Cell Biology of Alzheimer's Disease Pathogenesis: BACE1 and BIN1
Gopal Thinakaran, Ph.D.
Departmens of Neurobiology, Neurology, and Pathology
The University of Chicago
Alzheimer’s disease (AD) is pathologically characterized by the presence of numerous brain senile plaques and neurofibrillary tangles. Senile plaques contain extracellular deposition of β-amyloid (Aβ) peptides, derived by the sequential cleavage of the amyloid precursor protein (APP) by two aspartyl proteases, β-site APP cleaving enzyme (BACE1) and γ-secretase. Neurofibrillary tangles made of intraneuronal accumulation of hyperphosphorylated tau. Mutations in the genes encoding APP and presenilin 1 or 2 (the catalytic subunit of γ-secretase) cause autosomal dominant familial AD. Research in my lab investigates the mechanisms that regulate Aβ production and deposition. My lab has made important contributions to our understanding of APP trafficking as well as the biology of BACE1 and γ-secretase, the two enzymes that sequentially cleave APP to generate Aβ. Our research has provided valuable insights into the physiological and pathological functions of presenilins, regulation of APP trafficking and metabolism, modulation of amyloid production/deposition by post-translational modification of APP secretases and interaction with associated proteins, the subcellular sites and membrane microdomains involved in the generation of Aβ peptides, and neuronal transcytosis of BACE1. Recent studies in the lab focus on BIN1, the most significant late-onset AD susceptibility gene identified via genome-wide association studies. Our integrated approach that combines biochemical characterization, detailed subcellular localization, live-cell imaging, advanced microscopy, and electrophysiology, is beginning to uncover essential insights into the cellular and molecular mechanisms by which BIN1 elevates the risk for the late-onset AD.
Sponsored by the University of Rochester School of Medicine and Dentistry, the Del Monte Institute for Neuroscience, and the Department of Neuroscience
Thursday, February 28 at 4:00pm to 5:00pm
School of Medicine and Dentistry, K-307 (3-6408)
415 Elmwood Ave, Rochester, NY 14642
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