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The toxic A oligomer and Alzheimers disease: an emperor in need of clothes
Iryna Benilova1,2, Eric Karran1 & Bart De Strooper1,2
The toxic Ab oligomer hypothesis has attracted considerable attention among Alzheimers disease researchers as a way of resolving the lack of correlation between deposited amyloid-b (Ab) in amyloid plaquesin terms of both amount and location and cognitive impairment or neurodegeneration. However, the lack of a common, agreed-upon experimental description of the toxic Ab oligomer makes interpretation and direct comparison of data between different research groups impossible. Here we critically review the evidence supporting toxic Ab oligomers as drivers of neurodegeneration and make some suggestions that might facilitate progress in this complex field.
npg 2012 Nature America, Inc. All rights reserved.
Accumulation of abnormally folded proteins is a key histopatho-logical characteristic of many neurodegenerative disorders. In Huntingtons disease, the polyglutamine protein huntingtin is present in intranuclear inclusions; in prion disease, infectious prion particles bind to the membrane-bound protein. In Parkinsons disease, -synuclein aggregates as Lewy bodies in the cytoplasm of neurons. In Alzheimers disease, both intra- and extracellular amyloidsthat is, neuronal tangles containing phosphorylated tau and amyloid plaques consisting of amyloid peptides (A)are observed. Thus, aggregates accumulate extracellularly or in the cytoplasm, in the nucleus and at the cell membrane in different diseases.
A plausible generic explanation for the toxicity of intracellular aggregates involves the idea that the sequestration of crucial proteins together with amyloid leads to cellular dysfunction and death. Deregulated proteostasis could initiate and certainly enhance such protein failure. In Alzheimers disease, tau aggregates occur intracellularly and could indeed theoretically trap functional proteins, such as tau itself, possibly leading to microtubule destabilization or other cellular dysfunction and death. Alzheimers disease is somewhat unusual, however, in that there are two aggregatesintracellular tau and extracellular Athat potentially could result in neuronal dysfunction and death. A central question in the field is: by what mechanism might extracellular amyloid peptides such as A harm cells? An alternative hypothesis suggests that small soluble oligomeric structures consisting of amyloid peptides can cause cellular toxicity. Metastable oligomeric structures have indeed been described in preparations of amyloid-forming peptides such as -synuclein, tau, prion and A. When produced intracellularly, oligomers expose flexible hydro-phobic surfaces1 that might...