Li Gan, PhD
Senior Investigator, Gladstone Institute of Neurological Disease

Other Professional Titles

Professor, Neurology, University of California, San Francisco

Phone

(415) 734-2524

Fax

(415) 355-0824

Assistant

Erica Delin

On The Web

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. 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.

Lab Focus

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?

Achievements

Found that cathepsin B (CatB) degrades the protein amyloid β (Aβ) via a unique catabolic mechanism. Accumulation of Aβ, the key pathogen in AD, results from an imbalance of production and clearance/degradation.
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.
Discovered that the activation of sirtuins—class III histone deacetylases strongly associated with longevity—protects neurons by block NF-κB activation in microglia through deacetylation.
Found 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.
Discovered a new mechanism that contributes to the accumulation of tau, a key pathogen in AD and FTD. We found that tau is acetylated and acetylation blocks the degradation and tau. Moreover, reducing tau acetylation with a small molecule inhibitor leads to depletion of pathogenic phosphorylated-tau in neurons. These findings offer a novel therapeutic direction in AD and related neurodegenerative diseases.

Affiliations

  • Society for Neuroscience
  • New York Academy of Sciences, Women in Science

Professional titles

Professor, Neurology, University of California, San Francisco

Education

1990
BS
  • Peking University
1996
PhD
  • Yale University School of Medicine

Honors and Awards

2015 Inge Grundke-Iqbal Award for Alzheimer’s Research
2011 Glenn Award for Biological Mechanisms of Aging
2007 Hellman Family Award, UCSF