RETRACTED ARTICLE: A specific amyloid-β protein assembly in the brain impairs memory

Abstract

Poor memory function has been noted in individuals that developed Alzheimer's disease up to 15 years before the eventual diagnosis of the condition. Experiments in a mouse model for the disease have now tracked down a possible cause for this early symptom: the extracellular accumulation of a soluble amyloid-β peptide assembly, dubbed Aβ*. When Aβ* is isolated from these mice and injected into rats, the rats also experience temporary memory deterioration independent of plaque formation or neuronal loss, the classic hallmarks of Alzheimer's. This work points to Aβ* as a potential diagnostic, and raises the possibility that by targeting it early it may be possible to prevent or delay the permanent changes characteristic of the later stages of the disease. Mice of the type used to model Alzheimer's disease develop a hazy memory around middle age, well before they show neuronal loss and other disease-like symptoms — this has been attributed to extracellular accumulation of a soluble assembly of amyloid-β protein, dubbed Aβ star. Memory function often declines with age1, and is believed to deteriorate initially because of changes in synaptic function rather than loss of neurons2. Some individuals then go on to develop Alzheimer's disease with neurodegeneration. Here we use Tg2576 mice, which express a human amyloid-β precursor protein (APP) variant linked to Alzheimer's disease, to investigate the cause of memory decline in the absence of neurodegeneration or amyloid-β protein amyloidosis. Young Tg2576 mice (< 6 months old) have normal memory and lack neuropathology, middle-aged mice (6–14 months old) develop memory deficits without neuronal loss, and old mice (> 14 months old) form abundant neuritic plaques containing amyloid-β (refs 3–6). We found that memory deficits in middle-aged Tg2576 mice are caused by the extracellular accumulation of a 56-kDa soluble amyloid-β assembly, which we term Aβ*56 (Aβ star 56). Aβ*56 purified from the brains of impaired Tg2576 mice disrupts memory when administered to young rats. We propose that Aβ*56 impairs memory independently of plaques or neuronal loss, and may contribute to cognitive deficits associated with Alzheimer's disease.