The amyloid cascade hypothesis revisited memory loss in early AD is a synaptic disease caused by soluble Ap oligomers

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LTP is not memory but is widely recognized as a good experimental paradigm for the study of memory mechanisms. The rapid impact of oligomers on LTP thus is intuitively appealing in its relevance to AD, and in 1998 we proposed a new hypothesis that attributed early memory loss to oligomer-induced failure in synaptic plasticity (Lambert et al. 1998). The experimental foundation for this concept has been substantiated in multiple investigations (Chen et al. 2000; Vitolo et al. 2002; Klyubin et al. 2004, 2005; Wang et al. 2004a; Costello et al. 2005; Nomura et al. 2005; Puzzo et al. 2005; Trommer et al. 2005; Walsh et al. 2005), with especially strong support found in a major study of LTP by Walsh, Selkoe and colleagues (Walsh et al. 2002). That group showed that oligomers found in medium conditioned by hAPP-transfected CHO cells are exceptionally potent inhibitors of LTP in vivo. Western blots indicate that the cell-derived oligomers comprise mostly small SDS-stable oligomers, free of structures that might be considered protofibrils, although given antibody selectivity and gel conditions it is unclear whether mid-sized oligomers might also be present (e.g., 9-24-mers). As predicted, controls using insulin-degrading enzyme, which proteolyzes monomers but not oligomers, ruled out the possibility that monomeric Ap contributed to inhibition, whereas drugs that blocked Ap production also blocked accumulation of the neuro-logically active molecules.

The compelling verification that oligomers are neurologically significant and sufficiently stable to accumulate in a cell-conditioned media, along with the vaccine results validating the prediction that memory loss is reversible, provided impetus for significant modifications in the amyloid cascade hypothesis (Hardy and Selkoe 2002). The new cascade includes two significant emendations: 1) early memory loss now is attributed to synapse failure, not neuron death, and 2) synapse failure is attributed to Ap oligomers, not amyloid fibrils.

The hypothesis that Ap oligomers play a role in AD pathogenesis has stimulated interest in the broader possibility that toxic protein oligomers may be common to multiple diseases (Klein 2005). Ap is one of more than 20 different fibrillogenic proteins that are disease-linked and, until recently, it had been assumed that the pathogenic molecules were fibrillar. However, a number of these proteins now have been found to generate sub-fibrillar, oligomeric cytotoxins (Conway et al. 2000; Butler et al. 2003; Reixach et al. 2004). In some cases, contrary to earlier dogma, oligomers exhibit cytotoxicity but fibrils do not. Extrapolation from Ap as a specific case study thus is providing general insight into diseases of protein folding and mis-assembly. Strategies that target elimination of soluble oligomeric toxins could provide new therapeutics for a broad range of significant diseases.

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