7 These two peptides both appear to be next produced by normal γ-secretase function, and it is true that many of the mutations shift the pattern of cleavage of APP so that despite the overall reduction in APP cleavage, relatively more of the 42 amino acid peptide is produced, decreasing the 40/42 ratio.4 The β-amyloid 42 peptide does aggregate more readily than β-amyloid 40, and is more neurotoxic in in vitro assays.32,33 The ”toxic gain of function“ model suggests that this is critical to the cascade of events that ensue. Precisely what inhibitors of y secretase

do to this ratio is unclear, although at least some published data indicates that Inhibitors,research,lifescience,medical Inhibitors,research,lifescience,medical suppression of γ secretase activity can occur without a significant change in the 40/42 ratio.7 Perhaps this will prove critical to the success – or failure – of secretase inhibition in general. Only the clinical trials seem likely to

provide this answer. Use of antibodies, presumably to remove amyloid from the brain Antibody approaches to reducing β amyloid in brain began with the spectacular studies of Schenk and colleagues, who immunized mutant human APP transgenic mice with β-amyloid peptides, and selleckchem Imatinib Mesylate reported very significant reductions in amyloid deposition in these mice.34 Several others have confirmed and extended this early work,35,36 and human trials of “amyloid vaccination” have already Inhibitors,research,lifescience,medical been carried Inhibitors,research,lifescience,medical out. This is not the forum for discussing the controversial

nature of these studies: suffice it to say that the results were far from the ideal. A number of patients developed an encephalitis,37 and in some cases this appeared to be disastrous. Whether or not there was any benefit remains highly dubious,38,39 but from a mechanistic viewpoint this approach raises a fundamental question: just how is an immune response to amyloid peptides supposed to reduce β amyloid concentrations in the brain? Active immunization of transgenic mice with human amyloid peptides can Inhibitors,research,lifescience,medical produce the full range of B- and Tcell responses, in part because the human and mouse peptides differ in sequence – the human peptide is “foreign” to mice. Presumably the T-cell responses are what led to the encephalitis in humans immunized with human peptides, consistent with the induction of an autoimmune response.36,40,41 But why would a B cell Entinostat – an antibody-producing response – be helpful? Generally, antibodies in the circulation penetrate into the brain in only low concentrations.42 However, studies again in transgenic mice suggested that passive immunization, in which antibodies to β-amyloid were injected into the mice, have also been reported to cause significant reductions in the deposition of β-amyloid in the brains of the mice.43,44 There are two basic ideas of how this might work.