homeabout usour researchyour supportabout Alzheimer'snewspublicationslinkscontact ussearch

Our Publications


Klein Lab Scientific Literature

Our discovery of ADDLs has been widely acclaimed in scientific publications. With our latest report in the Proceedings of the National Academy of Sciences, citations number more than 2,100. Why is this number significant?

Link to our latest publication

Recent Articles

Amyloid ß oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis (Viola, KL & Klein, WL, Acta Neuropathol., 2015)

Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated Aß Oligomers (Wilcox, KC et al, Plos One, 2014)

Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease (Viola, KL et al, Nature Nanotech., 2014)

Modulation of Amyloid-b Aggregation by Histidine-Coordinating Cobalt(III) Schiff Base Complexes (Heffern, MC et al, Chembiochem., 2014)

Intracellular Aß pathology and early cognitive impairments in a transgenic rat overexpressing human amyloid precursor protein: a multidimensional study (Iulita, MF et al, Acta Neuropathol Commun., 2014)

Alzheimer’s Disease-Like Pathology Induced by Amyloid-β Oligomers in Nonhuman Primates (Forny-Germano, L et al, J Neurosci., 2014)

Accumulation of Intraneuronal Amyloid-β is Common in Normal Brain (Blair, JA et al, Curr Alzheimer Res., 2014)

Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease (Viola, KL et al, Nature Nanotech., 2014)

Evidence that small molecule enhancement of β-hexosaminidase activity corrects the behavioral phenotype in Dutch APPE693Q mice through reduction of ganglioside-bound Aβ (Knight, EM et al, Molecular Psychiatry, 2014)

Elucidating Molecular Mass and Shape of a Neurotoxic Aß Oligomer (Sebollela, A et al, ACS Chem Neurosci., 2014)

Alzheimer’s amyloid-ß oligomers induce hypothalamic inflammation 1 and peripheral insulin resistance in mice (Clarke, JR et al, J. Clin. Invest., 2014)

Alzheimer’s disease at the cross-roads (Spedding, M et al, Nat. Rev. Drug Disc., 2014)

Search our literature by

clicking on a numbered topic, at the right >>

1 Discovery of a new type of toxin and its presence in Alzheimer’s affected brain

2 A unifying mechanism for AD: Oligomers explain memory loss and neuropathology

3 Biomarkers and diagnostics

4 Therapeutics: Anti-ADDL vaccines and drugs

5 Related Alzheimer’s studies

6 Review articles

discovery of a new type of toxin


Soluble Aβ oligomers (ADDLs – Aβ-derived diffusible ligands) represent the archetype for a new type of toxin made by fibrillogenic disease causing proteins. ADDLs are found in AD-affected brain tissue and animal AD models.

Soluble state high resolution atomic force microscopy study of Alzheimer's beta-amyloid oligomers (Shekhawat GS et al, Appl Phys Lett, 2009)

Amyloid-β-Induced Pathological Behaviors Are Suppressed by Ginkgo biloba Extract EGb 761 and Ginkgolides in Transgenic Caenorhabditis elegans (Wu Y et al, J Neurosci, 2006)

Temporal Profile of Amyloid-β (Aβ) Oligomerization in an in Vivo Model of Alzheimer’s Disease: A Link Between Aβ and Tau Pathology (Oddo S et al, JBC, 2006)

Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1 (Ohno M et al, Eur J Neurosci, 2006)

PGH2-derived levuglandin adducts increase the neurotoxicity of amyloid β1–42 (Boutaud O, J Neurochem, 2006)

Alzheimer’s disease-affected brain: Presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss (Gong Y et al, PNAS, 2003)

Self-Assembly of Aβ1-42 into Globular Neurotoxins (Chromy BA, Biochem, 2003)

Femtomole Immunodetection of Synthetic and Endogenous Amyloid-β Oligomers and Its Application to Alzheimer’s Disease Drug Candidate Screening (Chang L et al, J Mol Neurosci, 2003)

Diffusible, nonfibrillar ligands derived from Aβ1–42 are potent central nervous system neurotoxins (Lambert MP et al, PNAS, 1998)

a unifying mechanism for Alzheimer's disease


ADDLs are toxic ligands that bind with specificity to particular synapses. ADDLs inhibit LTP, block reversal of LTD, and cause aberrant accumulation of an immediate early gene required for long-term memory. Besides disrupting memory mechanisms, ADDLs cause AD-like neuropathology, including oxidative damage, tau hyperphosphorylation, dendritic spine abnormalities, synapse elimination, insulin resistance, and nerve cell-specific death.

