Dr. Selkoe’s laboratory is interested in applying advanced biological methods to achieve a deeper understanding of the causes and basic mechanisms of Alzheimer’s and Parkinson’s diseases. We focus on the biochemistry and molecular and cell biology of neuronal degeneration with age, including in these two most common neurodegenerative diseases. The laboratory originally developed methods to purify and analyze the intraneuronal paired helical filaments and extracellular amyloid fibrils that are the hallmarks of AD neuropathology. They identified the protein tau as the subunit of the neurofibrillary tangles that are ubiquitous in AD and several other brain diseases. Extensive studies of the trafficking and processing of the β-amyloid precursor protein (APP), a transmembrane glycoprotein critically involved in AD, have been undertaken and continue. The lab first 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 studied. We discovered that presenilin is the catalytic center of γ-secretase, the first aspartyl intramembrane protease discovered, and we study its role in APP and Notch processing. Finally, a similar approach is being applied to the function and dysfunction of gene products implicated in PD, particularly α-synuclein. We recently discovered that α-synuclein exists normally as α-helically folded tetramers and that destabilization of the tetramers may lead to PD. We use a wide range of methods, including cell culture, protein biochemistry, molecular biology, immunohistochemistry, confocal and electron microscopy, electrophysiology and mouse modeling.