tackle one of today’s least understood diseases.