Li Gan, PhD

Professor
Neurology
415-734-2524

Cellular and Molecular Pathways in Neurodegeneration

With the world population aging rapidly, neurodegenerative diseases have emerged as major health challenges facing our modern society. 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 in AD and FTD.

We employ a combination of approaches, including genetic, biochemical, imaging, electrophysiological, and behavioral techniques. To dissect the mechanisms underlying the accumulation of amyloid b (Ab), the key pathogen in AD, we discovered that cathepsin B (CatB) degrades Ab 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 Ab levels in a CatB-dependent manner, establishing a critical role of CysC-CatB axis in regulating Ab 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 showed that their activation protects neurons by blocking NF-kB activation in microglia through deacetylation (Chen et al. JBC, 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. Moreover, we identified an Ab-induced aberrant neuronal network as the primary mechanism (Sun et al., Cell Stem Cell, in press).

We seek to further dissect the neurodegenerative mechanisms underlying the accumulation/degradation of protein aggregates and the altered communications between neurons and glia, especially microglia. 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.

Current Projects

  • 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?

Lab Members

Xu Chen, PhD
Postdoctoral Fellow
xu.chen@gladstone.ucsf.edu

Jon (Iker) Etchegaray, PhD
Postdoctoral Fellow
jon.etchegaray@gladstone.ucsf.edu

Cindy Huang, PhD
Postdoctoral Fellow
cindy.huang@gladstone.ucsf.edu

Peter Sohn, PhD
Postdoctoral Fellow
peter.sohn@gladstone.ucsf.edu

Maria Telpoukhovskaia, PhD
Postdoctoral Fellow
maria.telpoukhovskaia@gladstone.ucsf.edu​

Chao Wang, PhD
Postdoctoral Fellow
chao.wang@gladstone.ucsf.edu​

Lihong Zhiang,PhD
Postdoctoral Fellow
lihong.zhang@gladstone.ucsf.edu

David Le
Research Associate III
david.le@gladstone.ucsf.edu

Yaqiao Li
Research Associate II
yaqiao.li@gladstone.ucsf.edu

Faten Sayed
Neuroscience Graduate Student
faten.sayed@gladstone.ucsf.edu

Yungui Zhou, MD
Senior Research Associate
yungui.zhou@gladstone.ucsf.edu

Tara Tracy, PhD
Research Scientist
tara.tracy@gladstone.ucsf.edu

Erica Nguyen
Administrative Assistant
erica.nguyen@gladstone.ucsf.edu

Lab Website

Publications: