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Neuroscience Graduate Program at UCSF
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.
- 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?
Seo-Hyun Cho, Postdoctoral Fellow
Paul Li, Research Associate
Sang-Won Min, Postdoctoral Fellow
Sakura Minami, Postdoctoral Fellow
Kelly Nelson, Administrative Assistant
Yunqui Zhou, Senior Research Associate
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. (2008) Research progress in Alzheimer’s disease and dementia, Vol. 3, Nova Science Publisher, Inc., New York. Chapter X, pp 275-302.
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.
Gan L. (2007) Therapeutic potential of amyloid β-degrading enzymes in Alzheimer’s disease (review) Future Neurology 2: 133-137.
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-kB signaling. J. Biol. Chem. 280:40364-40374.
Kaczmarek LK, Bhattacharjee A, Desai R, Gan L, Song P, Christian AA, von Hehn, Whim MD, and Yang B. (2005) Regulation of the timing of MNTB neurons by short-term and long-term modulation of potassium channels. Hearing Res. 206:133-145.
Gresch O, Engel FB, Nesic D, Tran TT, England HM, Hickman ES, Korner I, Gan L, Chen S, Hammermann R, Wolf J, Muller-Hartmann H, Nix M, Siebenkotten G, Kraus G, and Lun K. (2004) New non-viral method for gene-transfer into primary cells. Methods 33: 151–163.
Esposito L*, Gan L*, Yu G, Essrich C, Mucke L. (2004) Intracellular Ab counteracts the antiapoptotic function of its precursor protein and primes proapoptotic pathways for activation by other insults J. Neurochem. 91:1260-1274. (*, authors contribute equally)
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 Ab-activated microglial cells using a functional genomics approach. J. Biol. Chem. 279: 5565–5572.
Ford BD, Liu Y, Mann MA, Krauss R, Phillips K, Gan L, Fischbach GD. (2003) Neuregulin-1 suppresses muscarinic receptor expression and acetylcholine-activated muscarinic K+ channels in cardiac myocytes. Biochem Biophys Res Commun. 308: 23–28.
Bhattacharjee A, Gan L, Kaczmarek LK. (2002) Localization of the Slack potassium channel in the rat central nervous system. J. Comp. Neurol. 454: 241–254.
Gan L, Anton KE, Masterson BA, Vincent V, Ye S, Gonzalez-Zulueta M. (2002) Specific interference with gene expression and gene function mediated by long dsRNA in neuronal cells J. Neurosci. Methods 121: 151–157.
Gan L, Hahn SJ, Kaczmarek LK. (1999) Cell-type specific expression of the Kv3.1 gene is mediated by negative elements in the 5' UTR in the proximal region of the Kv3.1 promoter. J. Neurochem. 73: 1350–1362.
Xu X, Yang D, Wyss-Coray T, Yan, J, Gan L, Sun Y, Mucke L. (1999) Wildtype but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc. Natl. Acad. Sci. USA 96: 7547–7552.
Joiner WJ, Tang MD, Wang L-Y, Dworezky SI, Boissard CG, Gan L, Gribkoff VK, Kaczmarek LK. (1998) Formation of intermediated-conductance calcium-activated potassium channels by interaction of Slack and Slo subunits. Nat. Neurosci. 1: 462–469.
Gan L, Kaczmarek LK. (1998) When, where, and how much? Expression of the Kv3.1 potassium channel in high frequency firing neurons. J. Neurobiol. 37: 69–79.
Wang L-Y, Gan L, Perney TM, Shwartz I, Kaczmarek LK. (1998) Activation of Kv3.1 channels in neuronal spine-like structures may induce local potassium depletion. Proc. Natl. Acad. Sci. USA 95: 1882–1887.
Wang L-Y, Gan L, Forsythe ID, Kaczmarek LK. (1998) Contribution of the Kv3.1 potassium channel to high-frequency firing in mouse auditory neurones. J. Physiol. Lond. 509: 183–194.
Kanemasa T, Gan L, Perney TM, Wang L-Y, Kaczmarek LK. (1995) The regulation of the Kv3.1 potassium current in NIH3T3 fibroblasts by PKC. J. Neurophysiol. 74: 207–217.
Gan L, Perney TM, Kaczmarek LK. (1996) Cloning and characterization of the promoter for a potassium channel expressed in high frequency firing neurons. J. Biol. Chem. 271: 5859–5865Li Gan, Ph.D.
415-734-2524
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Gladstone Institute of Neurological Disease
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Gladstone Institute of Neurological Disease
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