Professor, Molecular Biology and Biochemistry
School of Biological Sciences

Amyloid Aß; amyloid assembly; amyloid structure; Alzheimer's pathogenesis.

Fellow of the AAAS

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.

Nussbaum J, Schilling S, Cynis H, Silva A, Swanson E, Wangsanut T, Tayler K, Wiltgen B, Hatami A, Rönicke R, Hutter-Paier B, Reymann K, Alexandru A, Jagla W, Graubner S, Glabe C, Demuth HU, Bloom GS (2012) Prion-Like Behavior and Tau-dependent Cytotoxicity of beta-Amyloid Oligomers Seeded by Pyroglutamylated beta-Amyloid. Nature Accepted for publication.

Laganowsky A, Liu C, Sawaya MR, Whitelegge JP, Park J, Zhao M, Pensalfini A, Soriaga AB, Landau M, Teng PK, Cascio D, Glabe C, Eisenberg D (2012) Atomic view of a toxic amyloid small oligomer. Science 335:1228-1231.

Lasagna-Reeves CA, Glabe CG, Kayed R (2011) Amyloid-{beta} Annular Protofibrils Evade Fibrillar Fate in Alzheimer Disease Brain. J Biol Chem 286:22122-22130.

Kayed R, Canto I, Breydo L, Rasool S, Lukacsovich T, Wu J, Albay R, 3rd, Pensalfini A, Yeung S, Head E., March, J.L., and Glabe, CG. 2010. Conformation dependent monoclonal antibodies distinguish different replicating strains or conformers of prefibrillar Abeta oligomers. Mol Neurodegener, 5:57.

Wu, JW, Breydo, L, Isas, JM, Lee, J, Kuznetsov, YG, Langen, R, Glabe, C. 2010. Fibrillar Oligomers Nucleate the Oligomerization of Monomeric Amyloid {beta} but Do Not Seed Fibril Formation. J. Biol. Chem. 285(9):6071-6079.

Deshpande, A., H. Kawai, R. Metherate, C. G. Glabe, and J. Busciglio. 2009. A role for synaptic zinc in activity-dependent Abeta oligomer formation and accumulation at excitatory synapses. J Neurosci 29:4004-4015.

Mina, E. W., C. Lasagna-Reeves, C. G. Glabe, and R. Kayed. 2009. Poloxamer 188 copolymer membrane sealant rescues toxicity of amyloid oligomers in vitro. J Mol Biol 391:577-585.

Tomic, J. L., A. Pensalfini, E. Head, and C. G. Glabe. 2009. Soluble fibrillar oligomer levels are elevated in Alzheimer's disease brain and correlate with cognitive dysfunction. Neurobiol Dis. 35:352-358.

Kayed, R., A. Pensalfini, L. Margol, Y. Sokolov, F. Sarsoza, E. Head, J. Hall, and C. Glabe. 2009. Annular protofibrils are a structurally and functionally distinct type of amyloid oligomer. J Biol Chem 284:4230-4237.

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.

1/1/08 – 12/31/12 NIH 5PO1 AG00538 "Behavioral and neural plasticity in the aged."

7/1/11 – 6/30/12 Cure Alzheimer’s Fund. “The Role of Oligomeric Aß in Alzheimer’s Disease.”

R01AG033069 4/01/10 - 3/31/15 Structure and conformational diversity of amyloid oligomers.

AAAS

Society for Neuroscience

ASBMB

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

Cellular and Molecular Biosciences

Neurobiology

Alzheimer's Disease Research Center

Link to this profile
https://faculty.uci.edu/profile/?facultyId=2441

Last updated
03/21/2012