ADDLs and the signaling web that leads to Alzheimer’s disease

Today, it is widely accepted that ADDLs, soluble oligomeric assemblies of the amyloid β peptide, play a prominent role in triggering the cognitive deficits and neurodegeneration that constitute Alzheimer’s disease (AD). Within the past decade, the longstanding emphasis on fibrillar deposits and neuronal death has given way to a new paradigm involving ADDL-triggered aberrant synaptic signaling and consequent memory malfunction and neurodegeneration. As with any paradigm shift in biology, not all molecular details have been elucidated, and not all AD scientists are fully subscribed. Nevertheless, the ADDL paradigm affords a promising framework for ongoing AD research and for development of the first therapeutics endowed with the dual capabilities of immediate symptom reversal and long-term disease modification. In this review we provide a brief account of the discovery of ADDLs, followed by a summary of key results that address questions concerning ADDL structure and assembly, biological activity and therapeutic possibilities.