Novel cognitive enhancing strategies for Alzheimer's disease

Alzheimer's disease (AD), the major age-related form of dementia, is characterised by cognitive dysfunction. Strategies to enhance cognition could impact on quality of life for a significant proportion of our ageing population. In AD the transmembrane amyloid precursor protein (APP) is proteolytically cleaved to generate the neurotoxic amyloid-beta. However, under normal circumstances APP is cleaved to generate soluble APP (sAPP) that has neuroprotective and cognitive-enhancing effects which are mediated by sAPP binding to an unknown receptor on the surface of neurons. The objectives of this proposal are to take the essential next steps in exploring the cognitive enhancing potential of sAPP by: 1) identifying the receptor and binding partners for sAPP on the surface of neuronal cells; and 2) validating the identified receptor in sAPP's actions on synaptic plasticity and protection against oxidative stress. A range of biochemical, biophysical and cell biological approaches will be employed, including focused studies on human induced-pluripotent stem cell (iPSC)-derived neurons. Identification of the sAPP receptor and its binding partners will open the way to novel pharmacological approaches to mimic sAPP activity in AD.