William Klein Professor
Our team is helping lead the way toward a molecular basis for the cause, diagnosis, and treatment of Alzheimer’s disease. Alzheimer’s is a $200 billion a year epidemic that will confront virtually all families. In an early breakthrough study, we introduced the idea that neuron damage leading to AD is instigated by small toxic oligomers of the Aβ peptide. This new idea emerged from our discovery that oligomers are potent CNS toxins that rapidly destroy synaptic memory mechanisms. Our seminal paper (MP Lambert et al, PNAS 95:6448-6453, 1998) has been cited over 2500 times (Google Scholar). Since then, we have collaborated internationally to publish more than 100 papers investigating the oligomer hypothesis and how it might lead to mechanism-based diagnostics and therapeutics. Soluble Aβ oligomers, rather than plaques, are now widely regarded as triggering the neuron damage that causes dementia (see e.g., the review in Nature by Schnabel “Little Proteins, Big Clues,” Nature, 475, S12-14, 2011). Toxic Aβ oligomers have provided a structural archetype, moreover, for cytotoxins germane to over two dozen diseases of protein misfolding (including diabetes, Parkinson’s, and prion diseases).
Our ongoing research is highly collaborative and concerns five areas. (1) Structural biology. State-of-the-art facilities at CLP are being used to discover the molecular organization of toxic oligomers. Structure is poorly understood because of the difficulty in characterizing dynamic populations of oligomers in extremely dilute solutions. Approaches include unique native protein mass spectrometry and single molecule analysis using TIRF microscopy. (2) Cell and molecular mechanisms. How neuron damage is triggered by AβOs is being investigated in brain and stem cell culture systems. Experiments carried out with the help of BIF focus on early steps in the toxic mechanism. These include binding to toxin receptors, disrupted trafficking of ion channels and GPCRs, and altered signaling pathways. (3) Etiology. What causes AβOs to build up in AD is a major unknown. We are taking new approaches using non-transgenic models to investigate metabolic factors such as diabetes, hypercholesterolemia, and lysosome dysfunction. (4) Diagnostics. Because they appear early in disease and instigate the path to dementia, AβOs provide an optimal target for diagnostics. Ultrasensitive assays for clinical chemistry are being developed along with unique approaches to brain imaging by PET and molecular MRI using the resources of CAMI. (5) Therapeutics. Therapeutic antibodies are nearing clinical trials due to partnering between pharma and Acumen, a biotech built on our past work. New programs for drug discovery focus on peptides that attach to Aβ (to stop AβO formation), on insulin signaling (to block AβO toxicity), and on use of nanoscale synaptic membrane mimetics for high throughput screening (to obtain compounds that prevent AβO binding to toxin receptors).
Key collaborators include Disterhoft, Dravid, Luan, Meade, Mirkin, Thomas, and Van Duyne (Northwestern); Sligar (University of Illinois, Urbana-Champagne); De Felice and Ferreira (Federal University, Rio de Janeiro); Mori and Tomiyama (Osaka); Cuello (McGill); Nordberg (Karolinska); Jeans (Oxford).
- 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.