Operational dissection of [beta]-amyloid cytopathic effects on cultured neurons

Alzheimer disease (AD) affects mainly people over the age of 65 years, suffering from different clinical symptoms such as progressive decline in memory, thinking, language, and learning capacity. The toxic role of [beta]-amyloid peptide (A[beta]) has now shifted from insoluble A[beta] fibrils to smaller, soluble oligomeric A[beta] aggregates. The urgent need for efficient new therapies is high; robust models dissecting the physiopathological aspects of the disease are needed. We present here a model allowing study of four cytopathic effects of A[beta] oligomers (A[beta]O): oxidative stress, loss of synapses, disorganization of the neurite network, and cellular death. By generating a solution of A[beta]O and playing on the concentration of and time of exposure to A[beta]O, we have shown that it was possible to reproduce early effects (oxidative stress) and the long-term development of structural alterations (death of neurons). We have shown that 1) all toxic events were linked to A[beta]O according to a specific timing and pathway and 2) A[beta]O were probably the key intermediates in AD pathogenesis. The present model, using A[beta] peptide solution containing A[beta]O, reproduced essential neuropathological features of AD; the effects involved were similar whatever the kind of neurons tested (cortical vs. hippocampal). By using a single system, it was possible to embrace all toxic mechanisms at defined times and concentrations, to study each involved pathway, and to study the effects of new molecules on the different neurotoxic pathways responsible for development of AD. © 2013 Wiley Periodicals, Inc. [PUBLICATION ABSTRACT]