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picture of Charles G. Glabe
 Charles G. Glabe

University of California

3228 McGaugh Hall
 Mail Code: 3900
 Irvine, CA 92697

PHONE: (949)824-6081, 4229
FAX: (949) 824-8551

E-MAIL: cglabe@uci.edu

 

Charles G. Glabe
Professor, Molecular Biology and Biochemistry
School of Biological Sciences
PH.D., University of California, Davis
Research Interests
Amyloid Aß; amyloid assembly; amyloid structure; Alzheimer's pathogenesis.

 
Graduate Programs:
 Neurobiology Cellular and Molecular Biosciences
 
Professional Society AAAS Society for Neuroscience ASBMB
 
Abstract
Research in the Glabe lab focuses on the structure, aggregation and mechanisms of pathogenesis of amyloids in degenerative diseases. The main research programs center on the production of conformation dependent antibodies that specifically recognize distinct assembly states of amyloids, the use of these antibodies in dissecting the pathogenic mechanisms of amyloids and their applications in vaccine development. Other areas of interest include the mechanism of membrane permeabilization by amyloid oligomers. Dr. Glabe and his colleagues have discovered that fibrils and prefibrillar oligomers represent alternative aggregation pathways for many different types of amyloids and that they have distinct underlying structural motifs that are generic to the particular aggregation state and are recognized by specific conformation dependent antibodies. The prefibrillar oligomer antibody recognizes the oligomeric conformation of all amyloids tested and not the native conformation, random coil monomer or fibrillar amyloids regardless of protein sequence. We found that this antibody neutralizes the toxicity of amyloid oligomers in vitro and that vaccination of transgenic mouse models against the prefibrillar oligomers prevents amyloid deposition and cognitive dysfunction. The fibril specific antibody recognizes fibrils and soluble fibrillar oligomers of many different types of amyloids, but not prefibrillar oligomers, monomer or natively folded proteins. This indicates that fibrils have a generic structure that is distinct from that of prefibrillar oligomers, implying that they may have distinct toxic mechanisms. These discoveries indicate that amyloids share common structures and imply that they also share a common primary mechanism of amyloid oligomer pathogenesis. This suggests that therapies that specifically target these common structures may be effective for many different types of amyloid related degenerative diseases. Current work is focused on characterizing the detailed structures of these aggregation states and the common mechanisms of toxicity, which may involve the permeabilization of cellular membranes by prefibrillar oligomers.


Other Experience
Postdoctoral Fellow, Johns Hopkins University School of Medicine, 1978—1980

Postdoctoral Fellow, Univ. of California, San Francisco, 1980—1982

Staff Scientist, Worcester Foundation for Experimental Biology, 1982—1985
Updated: Last Updated: 04/23/2008

  Kayed, R., Head, E., Sarsoza, F., Necula, M., Margol, L., Wu, J., Breydo, L., Thompson, J.L., Rasool, S., Gurlo, T., Butler, P. and Glabe, C.G. (2007). Fibril specific, conformation dependent antibodies recognize a generic epitope common to amyloid fibrils and fibrillar oligomers that is distinct from prefibrillar oligomers. Molecular Neurodegeneration 2(18):1-11.

Necula, M., Breydo, L., Milton, S., Kayed, R., van der Veer W.E., Tone, P., Glabe, C.G. (2007) Methylene Blue Inhibits Amyloid Abeta Oligomerization by Promoting Fibrillization. Biochemistry 46(30):8850-8860.

Necula, M., Kayed, R., Milton, S., and Glabe, C. G. (2007) Small molecule inhibitors of aggregation indicate that amyloid beta oligomerization and fibrillization pathways are independent and distinct. J Biol Chem 282(14), 10311-10324.

Chen, Y. R., and Glabe, C. G. (2006). Distinct early folding and aggregation properties of alzheimer amyloid-beta peptide Abeta 40 and Abeta 42: Stable trimer or tetramer formation by Abeta 42. J Biol Chem. 281, 24414-24422.

Lesne, S., Koh, M. T., Kotilinek, L., Kayed, R., Glabe, C. G., Yang, A., Gallagher, M., and Ashe, K. H. (2006) NMDA receptor activation inhibits alpha-secretase and promotes neuronal amyloid-beta production. Nature 440, 352-357.

Oddo, S., Caccamo, A., Tran, L., Lambert, M. P., Glabe, C. G., Klein, W. L., and Laferla, F. M. (2006) Temporal profile of Abeta oligomerization in an in vivo model of Alzheimer's disease: A link between Abeta and tau pathology J. Biol. Chem. 281, 1599-604.

Demuro, A., E. Mina, R. Kayed, S.C. Milton, I. Parker, and C.G. Glabe. (2005). Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers. J Biol Chem 280(17): 17294-300.

Kayed, R., Sokolov, Y., Edmonds, B., McIntire, T.M., Milton, S.C., Hall, J.E. and Glabe, C.G. (2004) Permeabilization of Lipid Bilayers is a Common Conformation-Dependent Activity of Soluble Amyloid Oligomers in Protein Mis-folding Diseases. J. Biol. Chem. 729:46363-46366.

Kayed, R., Head, E., McIntire, T. M., Milton, S. C., Cotman, C .W. and Glabe, C. G. (2003) Common structure of soluble amyloid oligomers implies common mechanism of pathogenesis. Science. 300:486-489.
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