William L. Klein
Molecular basis of Alzheimer's disease; Signal transduction and the cell biology of memory-linked synapses
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).
TNF-α Mediates PKR-Dependent Memory Impairment and Brain IRS-1 Inhibition Induced by Alzheimer’s β-Amyloid Oligomers in Mice and Monkeys. Lourenco MV, Clarke JR, Frozza RL, Bomfim TR, Forny-Germano L, Batista AF, Sathler LB, Brito-Moreira J, Amaral OB, Silva CA, Freitas-Correa L, Espírito-Santo S, Campello-Costa P, Houzel J-C, Klein WL, Holscher C, Carvalheira JB, Silva AM, Velloso LA, Munoz DP, Ferreira ST, and De Felice FG. Cell Metabolism. 2013 December 3;18(6):831-843.
Disruption of neocortical histone H3 homeostasis by soluble Aβ: implications for Alzheimer's disease. Lithner CU, Lacor PN, Zhao W-Q, Mustafiz T, Klein WL, Sweatt JD, and Hernandez CM. Neurobiology of Aging. 2013 September;34(9):2081-2090.
FcγRIIb mediates amyloid-β neurotoxicity and memory impairment in Alzheimer’s disease. Kam T-I, Song S, Gwon Y, Park H, Yan J-J, Im I, Choi J-W, Choi T-Y, Kim J, Song D-K, Takai T, Kim Y-C, Kim K-S, Choi S-Y, Choi S, Klein WL, Yuan J, and Jung Y-K. Journal of Clinical Investigation. 2013 July 1;123(7):2791-2802.
Memantine Rescues Transient Cognitive Impairment Caused by High-Molecular-Weight Aβ Oligomers But Not the Persistent Impairment Induced by Low-Molecular-Weight Oligomers. Figueiredo CP, Clarke JR, Ledo JH, Ribeiro FC, Costa CV, Melo HM, Mota-Sales AP, Saraiva LM, Klein WL, Sebollela A, De Felice FG, and Ferreira ST. Journal of Neuroscience. 2013 June 5;33(23):9626-9634.
Nanodisc-solubilized membrane protein library reflects the membrane proteome. Marty MT, Wilcox KC, Klein WL, and Sligar SG. Analytical and Bioanalytical Chemistry. 2013 May;405(12):4009-4016.
Modeling Alzheimer’s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular Aβ and Differential Drug Responsiveness. Kondo T, Asai M, Tsukita K, Kutoku Y, Ohsawa Y, Sunada Y, Imamura K, Egawa N, Yahata N, Okita K, Takahashi K, Asaka I, Aoi T, Watanabe A, Watanabe K, Kadoya C, Nakano R, Watanabe D, Maruyama K, Hori O, Hibino S, Choshi T, Nakahata T, Hioki H, Kaneko T, Naitoh M, Yoshikawa K, Yamawaki S, Suzuki S, Hata R, Ueno S, Seki T, Kobayashi K, Toda T, Murakami K, Irie K, Klein WL, Mori H, Asada T, Takahashi R, Iwata N, Yamanaka S, and Inoue H. Cell Stem Cell. 2013 April 4;12(4):487-496.
Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. Pitt J, Thorner M, Brautigan D, Larner J, and Klein WL. FASEB Journal. 2013 January 1;27(1):199-207.
Brain Transit and Ameliorative Effects of Intranasally Delivered Anti-Amyloid-β Oligomer Antibody in 5XFAD Mice. Xiao C, Davis FJ, Chauhan BC, Viola KL, Lacor PN, Velasco PT, Klein WL, and Chauhan NB. Journal of Alzheimer's Disease. 2013;35(4):777-788.
Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice. Umeda T, Tomiyama T, Kitajima E, Idomoto T, Nomura S, Lambert MP, Klein WL, and Mori H. Life Sciences. 2012 December 10;91(23-24):1169-1176.
Synapse-Binding Subpopulations of Aβ Oligomers Sensitive to Peptide Assembly Blockers and scFv Antibodies. Velasco PT, Heffern MC, Sebollela A, Popova IA, Lacor PN, Lee KB, Sun X, Tiano BN, Viola KL, Eckermann AL, Meade TJ, and Klein WL. ACS Chemical Neuroscience. 2012 November 21;3(11):972-981.
View all publications by William L. Klein listed in the National Library of Medicine (PubMed).