c-Jun NH<sub>2</sub>-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Muresan, Zoia; Mureşan, Virgil

doi:10.1523/jneurosci.0152-05.2005

Cited by 74 publications

(84 citation statements)

References 51 publications

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“…Although JIP-3/JNK has been proved to phosphorylate APP in vivo (Muresan and Muresan, 2005), proteasome inhibition could not induce APP phosphorylation (data not shown). Thus, our results support the previous study that APP phosphorylation, transport of generated pAPP into neurites, and neurite extension are interdependent processes regulated by JIP-3/JNK, and are in a pathway distinct from stressactivated JNK signaling.…”

Section: Discussionmentioning

confidence: 92%

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

et al. 2011

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Amyloid beta (Aβ) precursor protein (APP) is a key protein in the pathogenesis of Alzheimer's disease (AD). Both APP and its paralogue APLP1 (amyloid beta precursor-like protein 1) have multiple functions in cell adhesion and proliferation. Previously it was thought that autophagy is a novel beta-amyloid peptide (Aβ)-generating pathway activated in AD. However, the protein proteolysis of APLP1 is still largely unknown. The present study shows that APLP1 is rapidly degraded in neuronal cells in response to stresses, such as proteasome inhibition. Activation of the endoplasmic reticulum (ER) stress by proteasome inhibitors induces autophagy, causing reduction of mature APLP1/APP. Blocking autophagy or JNK stress kinase rescues the protein expression for both APP and APLP1. Therefore, our results suggest that APP/APLP1 is degraded through autophagy and the APLP1 proteolysis is mainly mediated by autophagy-lysosome pathway.

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Section: Discussionmentioning

confidence: 92%

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

et al. 2011

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“…into account the side effects of therapeutic intervention based on inhibiting JNK activity by considering the physiological role of APP phosphorylation at T668 in neurite extension, a process known to be dependent on the JIP-3/JNK pathway (Muresan and Muresan, 2005). Another key question will be to examine the physiological role of JNK signaling in mediating amyloid toxicity in vivo.…”

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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“…Among different sites of phosphorylation, the phosphorylation at the threonine 668 residue (Thr 668 , numbering for the APP 695 isoform, i.e., Thr 743 for the APP 770 isoform) in the APP intracellular domain has received the most attention to date. This phosphorylation has been implicated in regulating APP localization to the growth cones and neurites (81,82). Significantly, the Thr 668 phosphorylated APP is shown to be preferentially transported to the nerve terminals (83), and the Thr 668 phosphorylated APP fragments are increased in AD, but not in control subjects (84), raising the possibility that this phosphorylation event may contribute to AD pathogenesis by regulating Aβ generation in neurons.…”

Section: Putative Functions Of Appmentioning

confidence: 99%

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

Nguyen¹

2015

Biomolecular Concepts

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Beta-amyloid precursor protein (APP) is a membrane-spanning protein with a large extracellular domain and a much smaller intracellular domain. APP plays a central role in Alzheimer's disease (AD) pathogenesis: APP processing generates β-amyloid (Aβ) peptides, which are deposited as amyloid plaques in the brains of AD individuals; point mutations and duplications of APP are causal for a subset of early-onset familial AD (FAD) (onset age < 65 years old). However, these mutations in FAD represent a very small percentage of cases (∼1%). Approximately 99% of AD cases are nonfamilial and late-onset, i.e., sporadic AD (SAD) (onset age > 65 years old), and the pathophysiology of this disorder is not yet fully understood. APP is an extremely complex molecule that may be functionally important in its full-length configuration, as well as the source of numerous fragments with varying effects on neural function, yet the normal function of APP remains largely unknown. This article provides an overview of our current understanding of APP, including its structure, expression patterns, proteolytic processing and putative functions. Importantly, and for the first time, my recent data concerning its epigenetic regulation, especially in alternative APP pre-mRNA splicing and in the control of genomic rearrangements of the APP gene, are also reported. These findings may provide new directions for investigating the role of APP in neuropathology associated with a deficiency in the enzyme hypoxanthine-guanine phosphoribosyltransferase (HGprt) found in patients with Lesch-Nyhan syndrome (LNS) and its attenuated variants (LNVs). Also, these findings may be of significance for research in neurodevelopmental and neurodegenerative disorders in which the APP gene is involved in the pathogenesis of diseases such as autism, fragile X syndrome (FXS) and AD, with its diversity and complexity, SAD in particular. Accurate quantification of various APPmRNA isoforms in brain tissues is needed, and antisense drugs are potential treatments.

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c-Jun NH₂-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Cited by 74 publications

References 51 publications

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

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

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

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c-Jun NH2-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein

Cited by 74 publications

References 51 publications

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

APP and APLP1 are degraded through autophagy in response to proteasome inhibition in neuronal cells

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

The human β-amyloid precursor protein: biomolecular and epigenetic aspects

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c-Jun NH₂-Terminal Kinase-Interacting Protein-3 Facilitates Phosphorylation and Controls Localization of Amyloid-β Precursor Protein