Cytoplasmic Fragment of Alcadein α Generated by Regulated Intramembrane Proteolysis Enhances Amyloid β-Protein Precursor (APP) Transport into the Late Secretory Pathway and Facilitates APP Cleavage

Takei, Norio; Sobu, Yuriko; Kimura, Akiko; Urano, Satomi; Piao, Yi; Araki, Yasuhisa; Taru, Hidenori; Yamamoto, Tohru; Hata, Satoshi; Nakaya, Tadashi; Suzuki, Toshiharu

doi:10.1074/jbc.m114.599852

Cited by 19 publications

(17 citation statements)

References 41 publications

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“…), and alcadein (calsyntenin) proteins (Takei et al . ). Vascular dysfunctions are present during the early phase of AD pathogenesis, probably attributable to the hypoperfusion of brain.…”

Section: Discussionmentioning

confidence: 97%

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Salminen

Kauppinen

Kaarniranta

2017

Journal of Neurochemistry

170

124

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Alzheimer's disease (AD) is associated with deficiencies in cerebrovascular functions, e.g. reduced cerebral blood flow and capillary amyloid angiopathy, both of which are evident during the early phase of AD, thus local hypoxia/ischemia could augment the pathogenesis of AD. There is abundant literature revealing that exposures to hypoxia/ischemia increase the amyloidogenic processing of amyloid-b precursor protein (APP) leading to the accumulation of amyloid-b peptides in brain. This hypoxia-induced response has been attributed to a significant increase in the activities of b-and csecretases, whereas a-secretase activity decreases in hypoxia. Recent studies have indicated that hypoxia-inducible factor-1a (HIF-1a) stimulates the transcription of the bsecretase 1 (BACE1) gene through the hypoxia-response element in the BACE1 promoter. Moreover, HIF-1a protein can directly interact with the c-secretase complex and increase its activity in a non-transcriptional manner. Hypoxia/ischemia also trigger endoplasmic reticulum stress and impair autophagy in brain, which consequently can stimulate the expression of presenilin 1 (PS1) and activate c-secretase. Subsequently, PS1 protein can stabilize HIF-1a protein and in addition, APP intracellular domain peptide is able to induce the expression of HIF-1a. The activation of b-and c-secretases is an evolutionarily conserved hypoxia response, e.g. it is also present in zebrafish. Given that b-and c-secretases have many substrates in addition to APP, one could postulate that AD pathology is a byproduct of the rescue process mediated by these two aspartyl proteinases under hypoxic/ischemic conditions. We will review the recent evidence indicating that vascular dysfunctions can provoke AD pathology by activating b-and c-secretases.

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“…), and alcadein (calsyntenin) proteins (Takei et al . ). Vascular dysfunctions are present during the early phase of AD pathogenesis, probably attributable to the hypoperfusion of brain.…”

Section: Discussionmentioning

confidence: 97%

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Salminen

Kauppinen

Kaarniranta

2017

Journal of Neurochemistry

170

124

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“…APP can interact as well with alcadein/calsyntenin, a type-1 transmembrane protein that contains cadherin repeat motifs [137] . Following sequential α-secretase and γ-secretase cleavages of alcadein, alcadein-ICD interacts with X11 and forms a ternary complex with APP-CTF [138] . Tripartite interaction of Dab1 and DISC1 (disrupted-in-schizophrenia-1, a protein with multiple coiled coil motifs) with APP through distinct binding sites in APP-CTF has been described [139] .…”

Section: App-mediated Intracellular Signalingmentioning

confidence: 99%

APP Receptor? To Be or Not To Be

Deyts

Wang

Parent

2016

Trends in Pharmacological Sciences

113

110

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Amyloid Precursor Protein (APP) and its metabolites play a critical role in Alzheimer’s disease pathogenesis. The idea that APP may function as a receptor has gained momentum based on its structural similarities to type I transmembrane receptors, and the identification of putative APP ligands. Here we review the recent experimental evidence in support of this notion and discuss how this concept is viewed in the field. Specifically, we focus on the structural and functional characteristics of APP as a cell surface receptor, and its interaction with adaptors and signaling proteins. We also address the importance of APP's function as a receptor in Alzheimer’s disease etiology and discuss how this function might be potentially important for the development of novel therapeutic approaches.

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“…APP metabolism is intimately involved in the pathogenesis of Alzheimer's disease (AD). Alcs are also subject to proteolytic cleavage by a combination of α‐ and γ‐secretases, yielding secreted p3‐Alc and the intracellular domain fragment Alc ICD [11,20,21]. As with Aβ, secreted p3‐Alc is detectable in cerebrospinal fluid (CSF) and later in blood.…”

Section: Introductionmentioning

confidence: 99%

Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

Hata

Omori

Kimura

et al. 2019

A&D Transl Res & Clin Interv

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IntroductionNeuronal p3-Alcβ peptides are generated from the precursor protein Alcadein β (Alcβ) through cleavage by α- and γ-secretases of the amyloid β (Aβ) protein precursor (APP). To reveal whether p3-Alcβ is involved in Alzheimer's disease (AD) contributes for the development of novel therapy and/or drug targets.MethodsWe developed new sandwich enzyme-linked immunosorbent assay (sELISA) systems to quantitate levels of p3-Alcβ in the cerebrospinal fluid (CSF).ResultsIn monkeys, CSF p3-Alcβ decreases with age, and the aging is also accompanied by decreased brain expression of Alcβ. In humans, CSF p3-Alcβ levels decrease to a greater extent in those with AD than in age-matched controls. Subjects carrying presenilin gene mutations show a significantly lower CSF p3-Alcβ level. A cell study with an inverse modulator of γ-secretase remarkably reduces the generation of p3-Alcβ37 while increasing the production of Aβ42.DiscussionAging decreases the generation of p3-Alcβ, and further significant decrease of p3-Alcβ caused by aberrant γ-secretase activity may accelerate pathogenesis in AD.

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Cytoplasmic Fragment of Alcadein α Generated by Regulated Intramembrane Proteolysis Enhances Amyloid β-Protein Precursor (APP) Transport into the Late Secretory Pathway and Facilitates APP Cleavage

Cited by 19 publications

References 41 publications

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

Hypoxia/ischemia activate processing of Amyloid Precursor Protein: impact of vascular dysfunction in the pathogenesis of Alzheimer's disease

APP Receptor? To Be or Not To Be

Decrease in p3‐Alcβ37 and p3‐Alcβ40, products of Alcadein β generated by γ‐secretase cleavages, in aged monkeys and patients with Alzheimer's disease

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