William Klein Professor
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.
- Figueiredo CP, Clarke JR, Ledo JH, Ribeiro FC, Costa CV, Melo HM, Mota-Sales AP, Saraiva LM, Klein WL, Sebollela A, De Felice FG, Ferreira ST. (2013). Memantine rescues transient cognitive impairment caused by high-molecular-weight aβ oligomers but not the persistent impairment induced by low-molecular-weight oligomers. J Neurosci, 33(23):9626-34. doi: 10.1523/JNEUROSCI.0482-13.2013.
- Velasco PT, Heffern MC, Sebollela A, Popova IA, Lacor PN, Lee KB, Sun X, Tiano BN, Viola KL, Eckermann AL, Meade TJ, Klein WL. (2012). Synapse-binding subpopulations of Aβ oligomers sensitive to peptide assembly blockers and scFv antibodies. ACS Chem Neurosci, 3(11):972-81. doi: 10.1021/cn300122k. Epub 2012 Oct 23.
- Pitt J, Thorner M, Brautigan D, Larner J, Klein WL. (2013). Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. FASEB J, 27(1):199-207.
- Klein WL. (2013). Synaptotoxic amyloid-β oligomers: a molecular basis for the cause, diagnosis, and treatment of Alzheimer's disease? J Alzheimers Dis, 33 Suppl 1:S49-65. Review.
- Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C, Arnold SE, Talbot K, Klein WL, Munoz DP, Ferreira ST, De Felice FG. (2012). An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers. J Clin Invest,122(4):1339-53.
- Ferreira ST, Klein WL. (2011). The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease. Neurobiol Learn Mem, 96(4):529-43.
- Renner M, Lacor PN, Velasco PT, Xu J, Contractor A, Klein WL, Triller A. (2010). Deleterious effects of amyloid β oligomers acting as an extracellular scaffold for mGluR5. Neuron, 66(5):739-54.
- Tomiyama T, Matsuyama S, Iso H, Umeda T, Takuma H, Ohnishi K, Ishibashi K, Teraoka R, Sakama N, Yamashita T, Nishitsuji K, Ito K, Shimada H, Lambert MP, Klein WL, Mori H. (2010). A mouse model of amyloid β oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo. J Neurosci, 30(14):4845-56.
- De Felice FG, Vieira MN, Bomfim TR, Decker H, Velasco PT, Lambert MP, Viola KL, Zhao WQ, Ferreira ST, Klein WL. (2009). Protection of synapses against Alzheimer's-linked toxins: insulin signaling prevents the pathogenic binding of Aβ oligomers. Proc Natl Acad Sci U S A,106(6):1971-6.
- Lacor PN, Buniel MC, Furlow PW, Clemente AS, Velasco PT, Wood M, Viola KL, Klein WL. (2007). Aβ 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.
- De Felice FG, Velasco PT, Lambert MP, Viola K, Fernandez SJ, Ferreira ST, Klein WL. (2007). Aβ oligomers induce neuronal oxidative stress through an N-methyl-D-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine. J Biol Chem, 282(15):11590-601.
- Georganopoulou DG, Chang L, Nam JM, Thaxton CS, Mufson EJ, Klein WL, Mirkin CA. (2005). Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease. Proc Natl Acad Sci U S A,102(7):2273-6.
- Lacor PN, Buniel MC, Chang L, Fernandez SJ, Gong Y, Viola KL, Lambert MP, Velasco PT, Bigio EH, Finch CE, Krafft GA, Klein WL. (2004) Synaptic targeting by Alzheimer's-related amyloid β oligomers. J Neurosci, 24(45):10191-200.
- Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, 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 U S A, (18):10417-22.
- Lambert MP, Barlow AK, Chromy BA, Edwards C, Freed R, Liosatos M, Morgan TE, Rozovsky I, Trommer B, Viola KL, Wals P, Zhang C, Finch CE, Krafft GA, Klein WL. (1998). Diffusible, nonfibrillar ligands derived from Aβ1-42 are potent central nervous system neurotoxins. Proc Natl Acad Sci U S A, 95(11):6448-53.