A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity

Expression of a familial Alzheimer's disease (AD)-linked mutant of amyloid beta precursor protein (APP) or the binding of transforming growth factor beta 2 to wild-type (wt)-APP causes neuronal death by activating an intracellular death signal (a APP-mediated intracellular death signal) in the absence of the involvement of amyloid beta (A beta) toxicity in vitro. These neuronal death models may therefore be regarded as A beta-independent neuronal death models related to AD. A recent study has shown that the A673T mutation in the APP isoform APP(770), corresponding to the A598T mutation in the most prevalent neuronal APP isoform APP(695) (an AD-protective mutant of APP), is linked to a reduction in the incidence rate of AD. Consistent with this, cells expressing the AD-protective mutant of APP produce less A beta than cells expressing wt-APP. In this study, transforming growth factor beta 2 caused death in cultured neuronal cells expressing wt-APP, but not in those expressing the AD-protective mutant of APP. This result suggests that the AD-protective mutation of APP reduces the incidence rate of AD by attenuating the APP-mediated intracellular death signal. In addition, a mutation that causes hereditary cerebral hemorrhage with amyloidosis-Dutch type also attenuated the APP-mediated intracellular death signal.