Structural basis of C-terminal β-amyloid peptide binding by the antibody ponezumab for the treatment of Alzheimer's disease.

Alzheimer's disease, the most common cause of dementia in the elderly and characterized by the deposition and accumulation of plaques, is composed in part of β-amyloid (Aβ) peptides, loss of neurons, and the accumulation of neurofibrillary tangles. Here, we describe ponezumab, a humanized monoclonal antibody, and show how it binds specifically to the carboxyl (C)-terminus of Aβ40. Ponezumab can label Aβ that is deposited in brain parenchyma found in sections from Alzheimer's disease casualties and in transgenic mouse models that overexpress Aβ.

Poloxamer 188 copolymer membrane sealant rescues toxicity of amyloid oligomers in vitro.

Amyloid oligomers and protofibrils increase cell membrane permeability, eventually leading to cell death. Here, we demonstrate that amyloid oligomer toxicity and membrane permeabilization can be reversed using the membrane sealant copolymer poloxamer 188. The data indicate that amyloid oligomer toxicity is caused by defects in the lipid bilayer of the type that are sealed by poloxamer 188.

Anti-A beta 1-11 antibody binds to different beta-amyloid species, inhibits fibril formation, and disaggregates preformed fibrils but not the most toxic oligomers.

Different strategies proposed as therapy for Alzheimer disease (AD) have aimed to reduce the level of toxic forms of A beta peptide in the brain. Here, we directly analyze the therapeutic utility of the polyclonal anti-A beta(1-11) antibody induced in 3xTg-AD mice vaccinated with the second generation prototype epitope vaccine. Substoichiometric concentrations of purified anti-A beta(1-11) antibody prevented aggregation of A beta(42) and induced disaggregation of preformed A beta(42) fibrils down to nonfilamentous and nontoxic species.

Different conformations of amyloid beta induce neurotoxicity by distinct mechanisms in human cortical neurons.

Characterization of soluble oligomeric amyloid beta (Abeta) species in the brains of Alzheimer's disease (AD) patients and transgenic models has raised the possibility that different conformations of Abeta may contribute to AD pathology via different mechanisms. To characterize the toxic effect of different Abeta conformations, we tested side by side the effect of well characterized Abeta oligomers (AbetaOs), Abeta-derived diffusible ligands (ADDLs), and fibrillar Abeta (Abetaf) preparations in human cortical neurons (HCNs). Both AbetaOs and ADDLs bind rapidly and with high affinity to synaptic contacts and cellular membranes.

Calcium dysregulation and membrane disruption as a ubiquitous neurotoxic mechanism of soluble amyloid oligomers.

Increasing evidence suggests that amyloid peptides associated with a variety of degenerative diseases induce neurotoxicity in their intermediate oligomeric state, rather than as monomers or fibrils. To test this hypothesis and investigate the possible involvement of Ca2+ signaling disruptions in amyloid-induced cytotoxicity, we made homogeneous preparations of disease-related amyloids (Abeta, prion, islet amyloid polypeptide, polyglutamine, and lysozyme) in various aggregation states and tested their actions on fluo-3-loaded SH-SY5Y cells. Application of oligomeric forms of all amyloids tested (0.

Mossy fiber plasticity and enhanced hippocampal excitability, without hippocampal cell loss or altered neurogenesis, in an animal model of prolonged febrile seizures.

Seizures induced by fever (febrile seizures) are the most frequent seizures affecting infants and children; however, their impact on the developing hippocampal formation is not completely understood. Such understanding is highly important because of the potential relationship of prolonged febrile seizures to temporal lobe epilepsy. Using an immature rat model, we have previously demonstrated that prolonged experimental febrile seizures render the hippocampus hyperexcitable throughout life.