ABSTRACT
Soluble forms of amyloid-ß peptide (Aß) are a molecular focus in Alzheimer's disease research. Soluble Aß dimers (≈8 kDa), trimers (≈12 kDa), tetramers (≈16 kDa) and Aß*56 (≈56 kDa) have shown biological activity. These Aß molecules have been derived from diverse sources, including chemical synthesis, transfected cells, and mouse and human brain, leading to uncertainty about toxicity and potency. Herein, synthetic Aß peptide-derived oligomers, cell- and brain-derived low-n oligomers, and Aß*56, were injected intracerebroventricularly (icv) into rats assayed under the Alternating Lever Cyclic Ratio (ALCR) cognitive assay. Cognitive deficits were detected at 1.3 µM of synthetic Aß oligomers and at low nanomolar concentrations of cell-secreted Aß oligomers. Trimers, from transgenic mouse brain (Tg2576), did not cause cognitive impairment at any dose tested, whereas Aß*56 induced concentration-dependent cognitive impairment at 0.9 and 1.3µM. Thus, while multiple forms of Aß have cognition impairing activity, there are significant differences in effective concentration and potency.
Subject(s)
Alzheimer Disease/metabolism , Amyloid beta-Peptides/chemical synthesis , Amyloid beta-Peptides/toxicity , Cognition Disorders/chemically induced , Peptide Fragments/chemical synthesis , Peptide Fragments/toxicity , Alzheimer Disease/genetics , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/genetics , Analysis of Variance , Animals , CHO Cells/chemistry , Chromatography, Gel/methods , Cognition Disorders/metabolism , Cognition Disorders/pathology , Cricetinae , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Administration Routes , Drug Administration Schedule , Humans , Injections, Intraventricular/methods , Mice , Mice, Transgenic , Microscopy, Atomic Force/methods , Peptide Fragments/chemistry , Peptide Fragments/genetics , Protein Structure, Tertiary , Rats , Silver Staining , Transfection/methodsABSTRACT
A central unresolved problem in research on Alzheimer disease is the nature of the molecular entity causing dementia. Here we provide the first direct experimental evidence that a defined molecular species of the amyloid-beta protein interferes with cognitive function. Soluble oligomeric forms of amyloid-beta, including trimers and dimers, were both necessary and sufficient to disrupt learned behavior in a manner that was rapid, potent and transient; they produced impaired cognitive function without inducing permanent neurological deficits. Although beta-amyloidosis has long been hypothesized to affect cognition, the abnormally folded protein species associated with this or any other neurodegenerative disease has not previously been isolated, defined biochemically and then specifically characterized with regard to its effects on cognitive function. The biochemical isolation of discrete amyloid-beta moieties with pathophysiological properties sets the stage for a new approach to studying the molecular mechanisms of cognitive impairment in Alzheimer disease and related neurodegenerative disorders.