Amyloid-β and Tau Pathology of Alzheimer's Disease Induced by Diabetes in an Animal Model (Bitel CL etal, J Alzheimers Dis, 2012)

An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer's disease- associated Aβ oligomers (Bomfim TR, etal, J Clin Invest, 2012)

Different β-amyloid oligomer assemblies in Alzheimer brains correlate with age of disease onset and impaired cholinergic activity (Bao F etal, Neurobiol Aging, 2012)

Transgenic mice as a model of pre-clinical Alzheimer's disease (Ferretti MT etal, Curr Alzheimer Res, 2011 - Abstract Only)

N-methyl-D-aspartate receptors are required for synaptic targeting of Alzheimer's toxic amyloid-β peptide oligomers (Decker H etal, J Neurochem, 2010)

Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5 (Renner M etal, Neuron, 2010)

A mouse model of amyloid beta oligomers: their contribution to synaptic alteration, abnormal tau phosphorylation, glial activation, and neuronal loss in vivo (Tomiyama T etal, J Neurosci, 2010)

A novel transgenic rat model with a full Alzheimer's-like amyloid pathology displays pre-plaque intracellular amyloid-beta-associated cognitive impairment (Leon WC etal, J Alzheimers Dis, 2010)

Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomer a{beta} (Zhao WQ etal, J Biol Chem, 2009)

Protection of synapses against Alzheimer's-linked toxins: Insulin signaling prevents the pathogenic binding of Aβ oligomers (Fernanda G. De Felicea, Marcelo N. N. Vieirab, Theresa R. Bomfimb, Helena Deckerb, Pauline T. Velascoa, Mary P. Lamberta, Kirsten L. Violaa, Wei-Qin Zhaoa, Sergio T. Ferreirab and William L. Klein. PNAS, 2009) 

Females exhibit more extensive amyloid, but not tau, pathology in an Alzheimer transgenic model (Hirata-Fukae C etal, Brain Res, 2008)

Alzheimer's disease-type neuronal tau hyperphosphorylation induced by Aβ oligomers (De felice FG et al, Neurobiol Aging, 2008)

Amyloid beta oligomers induce impairment of neuronal insulin receptors (Zhao W-Q et al, FASEB J, 2008

Aβ Oligomer-Induced Aberrations in Synapse Composition, Shape, and Density Provide a Molecular Basis for Loss of Connectivity in Alzheimer's Disease (Lacor PN et al, J neurosci, 2007

Aβ Oligomers Induce Neuronal Oxidative Stress through an N-Methyl-D-aspartate Receptor-dependent Mechanism That Is Blocked by the Alzheimer Drug Memantine De Felice FG et al, JBC, 2007

Synaptic Targeting by Alzheimer's-Related Amyloid β Oligomers (Lacor PN et al, J Neurosci, 2004

Selective neuronal degeneration induced by soluble oligomeric amyloid beta-protein (Kim H, FASEB J, 2003)

Soluble oligomers of β amyloid (1-42) inhibit long-term potentiation but not long-term depression in rat dentate gyrus (Wang H, Brain Res, 2002)

biomarkers and diagnostics


Development of new nanotechnology-based methodologies has provided ultrasensitive assays for ADDLs in cerebrospinal fluid. ADDL correlation with Alzheimer’s disease suggests their use as a biomarker for chemical diagnostics.

Nanoscale Synaptic Membrane Mimetic Allows Unbiased High Throughput Screen That Targets Binding Sites for Alzheimer's-Associated Aß Oligomers (Wilcox, KC et al, Plos One, 2014)

Towards non-invasive diagnostic imaging of early-stage Alzheimer’s disease (Viola, KL et al, Nature Nanotech., 2014)

Detection and Identification of Bioanalytes with High Resolution LSPR Spectroscopy and MALDI Mass Spectrometry (Anker JN etal, J Phys Chem C Nanomater Interfaces, 2009)

Detection of a Biomarker for Alzheimer's Disease from Synthetic and Clinical Samples Using a Nanoscale Optical Biosensor (Haes AJ et al, JACS, 2005) (abstract only)

Nanoparticle-based detection in cerebral spinal fluid of a soluble pathogenic biomarker for Alzheimer's disease (Georganopoulou DG et al, PNAS, 2005)

A Localized Surface Plasmon Resonance Biosensor: First Steps toward an Assay for Alzheimer’s Disease (Haes AJ et al, Nano Lett, 2004)

therapeutics: anti-ADDL vaccines and drugs


Antibodies have been developed that neutralize ADDLs but not their physiological precursors, providing prototypes for Alzheimer’s therapeutics. Additionally, various types of small organic molecules have been discovered that have the ability to block ADDL formation and toxicity.

Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons (Tchantchou F etal, J Alzheimers Dis, 2009)

Alzheimer's-associated Abeta oligomers show altered structure, immunoreactivity and synaptotoxicity with low doses of oleocanthal (Pitt J etal, Toxicol Appl Pharmacol, 2009)

Conformation-dependent single-chain variable fragment antibodies specifically recognize beta-amyloid oligomers (Wang XP etal, FEBS Lett, 2009)

Salvianolic acid B inhibits Aβ fibril formation and disaggregates preformed fibrils and protects against Aβ-induced cytotoxicty (Durairajan SSK et al, Neurochem Int, 2008)

Ibuprofen reduces Abeta, hyperphosphorylated tau and memory deficits in Alzheimer mice (McKee AC et al, Brain res, 2008)

Cyclic AMP enhancers and Abeta oligomerization blockers as potential therapeutic agents in Alzheimer's disease (De Felic FG et al, Curr Alz Res, 2007) (abstract only)

Monoclonal antibodies that target pathological assemblies of Aβ (Lambert MP, J Neurochem, 2007)

Targeting the neurotoxic species in Alzheimer’s disease: inhibitors of Aβ oligomerization (De Felice FG et al, FASEB J, 2004)

Per-6-substituted-per-6-deoxy β-cyclodextrins Inhibit the Formation of β-Amyloid Peptide Derived Soluble Oligomers (Wang Z et al, J Med Chem, 2004)

Per-6-Substituted β-Cyclodextrin Libraries Inhibit Formation of β-Amyloid-Peptide (Aβ)-Derived, Soluble Oligomers (Yu J et al, J Mol Neurosci, 2002)

Vaccination with soluble Aβ oligomers generates toxicity-neutralizing antibodies (Lambert MP, J Neurochem, 2001)

related Alzheimer's studies


Earlier studies on tau, amyloid, and Alzheimer’s disease linked Aβ toxicity to signal transduction and the generation of AD-type tau hyperphosphorylation, associated mitotic signaling with Alzheimer’s cell biology, and established a link between APP metabolism and high cholesterol.

Endoplasmic reticulum stress occurs downstream of GLUN2B subunit of N-methyl-d-aspartate receptor in mature hippocampal cultures treated with amyloid-β oligomers (Costa RO et al, Aging Cell, 2012 - Abstract Only)

Inhibition of choline acetyltransferase as a mechanism for cholinergic dysfunction induced by amyloid-β peptide oligomers (Nunes-Tavares N et al, J Biol Chem, 2012)

Aβ Oligomers-Induced Toxicity is Attenuated in Cells Cultured with NbActiv4TM Medium (Zhou Y and Klein WL, Neurotox Res, 2012 - Abstract Only)

Hypercholesterolemia accelerates intraneuronal accumulation of Aβ oligomers resulting in memory impairment in Alzheimer's disease model mice (Umeda T et al, Life Sci, 2012)

Intracellular Aβ-oligomers and early inflammation in a model of Alzheimer's disease (Ferretti MT et al, Neurobiol Aging, 2012)

Visualization of co-localization in Aβ42-administered neuroblastoma cells reveals lysosome damage and autophagosome accumulation related to cell death (Soura V etal, Biochem J, 2012)

Intraneuronal amyloid β oligomers cause cell death via endoplasmic reticulum stress, endosomal/lysosomal leakage, and mitochondrial dysfunction in vivo (Umeda T et al, J Neurosci Res, 2011)

Amyloid-β triggers the release of neuronal hexokinase 1 from mitochondria (Saraiva LM et al, PLoS One, 2010)

Novel demonstration of amyloid-β oligomers in sporadic inclusion-body myositis muscle fibers (Nogalska A etal, Acta Neuropathol, 2010)

Heat shock treatment reduces beta amyloid toxicity in vivo by diminishing oligomers (Wu Y etal, Neurobiol Aging, 2010) 

CCL2 accelerates microglia-mediated Abeta oligomer formation and progression of neurocognitive dysfunction (Kiyota T et al, PLoS One, 2009)

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice (Kiyota T etal, Mol Ther, 2009)

The E693Delta mutation in amyloid precursor protein increases intracellular accumulation of amyloid beta oligomers and causes endoplasmic reticulum stress-induced apoptosis in cultured cells (Nishitsuji K etal, Am J Pathol, 2009)

Decreased brain-derived neurotrophic factor depends on amyloid aggregation state in transgenic mouse models of Alzheimer's disease (Peng S etal, J Neurosci, 2009)

Rapid Impact of β-Amyloid on Paxillin in a Neural Cell Line (Berg MM et al, J Neurosci Res, 1997)

