title: A mutation protective against Alzheimer's disease renders amyloid β precursor protein incapable of mediating neurotoxicity.
abstract: 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.
authors.affiliation: Department of Pharmacology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Masaaki
authors.initials: M
authors.lastname: Matsuoka
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000633:toxicity*; D000686:Amyloidosis / Q000235:genetics / Q000473:pathology; D000818:Animals; D015153:Blotting, Western; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000502:physiology; D018773:Genes, erbB-1 / Q000235:genetics / Q000502:physiology; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020258:Neurotoxicity Syndromes / Q000235:genetics* / Q000473:pathology*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation
chemical_list: D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D048670:MAP Kinase Kinase 4
keywords: AD-protective mutation; APP; Alzheimer's disease; TGFβ2; amyloid β-independent