Molecular basis of Alzheimer's disease; Signal transduction and the cell biology of memory-linked synapses

Developing neurons make a quadrillion synapses, providing our brains their enormous computational power. These synapses degenerate in Alzheimer's-afflicted neurons, neurons die, and all mental capacity is lost. To discover molecules that make synapses in development and destroy them in Alzheimer's disease is the purpose of our group's research.

Experiments several years ago led us to a novel molecule we think likely to cause Alzheimer's synaptic degeneration and nerve cell death (Lambert et al, 1998). We call this neurotoxic molecule an "ADDL." ADDLs are small, soluble oligomers of the peptide Aß. ADDLs almost instantly block LTP, a classic model for synaptic plasticity and memory. Subsequently, they cause nerve cell death by apoptosis. Gene knockouts show ADDLs act through a signal transduction pathway involving Fyn, a protein tyrosine kinase others have discovered is involved physiologically in LTP and developmental apoptosis and is overexpressed in Alzheimer's disease. We now know that ADDLs occur at high levels in AD-affected brain (Gong et.al., 2003), giving clinical validation to our theory. ADDLs may one day provide a basis for discovery of new drugs to combat Alzheimer's, a devastating disease that afflicts over four million people in the United States.

Our experimental approach is interdisciplinary and has been enhanced by close collaborations with other laboratories at Northwestern and throughout the country. Recent students have developed new electron microscope methods to image the creation of synaptic junctions; created monoclonal antibodies to indentify transient membrane proteins involved in synaptogeneiss; introduced computer-aided video-microscopy to discover signals that control the movement of growth cones; used confocal laser immunofluorescence microsopy to localize Alzheimer's-associated cytoskeletal molecules in developing axons; applied in vitro mutagenesis to study trafficking of an Alzeimer's-associated membrane protein; introduced cloned human nerve cells to indentify molecules underlying mechanisms of nerve cell death; developed organotypic cultures of adult mouse brain as a model for Alzheimer's pathogensesis; used atomic force microscopy to characterize ADDL structure; developed flow cytometry and chemical crosslinking methods for ADDL receptor discovery; invented a process to modify cytoplasmic protein function by delivering antibodies into living cells; engineered and transfected inducible trans-gene into nerve cell lines to discover targets and functions of specific protein tyrosine kinases; developed conformation-sensitive anti-bodies to detect ADDLs at ultra-low levels; used confocal immunofluorescence imaging to reveal the impact of ADDLs on synaptic memory-gene expression.

Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease. J Neurosci. 2007 Jan 24;27(4):796-807.

Lambert MP, Velasco PT, Chang L, Viola KL, Fernandez S, Lacor PN, Khuon D, Gong Y, Bigio EH, Shaw P, De Felice FG, Krafft GA, Klein WL. Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 2007 Jan;100(1):23-35. Epub 2006 Nov 20.

Wu Y, Wu Z, Butko P, Christen Y, Lambert MP, Klein WL, Link CD, Luo Y. Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans. J Neurosci. 2006 Dec 13;26(50):13102-13.

Boutaud O, Montine TJ, Chang L, Klein WL, Oates JA. PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid beta1-42. J Neurochem. 2006 Feb;96(4):917-23. Epub 2006 Jan 12.

Oddo S, Caccamo A, Tran L, Lambert MP, Glabe CG, Klein WL, LaFerla FM. Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem. 2006 Jan 20;281(3):1599-604. Epub 2005 Nov 10.

Ohno M, Chang L, Tseng W, Oakley H, Citron M, Klein WL, Vassar R, Disterhoft JF. Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci. 2006 Jan;23(1):251-60.

Y. Gong, L. Chang, K.L. Viola, P.N. Lacor, M.P. Lambert, C.E. Finch, G.A. Krafft, W.L. Klein. (2003) “Alzheimer's disease-affected brain: Presence of oligomeric Aß ligands (ADDLs) suggests a molecular basis for reversible memory loss.” Proceedings of the National Academy of Sciences (Epub ahead of print)

B.A. Chromy, R.J. Nowak, M.P. Lambert, K.L. Viola, L. Chang, P.T. Velasco, B.W. Jones, S.J. Fernandez, P.N. Lacor, P. Horowitz, C.E. Finch, G.A. Krafft, and W.L. Klein. (2003) “Self-assembly of Aß1-42 into globular neurotoxins.” Biochemistry, in press

M.P. Lambert, K.L. Viola, B.A. Chromy, T.E. Morgan, G.A. Krafft, C.E. Finch, and W.L. Klein. (2001) “Vaccination with soluble Aß oligomers generates toxicity-neutralizing antibodies.” J. Neurochem.79:595-605.

M. P. Lambert, A. K. Barlow, B. A. Chromy, C. Edwards, R. Freed, M. Liosatos, T. E. Morgan, I. Rozovsky, B. Trommer, K. L. Viola, P. Wals, C. Zhang, C. E. Finch, and G. A. Krafft, W. L. Klein (1998). "Diffusible, nonfibrillar ligands derived from Aß1-42 are potent CNS neurotoxins." Proceedings of the National Academy of Sciences 95: 6448-6453.

S. Bodovitz and W. L. Klein (1996). "Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein." 271: 4436-4440.

K. Barber, S. A. Enam, S. Bodovitz, M. Falduto, D. Frail and W. L. Klein (1995). "Particulate forms of APP in the extracellular milieu of cultured cells." Experimental Neurology 132: 42-53.

C. Zhang, M. P. Lambert, C. Bunch, K. Barber, W. S. Wade, G. A. Krafft and W. L. Klein (1994). "Focal adhesion kinase expressed by nerve cell lines shows increased tyrosine phosphorylation in response to Alzheimer's A beta peptide." Journal of Biological Chemistry 269: 25247-25250.

W. Pope, S. A. Enam, N. Bawa, B. E. Miller, H. A. Ghanbari and W. L. Klein (1993). "Phosphorylated tau epitope of Alzheimer's disease is coupled to axon development in the avian central nervous system." Experimental Neurology 120: 106-113.

REVIEWS:

Klein, W.L. (2002) “Aß toxicity in Alzheimer’s Disease: emergence of ADDLs and protofibrils as drug and vaccine targets.” Neurochem. Intl., 41:345-352.

Klein, W.L. (2002) “ADDLs and protofibrils- the missing links?” Neurobiol. Aging. 23:231-233.

Klein, W.L., Krafft, G.A., and Finch, C.E. (2001) Targeting small Aß oligomers: the solution to an Alzheimer's disease conundrum? Trends Neurosci. 24: 219-224.

Klein, W.L. (2000) Aß toxicity in Alzheimer’s Disease. In Molecular Mechanisms of Neuro-degenerative Diseases. Chesselet, M-F, ed. (Los Angeles, CA: Humana Press). Ch. 1, pp. 1-47.

View all publications by publications by William L. Klein listed in the National Library of Medicine (PubMed).