Li Gan, Ph.D.
Assistant 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 focuses on dissecting the molecular pathways in Alzheimer’s disease (AD) and frontotemporal dementia (FTD), two of the most common dementia in the elderly population. We are intrigued by two interconnected mechanisms that are common to neurodegenerative processes: the accumulation of protein aggregates and miscommunications between neurons and glia, especially microglia. Accumulation of protein aggregates could activate microglia, exacerbating neurodegeneration. On the other hand, microglia could be activated to remove abnormal protein aggregates. We are particularly interested in how aging-related pathways, such as sirtuins, modulate the processes underlying the abnormal accumulation and microglial activation.
Significance
With the world population aging rapidly, neurodegenerative diseases have emerged as major health challenges facing our modern society. We seek to dissect molecular pathways underlying the degenerative processes. Our long-term goal is to develop new small-molecule or cell-based approaches to delay or prevent the progression of these devastating aging-associated diseases.
Approaches
We employ a combination of approaches, including genetic, biochemical, imaging, electrophysiological, and behavioral techniques. To dissect the causative pathogenic pathways underlying AD and FTD, we use a range of model systems, from genetic modified mice to brain slices and primary neuronal and glial cultures.
Contributions
Accumulation of amyloid β, the key pathogen in AD, results from an imbalance of production and clearance/degradation. We found that cathepsin B (CatB) degrades Aβ via a unique catabolic mechanism (Mueller-Steiner et. al, Neuron, 2006). We further showed that reducing cystatin C (CysC), the endogenous inhibitor of CatB, lowers Aβ levels in a CatB-dependent manner, establishing a critical role of CysC-CatB axis in regulating Aβ degradation and clearance (Sun et al., Neuron, 2008). In human brains, aging is associated with the upregulation of genes involved in inflammatory responses. Sirtuins, including SIRT1, are class III histone deacetylases and are strongly associated with longevity. We discovered that their activation protects neurons by blocking NF-κB activation in microglia through deacetylation (Chen et al., J. Biol. Chem., 2005). Stem cell–based regeneration is a promising yet highly challenging therapeutic direction in neurodegenerative diseases. One major obstacle is that the toxic microenvironment in diseased brain may have adverse effects on the functional integration of recruited or transplanted stem cells. We discovered that the neural stem cells in the hippocampus of AD mice exhibit abnormal development and impaired functional integration. By combining in vivo labeling, confocal microscopy and electrophysiological recordings, we identified an Aβ-induced aberrant neuronal network as the primary mechanism (Sun et al., Cell Stem Cell, in press).
Some questions addressed in the ongoing studies:
Do aging-related pathways affect the stability and clearance of protein aggregates in AD and FTD?
How does aging affect inflammatory and protective function of microglia?
Can we generate patients-specific microglia to remove abnormal protein aggregates?
What are the roles of aging-associated epigenetic modification in neuronal injury and inflammatory responses?
Li Gan, Ph.D.