Inflammation and APP processing in Alzheimer’s Disease

The generation of amyloid  peptide (A) from cleavage of the amyloid precursor protein (APP) and the subsequent aggregation of A as soluble oligomers is central to the pathogenesis of Alzheimer’s Disease (AD). APP is first cleaved by -secretase followed by -secretase to yield A and sAPP in an amyloidogenic pathway, or alternatively cleaved by -secretase followed by -secretase to yield a p3 fragment and neurotrophic sAPP in a non-amyloidogenic pathway. The identification of new approaches for reducing A burden either by inhibition of -secretases, stimulation of -secretase, enhancing A clearance, or by maintaining neuronal homeostasis remains a major therapeutic goal for AD particularly at its very early stages. A characteristic of AD is inflammation caused in part by the recruitment of microglial cells to A containing plaques and subsequent release of inflammatory cytokines. This project will investigate the precise mechanistic links between cytokines such as TNF, A production and subsequent synaptic damage using primary cell cultures of neurones and microglia coupled to molecular approaches, biochemistry and cell imaging.