Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Taru, Hidenori; Suzuki, Toshiharu

doi:10.3233/jad-2009-1148

Cited by 19 publications

(16 citation statements)

References 86 publications

(116 reference statements)

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“…Many adaptor proteins with a phosphotyrosine binding domain, including Fe65, X11/Mint, Disabled-1 (Dab-1), and JNK-interacting protein family members, have been shown to bind to the YENPTY internalization motif within the cytoplasmic domain of APP (30). Overexpression or knock-out of some of these adaptors affects A␤ generation and deposition in the brains of transgenic mice, suggesting a physiological role for these proteins in regulating APP processing.…”

Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis

Xiao

Gil

Yan

et al. 2012

Journal of Biological Chemistry

148

125

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Background: Recent GWA studies have demonstrated an association between the endocytic clathrin adaptor PICALM and Alzheimer disease. Results: Manipulation of PICALM expression selectively alters APP endocytosis and A␤ production in neural cells and plaque deposition in APP transgenic mice. Conclusion: PICALM is involved in intracellular APP processing and plaque pathogenesis. Significance: Understanding cellular mechanisms involved in APP processing may reveal novel targets for intervention.

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Section: Discussionmentioning

confidence: 99%

Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis

Xiao

Gil

Yan

et al. 2012

Journal of Biological Chemistry

148

125

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“…However, a role of Pin1 in promoting the nonamyloidogenic processing of APP has also been described previously (Pastorino et al, 2006). In addition, one study suggests that the interaction of Fe65 with the nonphosphorylated form of APP stabilizes APP and inhibits A␤ production (Ando et al, 2001), while others have found that overexpression of Fe65 promotes the production of A␤ (Taru and Suzuki, 2009). Littermates were injected 1 month after birth with tamoxifen, to produce animals lacking MKK4 and MKK7 expression in the brain (mkk4/7 ⌬br ) and suitable controls (mkk4/7 wt ).…”

Section: Discussionmentioning

confidence: 99%

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Mazzitelli¹,

Xu²,

Ferrer³

et al. 2011

J. Neurosci.

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Phosphorylation plays a central role in the dynamic regulation of the processing of the amyloid precursor protein (APP) and the production of amyloid-␤ (A␤), one of the clinically most important factors that determine the onset of Alzheimer's disease (AD). This has led to the hypothesis that aberrant A␤ production associated with AD results from regulatory defects in signal transduction. However, conflicting findings have raised a debate over the identity of the signaling pathway that controls APP metabolism. Here, we demonstrate that activation of the c-Jun N-terminal protein kinase (JNK) is essential for mediating the apoptotic response of neurons to A␤. Furthermore, we discovered that the functional loss of JNK signaling in neurons significantly decreased the number of amyloid plaques present in the brain of mice carrying familial AD-linked mutant genes. This correlated with a reduction in A␤ production. Biochemical analyses indicate that the phosphorylation of APP at threonine 668 by JNK is required for ␥-mediated cleavage of the C-terminal fragment of APP produced by ␤-secretase. Overall, this study provides genetic evidence that JNK signaling is required for the formation of amyloid plaques in vivo. Therefore, inhibition of increased JNK activity associated with aging or with a pathological condition constitutes a potential strategy for the treatment of AD.

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“…In addition to suppression of the amyloidogenic cleavage of mAPP by direct binding between the PTB/PI domain of X11s and the 681-GYENPTY-687 motif in the APP cytoplasmic region [19], [20], X11s show other regulations in APP metabolism. Indeed, cells overexpressing X11s showed intracellular imAPP accumulation, which means a suppression of APP maturation by invalidation of O -glycosylation [1].…”

Section: Introductionmentioning

confidence: 99%

Intracellular Trafficking of the Amyloid β-Protein Precursor (APP) Regulated by Novel Function of X11-Like

et al. 2011

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BackgroundAmyloid β (Aβ), a causative peptide of Alzheimer's disease, is generated by intracellular metabolism of amyloid β-protein precursor (APP). In general, mature APP (mAPP, N- and O-glycosylated form) is subject to successive cleavages by α- or β-, and γ-secretases in the late protein secretory pathway and/or at plasma membrane, while immature APP (imAPP, N-glycosylated form) locates in the early secretory pathway such as endoplasmic reticulum or cis-Golgi, in which imAPP is not subject to metabolic cleavages. X11-like (X11L) is a neural adaptor protein composed of a phosphotyrosine-binding (PTB) and two C-terminal PDZ domains. X11L suppresses amyloidogenic cleavage of mAPP by direct binding of X11L through its PTB domain, thereby generation of Aβ lowers. X11L expresses another function in the regulation of intracellular APP trafficking.MethodologyIn order to analyze novel function of X11L in intracellular trafficking of APP, we performed a functional dissection of X11L. Using cells expressing various domain-deleted X11L mutants, intracellular APP trafficking was examined along with analysis of APP metabolism including maturation (O-glycosylation), processing and localization of APP.ConclusionsX11L accumulates imAPP into the early secretory pathway by mediation of its C-terminal PDZ domains, without being bound to imAPP directly. With this novel function, X11L suppresses overall APP metabolism and results in further suppression of Aβ generation. Interestingly some of the accumulated imAPP in the early secretory pathway are likely to appear on plasma membrane by unidentified mechanism. Trafficking of imAPP to plasma membrane is observed in other X11 family proteins, X11 and X11L2, but not in other APP-binding partners such as FE65 and JIP1. It is herein clear that respective functional domains of X11L regulate APP metabolism at multiple steps in intracellular protein secretory pathways.

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Regulation of the Physiological Function and Metabolism of AβPP by AβPP Binding Proteins

Cited by 19 publications

References 86 publications

Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis

Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis

The Loss of c-Jun N-Terminal Protein Kinase Activity Prevents the Amyloidogenic Cleavage of Amyloid Precursor Protein and the Formation of Amyloid PlaquesIn Vivo

Intracellular Trafficking of the Amyloid β-Protein Precursor (APP) Regulated by Novel Function of X11-Like

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