Why Alzheimer's is a Disease of Memory:Synaptic Targeting by Pathogenic Ap Oligomers (ADDLs)

摘要

Early Alzheimer's disease manifests as a crippling inability to form new memories, but why Alzheimer's is specific for memory has yet to be answered. As evidenced by this meeting, research increasingly focuses on deterioration of synapses and dendritic spines (1), a concept introduced more than 30 years ago by Scheibel and colleagues (2). This synaptic damage is now attributed to the impact of soluble Abeta oligomers, thanks to contributions from multiple laboratories. Abeta oligomers (here referred to as "ADDLs") were identified in 1998 as a new type of toxin, structurally distinct from amyloid fibrils, that rapidly prevented LTP (3). AD DL-induced disruption of plasticity is measurable at multiple levels, including ectopic over-expression of Arc, a spine cytoskeletal protein essential for memory formation. Confirming predictions based on the Arc response, ADDLs cause critical receptors to be eliminated from synaptic membranes and induce aberrations in spine morphology, with sustained presence of ADDLs resulting in spine elimination (4).