Biography: My research career has been dedicated to elucidating the molecular basis of Alzheimer’s disease (AD). Awards for my work include a Zenith Award from the Alzheimer’s Association, the MetLife Award for Biomedical Research, and the Potamkin Prize from the American Academy of Neurology. My lab has been especially focused on the γ-secretase complex, a protease that plays central roles in Alzheimer pathogenesis. We reported the first designed inhibitors of γ-secretase and used these as tools to characterize, isolate, identify and purify this unusual multi-component membrane protein complex. Most notably, we discovered that presenilin, mutated in early-onset familial Alzheimer’s disease (FAD), is a novel intramembrane aspartyl protease. We have elucidated fundamental biochemical, mechanistic, and structural features of this protease complex and developed different classes of inhibitors as biological tools and therapeutic prototypes. In recent years, we have advanced the biochemical understanding of the multiple proteolytic functions of γ-secretase, how it recognizes substrates, and how substrate recognition and processing is altered by Alzheimer-causing mutations. Most recently, we have discovered that FAD mutations lead to stalled and stabilized γ-secretase enzyme-substrate (E-S) complexes that can trigger synaptic degeneration in the absence of amyloid β-peptide (Aβ) formation. Current work involves multi-disciplinary, collaborative efforts to confirm and build on this hypothesis, elucidate mechanisms of synaptic degeneration, explore relevance to sporadic late-onset Alzheimer’s disease, and identify means of rescuing stalled complexes as a new approach to Alzheimer's drug discovery.
Abstract: Alzheimer’s disease is a progressive neurodegenerative disorder associated with old age that presents as a loss of memory and cognition. Plaque deposition of the 42-residue form of the amyloid β-peptide (Aβ42) in the brain is an early pathological event, occurring many years before the appearance of symptoms. Genetics and biochemistry support the amyloid hypothesis of Alzheimer's pathogenesis: Dominantly inherited mutations that cause Alzheimer’s disease in midlife are found in the substrate and enzyme that produce Aβ, and these mutations generally skew Aβ production toward the aggregation-prone Aβ42. Nevertheless, doubts remain whether Aβ42 is the primary disease driver and most appropriate therapeutic target. Here I will present our work on the protease γ-secretase that produces Aβ, including the development of chemical probes that contributed to the characterization, purification, identification, and mechanistic understanding of this membrane-embedded protease complex and its role in pathogenesis.
