It's probable that you won't be acquainted with every detail of this article once you have read it, but you will at least remember that it was about the causes of Alzheimer's disease. Unfortunately, a person suffering with Alzheimer's will most likely have forgotten that he has even read the article soon after finishing. Indeed, losing memory is one prominent symptom of Alzheimer's disease. The brains of afflicted individuals exhibit characteristic and invariant alterations, which are believed to account ultimately for the loss of neurons and synapses. These include the formation of intracellular neurofibrillary tau tangles and extracellular plaques of neurotoxic amyloid-β peptide, where aberrant cleavage products of the amyloid-β precursor protein assemble to form insoluble plaques. Although the molecular details of the pathology of Alzheimer's are not completely understood, transgenic mouse models have enabled neurobiologists to dissect some of the underlying pathogenic processes.
One such transgenic mouse model that has successfully reproduced amyloid plaque pathology in an age-dependent manner is called Tg2576. These mice express a human variant of the amyloid-β precursor protein (APPswe),which is associated with the early-onset of Alzheimer's disease. As a result of APPswe expression in the brain, Tg2576 mice develop amyloid plaques as well as damaged neurons and there is good evidence that the occurrence of amyloid-β peptide is responsible for the observed age-related memory loss. However, it was not clear which form of the amyloid-β peptides triggers memory loss; no forms of the peptide had been found that corresponded with the onset of memory decline. Previous studies had proposed that soluble assemblies of the amyloid-β peptide might affect memory, but the existence of such a soluble amyloid-β oligomer was uncertain until a US team of neurobiologists led by Karen Ashe provided evidence in a recently published Nature article that the memory-loss trigger may be a soluble dodecamer of the amyloid-β peptide.
The key to their discovery was a new extraction method to quantify and compare amyloid-β species from different subcellular compartments in the brains of Tg2576 mice. The scientists identified a 56-kDa dodecameric form of the amyloid-β protein (Aβ*56) in the extracellular soluble fraction of forebrain extracts that appeared at the same time as six-month old TG2576 mice began exhibiting memory loss. As there was no evidence of a correlation between memory loss and intracellular or membrane-associated amyloid-βspecies, the finding suggested that Aβ*56 may be responsible for memory loss. However, if Aβ*56 really disrupts memory, it should also cause memory loss when applied externally to the animals' brains. To test this, the team purified Aβ*56 from the brains of impaired Tg2576 mice and injected it into the lateral ventricles of young rats. Subsequent tests on the rat's behaviour in a water maze revealed that Aβ*56 transiently disrupts memory but does not impair the animals ability to learn.
Analysing the pathogenesis of Alzheimer's disease is like solving a complex puzzle. It is clear that altered proteolytic processing of amyloid-βprecursor protein resulting in an insoluble molecule is an important piece in this puzzle. Karen Ashe and coworkers' have added another piece to this complex puzzle by clearly showing the transient effects of the soluble Aβ*56 oligomer on memory loss. Although it is not clear precisely how Aβ*56 disrupts memory, the identification of a specific oligomer involved in memory loss may facilitate the development of new diagnostics and therapeutics to combat Alzheimer's disease.
