Biomedical Sciences Graduate Program | University of California, San Francisco

Li Gan, PhD
Molecular pathways in neurodegenerative diseases

Selected Publications | Complete Publications

phone	(415) 734-2524
email	lgan@gladstone.ucsf.edu
additional websites	Lab website
secondary research affiliation	Developmental & Stem Cell Biology

     With the world population aging rapidly, neurodegenerative diseases have emerged as major health challenges facing our modern society. Our laboratory focuses on dissecting molecular pathways in Alzheimer’s disease (AD) and frontotemporal dementia (FTD). We study three interconnected mechanisms that are common to neurodegenerative processes: abnormal protein accumulation, neuron-glia miscommunication, and aging. Using biochemical, genetic, electrophysiological, and behavioral approaches, we have made significant progress in the past few years.
     1) Accumulation of amyloid beta (Abeta), a peptide strongly implicated in AD pathogenesis, results from an imbalance of its production and clearance/degradation. We found that cathepsin B (CatB) degrades Abeta via a unique catabolic mechanism. We further showed that reducing cystatin C (CysC), the endogenous inhibitor of CatB, lowers Abeta levels in a CatB-dependent manner, establishing a critical role of CysC-CatB axis in regulating Abeta degradation and clearance.
     2) 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. In primary neuronal and glial cultures, we discovered that their activation protects neurons by blocking NF-kappa B activation in microglia through deacetylation. These findings directly linked the anti-inflammatory function of SIRT1 with its potent neuroprotective effects, supporting a pivotal role for microglia-to-neuron communication in the neurodegenerative processes.
     3) 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 Abeta-induced aberrant neuronal network as the primary mechanism.
     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. We are particularly interested in how these two mechanisms may be modulated by aging related factors, such as the sirtuins. Our long-term goal is to develop new small-molecule or cell-based approaches to delay or prevent the progression of neurodegeneration.

Selected Publications

Sun B, Halabisky B, Zhou Y, Yu G, Mucke L and Gan L. (2009) Imbalance between GABAergic and glutermatergic transmissions impairs adult neurogenesis in an animal model of Alzheimer's disease. Cell Stem Cell. In press.

Sanchez-Mejia R, Newman JW, Toh S, Yu G, Zhou Y, Halabisky B, Cisse M, Scearce-Levie K, Cheng IH, Gan L, Palop JJ, Bonventre JV and Mucke L. (2008) Phopholipase A2 reduction ameliorates cognitive deficits in a mouse model of Alzheimer’s disease. Nat. Neurosci. 11:1311-1318.

Sun B, Zhou Y, Halabisky B, Lo I, Cho SH, Devidze N, Mueller-Steiner S, Wang X, Grubb A, and Gan L. (2008) Cystatin C-cathepsin B axis regulates soluble amyloid beta and associated neuronal deficits in an animal model of Alzheimer’s disease. Neuron 60:247-257.

Gan L and Mucke L. (2008) Paths of convergence: sirtuins in aging and neurodegeneration (review). Neuron 58: 10–14.

Gan L (2007) Therapeutic potential of sirtuin-activating compounds in Alzheimer’s disease (review) Drug News and Perspectives 20:233-9.

Mueller-Steiner S, Zhou Y, Arai H, Sun B, Roberson ED, Chen J, Yu G, Wong X, Esposito L, Mucke L, and Gan L. (2006) Anti-amyloidogenic and neuroprotective functions of cathepsin B: implications for Alzheimer’s disease. Neuron 51:703–714.

Chen J, Zhou Y, Mueller-Steiner S, Chen LF, Kwon H, Yi S, Mucke L, and Gan L. (2005) SIRT1 protects against microglia-dependent beta amyloid toxicity through inhibiting NF-kappa B signaling. J. Biol. Chem. 280:40364-40374.

Gan L, Ye S, Chu A, Anton K, Yi S, Vincent V, Von Schack D, Chin, Murray DJ, Patthy L, Gonzalez-Zulueta M, Nikolich K, Urfer R. (2004) Identification of cathepsin B as a mediator of neuronal death induced by Abeta-activated microglial cells using a functional genomics approach. J. Biol. Chem. 279: 5565–5572.

information last updated October 2009