Biological targeting and activity of pre-fibrillar Aβ assemblies

The body of work from the past decade has advanced our understanding of how toxic oligomers of Aβ are capable of eliciting the spectrum of pathological and behavioral hallmarks of Alzheimer's disease. These potent neurotoxins now provide a molecular basis for the cause of this disease as well as a basis for identifying and evaluating diagnostic and therapeutic strategies. Oligomer toxicity is mediated by a number of factors-both in the targeting of these toxins to the neuronal synapses and in the transduction of this targeting into intracellular signals resulting in synapse loss and, eventually, cell death. Recent investigations have focused on defining the mechanisms of binding of toxic Aβ oligomers, the pathways modulated by these events, and strategies to treat Alzheimer's disease by targeting both aspects. One promising facet of recent research highlighted in this chapter, and in which Aβ oligomers play a central role, is the unfolding of connection between Alzheimer's disease and insulin signaling in the aging brain.