Editorial Central & Peripheral Nervous Systems: Amyloid β Peptide in Alzheimer's Disease Pathology: Towards a Rational Basis for Drug Discovery?

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Abstract
The role of the 39 - 43 amyloid β peptide known as Aβ in the pathophysiology of Alzheimer's Disease (AD) is a continuing area of active research, with often confusing and contradictory results. Considerable in vitro work suggests that this peptide, which is produced from amyloid precursor protein (APP) and can be overproduced in familial forms of AD, is neurotoxic. Inhibition of either the production of Aβ or its cellular actions represents a viable approach to the exploration of novel neurorestorative therapies for AD. Transgenic models of Aβ overproduction are a key to understanding the in vivo role of the peptide. The elusiveness of such models appears to have been addressed by recent reports of two mouse models in which overexpression of Aβ has resulted in some of the characteristic hallmarks of AD. However, the ability to select compounds for evaluation in such models remains highly dependent on preliminary in vitro testing, in which the effects of synthetic Aβ in CNS cell lines or primary cultures are examined. Such studies have been notoriously inconsistent in terms of batch-to-batch variability in peptide toxicity. While the solvent, pH and age of Aβ solutions can affect the physical form of the peptide (which, in turn, can be correlated with the neurotoxic potential of Aβ batches), there is still no way by which reliably neurotoxic lots of Aβ can be obtained. As a consequence, information involving the in vitro effects of Aβ is questionable and does not represent a good basis for a drug discovery effort. This is compounded by the fact that studies related to Aβ in solution in vitro often do not take into account the potential presence of clearance chaperones, like apolipoprotein E, and ‘pathological’ chaperones, like α1-antichymotrypsin.