In major neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, the abnormal accumulation of one or more polypeptides within or around neurons is central to pathogenesis. R. Nixon’s research focuses on two aspects of neurobiology that govern the fate of normal and pathogenic proteins: the regulation of proteolytic processing and the control of protein export into axons and synapses. R. Nixon’s team have identified dysfunction of the endosomal-lysosomal system involving altered endocytosis and mistrafficking of proteases to endosomes, as the earlies known pathological response of neurons in Alzheimer’s disease. Cell modeling studies showed early endosomes to be major generators of the toxic beta-amyloid peptide and implicated dysfunction of endosomes in the mechanism of beta-amyloid accumulation in 'sporadic' Alzheimer’s. Consequences of endosomal-lysosomal and calpain system dysfunction on processing of Alzheimer-related proteins, receptor-mediated signal transduction, and neuronal cell death pathways were identified using genetic manipulations together with cell culture models. It was shown that calpain inhibitors improve memory and synaptic transmission in a mouse of Alzheimer disease.