Li Gan, Ph.D.
Staff Research Investigator
Gladstone Institute of Neurological Disease
Assistant Professor of Neurology
University of California, San Francisco
Email: lgan@gladstone.ucsf.edu
Telephone: 415-734-2524
Fax: 415-355-0824
Areas of investigation
Our laboratory studies molecular mechanisms of neurodegeneration in Alzheimer’s disease (AD) and related neurological disorders. Our current research focuses on identifying key factors produced in neuronal and glial cells that contribute to the degenerative processes in AD. Using genetic inactivation or RNA interference-mediated gene silencing to inhibit key mediators, we hope to prevent or slow down neurodegeneration in primary neuronal cells or AD transgenic models.
Significance
Neurons in the mammalian central nervous system are postmitotic, highly differentiated cells that are largely irreplacable. In AD, the most common dementia in the elderly, cognitive decline and memory loss are closely associated with neuronal loss and synaptic deficits in selected regions of the brain. Amyloid b (Ab) peptides have been implicated as a central factor in the pathogenesis of AD. Besides causing direct toxic effects on neuronal and synaptic functions, Ab also serves as an inflammatory stimulus that provokes microglia-mediated neurotoxicity. Understanding the molecular pathways in neurons and microglia that mediate Ab-dependent neurodegeneration would facilitate the development of novel mechanism-based therapies for AD.
Approaches
We use a combination of cellular, molecular, and biochemical approaches in neuronal/microglial cultures and in transgenic mouse models. To uncover molecular pathways underlying AD pathogenesis, we use lentiviral vector-mediated gene delivery and small interfering RNA (siRNA)-based gene silencing to modulate expression levels of key molecular mediators. Primary neuronal and glial cultures and transgenic animals serve as in vitro and in vivo models to recapitulate critical features of Ab-induced inflammation and neurodegeneration.
Contributions
Using a strategy that integrates large-scale expression profiling with custom-made cDNA arrays and siRNA-based gene silencing, we identified the cysteine proteinase cathepsin B as a key player in microglia-mediated cell death. Our study established a functional link of cathepsin B with Ab-dependent neurodegeneration and highlights the feasibility of using cathepsin B inhibitors for therapeutic intervention in AD. In parallel studies, we have established a lentiviral vector-based system that allows for the temporal and brain region-specific modulation of diverse genes in vivo.
Some questions addressed in the ongoing studies:
How do microglial cells interact with Ab of different assembly states?
How do Ab peptides modulate synaptic transmission?
Can expression of RNAi by viral vectors be used as gene therapy to inhibit the production of Ab peptides and to reverse AD-related pathologies in transgenic mice?
What are the roles of microglial cathepsin B in neurodegeneration?
Li Gan, Ph.D.