Our laboratory is interested in the biochemistry and molecular and cell biology of neuronal degeneration during aging of the mammalian brain, particularly in Alzheimer's (AD) and Parkinson's (PD) diseases. The laboratory originally developed methods for the purification and analysis of the intraneuronal paired helical filaments and extracellular amyloid fibrils that are the hallmarks of the neuropathology of AD. Extensive studies of the trafficking and processing of the β-amyloid precursor protein (APP), a type 1 integral membrane glycoprotein critically involved in AD, have been undertaken and continue. The laboratory discovered that Aβ is normally produced from APP throughout life, enabling dynamic cell biological studies of the mechanism of Aβ production and its pharmacological inhibition. The function of APP and the toxic properties of various Aβ assemblies on cultured neurons and in relevant mouse models are being examined. The identification of presenilin as the active site of γ-secretase and its role in APP and Notch signaling functions are also under study. Finally, a similar approach is being applied to the function and dysfunction of gene products implicated in PD, particularly alpha-synuclein. A wide range of methods is employed, including cell culture, protein biochemistry, molecular biology, immunohistochemistry, light and electron microscopy, electrophysiology and animal modeling.