Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels

Vincent, Bruno

doi:10.1016/j.brainresbull.2016.03.020

Cited by 36 publications

(25 citation statements)

References 150 publications

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“…Most importantly, however, the amount, availability and activity of the secretases eventually decide the “biological fate” of the full-length protein by liberating its biologically active fragments. In contrast to the levels of App mRNA, which appear to be tightly controlled and provide neurons with a basal supply of APP, the activity and/or expression of secretases is regulated by neuronal activity and many other conditions, which have been reviewed elsewhere (Endres and Fahrenholz, 2012; Sun et al, 2012; Vassar et al, 2014; Vincent, 2016). …”

Section: Discussionmentioning

confidence: 99%

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco

Paul

Schlaudraff

et al. 2016

Front. Mol. Neurosci.

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The physiological role of amyloid precursor protein (APP) has been extensively investigated in the rodent hippocampus. Evidence suggests that APP plays a role in synaptic plasticity, dendritic and spine morphogenesis, neuroprotection and—at the behavioral level—hippocampus-dependent forms of learning and memory. Intriguingly, however, studies focusing on the role of APP in synaptic plasticity have reported diverging results and considerable differences in effect size between the dentate gyrus (DG) and area CA1 of the mouse hippocampus. We speculated that regional differences in APP expression could underlie these discrepancies and studied the expression of APP in both regions using immunostaining, in situ hybridization (ISH), and laser microdissection (LMD) in combination with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. In sum, our results show that APP is approximately 1.7-fold higher expressed in pyramidal cells of Ammon’s horn than in granule cells of the DG. This regional difference in APP expression may explain why loss-of-function approaches using APP-deficient mice revealed a role for APP in Hebbian plasticity in area CA1, whereas this could not be shown in the DG of the same APP mutants.

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Section: Discussionmentioning

confidence: 99%

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Turco

Paul

Schlaudraff

et al. 2016

Front. Mol. Neurosci.

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“…A disintegrin and metalloprotease 10 (ADAM10) is considered the major ␣-secretase that regulates the constitutive cleavage of APP (15,17). Newly synthesized ADAM10 is transported along the secretory pathway to the PM (18). Like other metalloproteinases, ADAM10 is synthesized as an inactive preprotein and then is activated following cleavage by a convertase within the secretory pathway, most likely in the late Golgi and/or during transport from the Golgi to the cell surface (19,20).…”

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confidence: 99%

The trans-Golgi network is a major site for α-secretase processing of amyloid precursor protein in primary neurons

Tan¹,

Gleeson

2019

Journal of Biological Chemistry

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Edited by Paul E. FraserAmyloid precursor protein (APP) is processed along the amyloidogenic pathway by the ␤-secretase, BACE1, generating ␤-amyloid (A␤), or along the nonamyloidogenic pathway by ␣-secretase, precluding A␤ production. The plasma membrane is considered the major site for ␣-secretase-mediated APP cleavage, but other cellular locations have not been rigorously investigated. Here, we report that APP is processed by endogenous ␣-secretase at the trans-Golgi network (TGN) of both transfected HeLa cells and mouse primary neurons. We have previously shown the adaptor protein complex, AP-4, and small G protein ADP-ribosylation factor-like GTPase 5b (Arl5b) are required for efficient post-Golgi transport of APP to endosomes. We found here that AP-4 or Arl5b depletion results in Golgi accumulation of APP and increased secretion of the soluble ␣-secretase cleavage product sAPP␣. Moreover, inhibition of ␥-secretase following APP accumulation in the TGN increases the levels of the membrane-bound C-terminal fragments of APP from both ␣-secretase cleavage (␣-CTF, named C83 according to its band size) and BACE1 cleavage (␤-CTF/ C99). The level of C83 was ϳ4 times higher than that of C99, indicating that ␣-secretase processing is the major pathway and that BACE1 processing is the minor pathway in the TGN. AP-4 silencing in mouse primary neurons also resulted in the accumulation of endogenous APP in the TGN and enhanced ␣-secretase processing. These findings identify the TGN as a major site for ␣-secretase processing in HeLa cells and primary neurons and indicate that both APP processing pathways can occur within the TGN compartment along the secretory pathway.

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“…The activity of the α‐secretase ADAM10 is controlled by several endogenous proteins and signaling pathways through which the modulation of its activity can be mediated at multiple levels. Indeed, the modulation of ADAM10 can be performed by interfering with its gene transcription, translation, trafficking, and maturation as well as by controlling endogenous key ADAM10‐regulating proteins, cell surface receptors, or membrane fluidity . Several compounds have been reported to activate ADAM10 gene transcription (Figure ).…”

Section: α‐Secretase Activatorsmentioning

confidence: 99%

“…Indeed, the modulation of ADAM10 can be performed by interfering with its gene transcription, translation, trafficking, and maturation as well as by controlling endogenous key ADAM10-regulating proteins, cell surface receptors, or membrane fluidity. 217 Several compounds have been reported to activate ADAM10 gene transcription ( Figure 19). Thus, acitretin (compound 124), a therapeutic drug for psoriasis, has been reported to stimulate ADAM10 gene transcription via the activation of all trans-retinoic acid (RA) receptors.…”

Section: α-Secretase Activatorsmentioning

confidence: 99%

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

Schaduangrat

Prachayasittikul

Choomwattana

et al. 2019

Medicinal Research Reviews

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The continual increase of the aging population worldwide renders Alzheimer's disease (AD) a global prime concern. Several attempts have been focused on understanding the intricate complexity of the disease's development along with the on‐ andgoing search for novel therapeutic strategies. Incapability of existing AD drugs to effectively modulate the pathogenesis or to delay the progression of the disease leads to a shift in the paradigm of AD drug discovery. Efforts aimed at identifying AD drugs have mostly focused on the development of disease‐modifying agents in which effects are believed to be long lasting. Of particular note, the secretase enzymes, a group of proteases responsible for the metabolism of the β‐amyloid precursor protein (βAPP) and β‐amyloid (Aβ) peptides production, have been underlined for their promising therapeutic potential. This review article attempts to comprehensively cover aspects related to the identification and use of drugs targeting the secretase enzymes. Particularly, the roles of secretases in the pathogenesis of AD and their therapeutic modulation are provided herein. Moreover, an overview of the drug development process and the contribution of computational (in silico) approaches for facilitating successful drug discovery are also highlighted along with examples of relevant computational works. Promising chemical scaffolds, inhibitors, and modulators against each class of secretases are also summarized herein. Additionally, multitarget secretase modulators are also taken into consideration in light of the current growing interest in the polypharmacology of complex diseases. Finally, challenging issues and future outlook relevant to the discovery of drugs targeting secretases are also discussed.

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Regulation of the α-secretase ADAM10 at transcriptional, translational and post-translational levels

Cited by 36 publications

References 150 publications

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

Region-Specific Differences in Amyloid Precursor Protein Expression in the Mouse Hippocampus

The trans-Golgi network is a major site for α-secretase processing of amyloid precursor protein in primary neurons

Multidisciplinary approaches for targeting the secretase protein family as a therapeutic route for Alzheimer's disease

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