A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity
Version of Record online: 9 APR 2014
© 2014 International Society for Neurochemistry
Journal of Neurochemistry
Volume 130, Issue 2, pages 291–300, July 2014
How to Cite
J. Neurochem. (2014) 130, 291–300.
- Issue online: 7 JUL 2014
- Version of Record online: 9 APR 2014
- Accepted manuscript online: 19 MAR 2014 12:23PM EST
- Manuscript Accepted: 14 MAR 2014
- Manuscript Revised: 23 FEB 2014
- Manuscript Received: 19 OCT 2013
- Grant-in-Aid for Scientific Research. Grant Number: 23390059
- Ministry of Education, Culture, Sports, Science, and Technology. Grant Number: 25460343
- AD-protective mutation;
- Alzheimer's disease;
- amyloid β-independent;
- APP ;
Expression of a familial Alzheimer's disease (AD)-linked mutant of amyloid β precursor protein (APP) or the binding of transforming growth factor β2 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 β (Aβ) toxicity in vitro. These neuronal death models may therefore be regarded as Aβ-independent neuronal death models related to AD. A recent study has shown that the A673T mutation in the APP isoform APP770, corresponding to the A598T mutation in the most prevalent neuronal APP isoform APP695 (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 Aβ than cells expressing wt-APP. In this study, transforming growth factor β2 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.
The A598T mutation of amyloid precursor protein APP is linked to a reduction in the incidence rate of Alzheimer's disease (AD). This study shows that TGFβ2 causes death in neuronal cells expressing wild-type APP, but not in those expressing the AD-protective mutant of APP, suggesting that the AD-protective mutation of APP reduces the incidence rate of AD by attenuating the APP-mediated intracellular death signal.