Aβ peptide enhances focal adhesion kinase/Fyn association in a rat CNS nerve cell line (Zhang C et al, Neurosci Lett, 1996)

Cholesterol Modulates α-Secretase Cleavage of Amyloid Precursor Protein (Bodovitz S and Klein WL, JBC, 1996)

Iron Levels Modulate α-Secretase Cleavage of Amyloid Precursor Protein (Bodovitz S et al, J Neurochem, 1995)

Interaction of beta-amyloid peptides with integrins in a human nerve cell line (Sabo S et al, Neurosci Lett, 1995)

Particulate Forms of APP in the Extracellular Milieu of Cultured Cells (Barber K et al, Exp Neurol, 1995)

β/A4-evoked Degeneration of Differentiated SH-SY5Y Human Neuroblastoma Cells (Lambert MP et al, J Neurosci Res, 1994)

Microtubule-Associated Protein Tau Is Hyperphosphorylated during Mitosis in the Human Neuroblastoma Cell Line SH-SY5Y (Pope WB et al, Exp Neurol,  1994)

Focal Adhesion Kinase Expressed by Nerve Cell Lines Shows Increased Tyrosine Phosphorylation in Response to Alzheimer's Aβ Peptide (Zhang C et al, JBC, 1994)

Phosphorylated Tau Epitope of Alzheimer's Disease Is Coupled to Axon Development in the Avian Central Nervous System (Pope W et al Exp Neurol, 1993)

review articles

Amyloid ß oligomers in Alzheimer’s disease pathogenesis, treatment, and diagnosis (Viola, KL & Klein, WL, Acta Neuropathol., 2015)

Synaptotoxic Amyloid-β Oliogomers: A Molecular Basis for the Cause, Diagnosis, and Treatment of Alzheimer's Disease? (Klein, WL, J Alzheimers Dis, 2012)

The Aβ oligomer hypothesis for synapse failure and memory loss in Alzheimer's disease (Ferreira ST and Klein WL, Neurobiol Learn Mem, 2011)

Aβ oligomer-induced synapse degeneration in Alzheimer's disease (Wilcox KC, etal, Cell Mol Neurobiol, 2011)

ADDLs and the signaling web that leads to Alzheimer's disease (Krafft GA and Klein WL, Neuropharmacology, 2010)

Targeting generation of antibodies specific to conformation epitopes of amyloid beta-derived neurotoxins (Lambert MP etal, CNS Neurol Disord Drug Targets, 2009)

Why Alzheimer's is a disease of memory: the attack on synapses by A beta oligomers (ADDLs) (Viola KL et al, J Nutr Health Aging, 2008 - Abstract Only)

Why Alzheimer’s is a disease of memory: Synaptic targeting by pathogenic Aβ oligomers (ADDLs) (Klein WL et al, In: Synaptic Plasticity and the Mechanism of Alzheimer’s Disease, 2008)

Soluble Aβ oligomers in Alzheimer’s disease (Vieira MNN et al, In: Neurodegenerative Diseases: From Molecular Concepts to Therapeutic Targets,2008)

Advances on the Understanding of the Origins of Synaptic Pathology in AD (Lacor PN, Curr Genomics, 2008)

Molecules that Disrupt Memory Circuits in Alzheimer’s Disease: The Attack on Synapses by Aβ Oligomers (ADDLs) (Klein WL et al, In: Memories: Molecules and Circuits, 2007)

Synaptic targeting by Aβ oligomers (ADDLS) as a basis for memory loss in early Alzheimer’s disease (Klein WL, Alz & Dementia, 2006)

Cytotoxic intermediates in the fibrillation pathway: Aβ oligomers in Alzheimer’s disease as a case study (Klein WL, In: Protein Misfolding, Aggregation, and Conformational Diseases, 2006)

Small assemblies of unmodified amyloid β-protein are the proximate neurotoxin in Alzheimer’s disease (Klein WL et al, Neurobiol Aging, 2004)

ADDLs & protofibrils—the missing links?(Klein WL, Neurobio Aging, 2002)

Aβ toxicity in Alzheimer’s disease: globular oligomers (ADDL’s) as new vaccine and drug targets (Klein WL, Neurochem Int, 2002)

Targeting small Abeta oligomers: the solution to an Alzheimer's disease conundrum? (Klein WL etal, TINs, 2001)

Aβ toxicity in Alzheimer’s Disease (Klein WL, In: Contemporary Clinical Neuroscience: Molecular Mechanisms of Neurodegenerative Diseases, 2000)


The Klein Lab at Northwestern University
2205 Tech Drive
Evanston, Illinois 60208-3520


web site developed by    

maintained by Allan Dong