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.

Diffusible, nonfibrillar ligands derived from Aβ_1–42 are potent central nervous system neurotoxins (Lambert MP et al, PNAS, 1998)

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 Aβ_1-42 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)

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

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

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)

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.

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)

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)

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

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

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

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

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.

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

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)
 

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.

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

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

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)

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)

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)
 

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.

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)

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)

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)

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)

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

review articles

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

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

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)

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

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)

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)

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)