Cell and structural biology of Alzheimer’s disease; memory-linked synapse structure and signal transduction

We have discovered novel neurotoxins that appear to account for memory failure in Alzheimer’s disease. We call these molecules “ADDLs,” and they comprise small soluble oligomers of the amyloid _ peptide. ADDLs target memory-linked synapses and interfere with mechanisms essential for memory formation. We do not know how this happens at the molecular level, but current experiments are designed to discover specific ADDL toxin receptors and elucidate how these toxin receptors disrupt memory-linked synaptic structure and signaling. Structural studies of ADDLs, which are tremendously elevated in AD-afflicted brain, should play an important role in developing the first effective therapeutic Alzheimer’s drugs and vaccines. Discovering how ADDLs disrupt memory formation ultimately may give new insight into molecular memory mechanisms as well as the brain’s potential for memory enhancement.

e-mail Dr. Klein
ph: 847.491.5510
fax: 847.491.5211

Selected References:

• Hirata-Fukae C, Li HF, Hoe HS, Gray AJ, Minami SS, Hamada K, Niikura T, Hua F, Tsukagoshi-Nagai H, Horikoshi-Sakuraba Y, Mughal M, Rebeck GW, LaFerla FM, Mattson MP, Iwata N, Saido TC, Klein WL, Duff KE, Aisen PS, Matsuoka Y. (2008) Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model. Brain Research. 1216:92-103.

• McKee AC, Carreras I, Hossain L, Ryu H, Klein WL, Oddo S, LaFerla FM, Jenkins BG, Kowall NW, Dedeoglu A. (2008) Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice. Brain Research. 1207:225-36.

• Viola KL, Velasco PT, Klein WL. (2008) Why Alzheimer's is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). J Nutr Health Aging. 12(1):51S-7S. Review.

• Durairajan SS, Yuan Q, Xie L, Chan WS, Kum WF, Koo I, Liu C, Song Y, Huang JD, Klein WL, Li M. (2008) Salvianolic acid B inhibits Abeta fibril formation and disaggregates preformed fibrils and protects against Abeta-induced cytotoxicty. Neurochem Int. 52(4-5):741-50.

• Zhao WQ, De Felice FG, Fernandez S, Chen H, Lambert MP, Quon MJ, Krafft GA, Klein WL. (2008) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. 22(1):246-60.

• De Felice FG, Wasilewska-Sampaio AP, Barbosa AC, Gomes FC, Klein WL, Ferreira ST. (2007) Cyclic AMP enhancers and Abeta oligomerization blockers as potential therapeutic agents in Alzheimer's disease. Curr Alzheimer Res. 4(3):263-71. Review.

• Zhao, W, De Felice, FG, Fernandez, S, Chen, H, Lambert, MP, Quon, M, Krafft, GA, Klein, WL (2007) Amyloid beta oligomers induce impairment of neuronal insulin receptors. FASEB J. [Epub ahead of print].

• De Felice FG, Lambert MP, Viola KL, Velasco PT, Fernandez SJ, Ferreira ST, Klein WL. (2007) Aβ oligomers induce neuronal oxidative stress through an NMDA receptor-dependent mechanism that is blocked by the Alzheimer's drug memantine. J Biol Chem. 282(15):11590-601.

• De Felice FG, Wu D, Lambert MP, Fernandez SJ, Velasco PT, Lacor PN, Bigio EH, Jerecic J, Acton PJ, Shughrue PJ, Chen-Dodson E, Kinney GG, Klein WL. (2007) Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers. Neurobiol. Aging. [Epub ahead of print]

•Lacor PN, Buniel MC, Furlow PW, Sanz Clemente A, Velasco PT, Wood M, Viola KL, Klein WL. (2007) Abeta oligomer-induced aberrations in synapse composition, shape and density provide a molecular basis for loss of connectivity in Alzheimer’s disease. J Neurosci. 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, and Klein WL. (2007) Monoclonal antibodies that target pathological assemblies of Abeta. J Neurochem. 100(1):23-35.

• Georganopoulou DG, Chang L, Klein WL, and Mirkin CA. (2005) Nanoparticle-based detection of a soluble pathogenic biomarker for Alzheimer’s Disease. Proc Natl Acad Sci, 102(7): 2273-6.

• Lacor PN, Buniel MC, Gong Y, Chang L, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, and Klein WL. (2004) Synaptic targeting by Alzheimer’s related Aβ oligomers. J Neurosci, 24:10191-10200.

• Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, and Klein WL. (2003) Alzheimer's disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proc Natl Acad Sci USA, 100(18):10417-10422.

• Lambert MP, Barlow AK, Chromy B, Edwards C, Freed F, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, and Klein WL. (1998) Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci 95:6448-6453.

*Please Note: By clicking on the above links, a .pdf may be downloaded to your desktop.

Other Links:

• Link to the Klein Lab website

• Cognitive Neurology Alzheimer's Disease Center (CNADC)