Why Alzheimer's is a disease of memory: the attack on synapses by A beta oligomers (ADDLs).
Individuals with early-stage Alzheimer's disease (AD) suffer from profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active A beta oligomers (1). We have named these oligomers "ADDLs" (for pathogenic A beta-Derived Diffusible Ligands). ADDLs constitute metastable alternatives to the disease-defining A beta fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as A beta 12mers (2) (approximately 54 kDa) and can be found in dot-like clusters distinct from senile plaques (3). Oligomers of equal mass have been reported to occur in tgmouse AD models where they emerge concomitantly with memory failure (4), consistent with ADDL inhibition of LTP (1). In cell biology studies, ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors (5,6). Binding produces ectopic expression of the memory-linked immediate early gene Arc. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition (7) are predicted consequences of Arc overexpression, a pathology associated with memory dysfunction in tg-Arc mice. Significantly, the attack on synapses provides a plausible mechanism unifying memory dysfunction with major features of AD neuropathology; recent findings show that ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation. Acting as novel neurotoxins that putatively account for memory loss and neuropathology, ADDLs present significant targets for disease-modifying therapeutics in AD.
Viola
K L
KL
Department of Neurobiology and Physiology, Cognitive Neurology and Alzheimer's Disease Center, Northwestern University, Evanston, IL 60208, USA.
Velasco
P T
PT
Klein
W L
WL
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000633:toxicity; D001923:Brain Chemistry; D006801:Humans; D008024:Ligands; D008568:Memory / Q000502:physiology; D009434:Neural Pathways / Q000473:pathology*; D009474:Neurons / Q000473:pathology; D013569:Synapses / Q000473:pathology*
D016229:Amyloid beta-Peptides; D008024:Ligands