13 Jul 2000

The centrality of the amyloid hypothesis for AD pathology is evident at this conference not only by the sheer number of papers and posters devoted to it (708 out of a total of 1279, as opposed to 163 for apoE and 152 for presenilin, for example), but also by the tremendous excitement surrounding the announcement by Schenk that treatments based on immunization to this protein are coming along quite nicely. But is all well in amyloidville? The occasional fly keeps settling on the body of evidence that has accumulated regarding the premise that this protein is truly the cause of the neuronal death and destruction in the AD brain. A rather large fly landed today in the form of a poster from Glenda Bishop and Stephen Robinson (Abstract 1027) concluding that intracerebral injections of Aß in the rat do not give rise to obvious toxicity. In fact, they reported that such injections protected against injury caused by ferric ammonium citrate injections. (Well, they are from down under, maybe things work backwards in the southern hemisphere?) This is not the first time that amyloid has not lived up to its reputation as neuron-slayer, but most investigators who fail to find toxicity usually keep it to themselves. A second fly could be found only two poster aisles away by a group from Elan (Abstract 1188) claiming that neither the monomeric nor the fibrillar form of amyloid (1-40) is toxic. However, they did find toxicity if they pretreated the cells with the fibrillar form and then followed with the monomeric form. The conclusion being that ongoing fibrillization is necessary to observe toxicity. This proposed mechanism may in fact be the explanation for the not uncommon failure to observe amyloid toxicity in vitro and in vivo. It may also be consistent with the observation that only fibrillar plaques in transgenic mice appear to be associated with neuritic pathology. If ongoing fibril formation is necessary to observe toxicity, any means of interfering with this process could theoretically be an effective means of countering amyloid toxicity, including the vaccine approach.—Keith Crutcher