Complex regulation of Î³-secretase: from obligatory to modulatory subunits

Gertsik, Natalya; Chiu, Danica; Li, Yueming

doi:10.3389/fnagi.2014.00342

Cited by 57 publications

(68 citation statements)

References 104 publications

(124 reference statements)

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“…Accordingly, we hypothesized that the potential “NCT‐APP/Aβ” interface could directly contribute to the stability of E‐S interactions and thereby modulate the length of Aβ products. Note that the established role of the non‐catalytic subunits (NCT, PEN‐2 and APH1) of the protease in PSEN/GSEC function and turnover (Gertsik et al , ; Carroll & Li, ) supports their contribution to the stability of GSEC‐APP/Aβ complexes.…”

Section: Discussionmentioning

confidence: 94%

Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ‐secretase modulators

et al. 2019

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γ‐Secretase complexes ( GSEC s) are multimeric membrane proteases involved in a variety of physiological processes and linked to Alzheimer's disease ( AD ). Presenilin ( PSEN , catalytic subunit), Nicastrin ( NCT ), Presenilin Enhancer 2 ( PEN ‐2), and Anterior Pharynx Defective 1 ( APH 1) are the essential subunits of GSEC s. Mutations in PSEN and the Amyloid Precursor Protein ( APP ) cause early‐onset AD . GSEC s successively cut APP to generate amyloid‐β (Aβ) peptides of various lengths. AD ‐causing mutations destabilize GSEC ‐ APP /Aβ n interactions and thus enhance the production of longer Aβs, which elicit neurotoxic events underlying pathogenesis. Here, we investigated the molecular strategies that anchor GSEC and APP /Aβ n during the sequential proteolysis. Our studies reveal that a direct interaction between NCT ectodomain and APP C99 influences the stability of GSEC ‐Aβn assemblies and thereby modulates Aβ length. The data suggest a potential link between single‐nucleotide variants in NCSTN and AD risk. Furthermore, our work indicates that an extracellular interface between the protease ( NCT , PSEN ) and the substrate ( APP ) represents the target for compounds ( GSM s) modulating Aβ length. Our findings may guide future rationale‐based drug discovery efforts.

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Section: Discussionmentioning

confidence: 94%

Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ‐secretase modulators

et al. 2019

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“…The function of c-secretase complex is tightly regulated since there are distinct control mechanisms through its four subunits (Gertsik et al 2015). There is abundant evidence that hypoxia/ischemia increase the expression and activity of c-secretase in the brain and neuronal cultures (Pennypacker et al 1999;Li et al 2009;Pluta et al 2013a;Kocki et al 2015).…”

Section: Epigeneticsmentioning

confidence: 99%

“…NCT, APH-1, and PEN2, (ii) several interacting proteins, e.g. c-secretase activating proteins (GSAPs), voltage-dependent anion channel 1 (VDAC1), and HIF-1a, and (iii) lipid microdomains called lipid rafts (Ehehalt et al 2003;Wakabayashi et al 2009;Hur et al 2012;Gertsik et al 2015;Inoue et al 2015). Moreover, APP has its own interactome which probably affects the processivity of APP (Bai et al 2008).…”

Section: Protein Interactionsmentioning

confidence: 99%

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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“…The main β-secretase in AD was identified as beta amyloid converting enzyme 1 (BACE1) [3]. Gamma secretase is a tetramer comprising presenilin 1 or 2 (PSEN1/2), anterior pharynx-defective 1 (APH-1), nicastrin (NCT), and presenilin enhancer 2 (PEN-2) [4]. …”

Section: Introductionmentioning

confidence: 99%

Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

Decourt¹,

Lahiri

Sabbagh

2017

CAR

311

212

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Alzheimer’s disease (AD) affects an estimated 44 million individuals worldwide, yet no therapeutic intervention is available to stop the progression of the dementia. Neuropathological hallmarks of AD are extracellular deposits of amyloid beta (Aβ) peptides into plaques, intraneuronal accumulation of hyperphosphorylated tau protein forming tangles, and chronic inflammation. A pivotal molecule in inflammation is the pro-inflammatory cytokine TNF-α. Several lines of evidence using genetic and pharmacological manipulations indicate that TNF-α signaling exacerbates both Aβ and tau pathologies in vivo. Interestingly, preventive and intervention anti-inflammatory strategies demonstrated a reduction in brain pathology and an amelioration of cognitive function in rodent models of AD. Phase I and IIa clinical trials suggest that TNF-α inhibitors might slow down cognitive decline and improve daily activities in AD patients. In the present review, we summarize the evidence pointing towards a beneficial role of anti-TNF-α therapies to prevent or slow the progression of AD. We also present possible physical and pharmacological interventions to modulate TNF-α signaling in AD subjects along with their limitations.

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Complex regulation of Î³-secretase: from obligatory to modulatory subunits

Cited by 57 publications

References 104 publications

Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ‐secretase modulators

Extracellular interface between APP and Nicastrin regulates Aβ length and response to γ‐secretase modulators

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

Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease

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