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    • Notch signaling maintains the balance between

    2022-03-08

    Notch signaling maintains the balance between neural stem cells and neural progenitors (Aguirre et al., 2010, Basak and Taylor, 2007, Mizutani et al., 2007). Conditional knock out of Notch causes depletion in the progenitor pool, showing that Notch is required for the maintenance of neural stem cells (Basak et al., 2012). Notch inhibits the differentiation of progenitors into neurons and promotes the differentiation of glia progenitors into astrocytes (Bai et al., 2007, Shimojo et al., 2008). Scientists, looking to accelerate neural differentiation of induced pluripotent stem cells (iPSCs), took advantage of Notch signaling. By adding a gamma-secretase inhibitor, researchers are able to drive iPSCs to neurons (Borghese et al., 2010, Chambers et al., 2012, Chen et al., 2014, Wang et al., 2015) (Fig. 3). PS1 is also involved in adult neural stem cells. Scientists knocked down PS1 and saw a decrease in neurogenesis in the subgranular zone of the hippocampus (Gadadhar et al., 2011). Also, by knocking-in PS1 familial mutations or using a transgenic mouse expressing a chimeric human-mouse version of APP with the Swedish mutation, a severe and well studied familial mutant, researchers observed a decrease neural proliferation (Haughey et al., 2002, Wang et al., 2004). Many groups have seen a similar effect with other PS1- dependent AD mouse models, including PS1 mutants and PS1 knock downs (Bonds et al., 2015, Choi et al., 2008, Demars et al., 2010, Donovan et al., 2006, Rodriguez et al., 2008, Wen et al., 2004, Zhang et al., 2007). Conditional knock-out of PS1 in forebrain alone is enough to reduce neurogenesis (Saura et al., 2005), highlighting the importance of PS1 in the maintenance of neural stem cells.
    Gamma-secretase in neuronal structures: beyond Aβ and notch GS, through its other substrates, is involved in many neuronal processes. One such process is axonal guidance, and many GS substrates are involved. For example, the Netrin receptor, DCC, must be processed for SB 216763 to recognize midline guidance cues (Serafini et al., 1994). GS inhibition leads to an accumulation of DCCCTF (Taniguchi et al., 2003) and increased neurites. Another GS substrate, ephrinB and its receptor are involved in spine maturation and synaptogenesis (Barthet et al., 2013). It contributes to deficits in neuronal circuits, and acts with BACE to regulate growth cone collapse and recovery in axon path finding through CHL1 processing (Barao et al., 2015). GS is also crucial for synaptic morphology. Synaptic dysfunction precedes neurodegeneration and is crucial to brain health. GS substrates include cell adhesion molecules-neuroligin in the post synaptic membrane is involved in cell signaling (Marballi et al., 2012). Disruptions in this pathway are implicated in schizophrenia (Mei and Xiong, 2008). Finally, GS activity regulates dendritic spine density. EphrinA4 is cleaved by GS and regulates dendritic spine morphology. EphrinA4 cleavage is disrupted by FAD mutations, and its activity is increased by synaptic activity (Inoue et al., 2009).
    Conclusion Gamma-secretase is an enzyme complex involved in multiple signaling pathways through its numerous substrates (Fig. 4). GS is best known for its role in AD, where aberrant cleavage of APP can cause neurodegeneration. Developing therapeutics that block amyloidogenic cleavage, without altering other substrates would decrease Aβ peptides in the brain without the negative side effects associated with other GS substrates.
    Conflict of interest
    Introduction The aspartyl-protease γ-secretase produces amyloid β peptide (Aβ), a causative protein in Alzheimer's disease (AD). Aβ is produced after sequential cleavage of the amyloid β precursor protein (APP) by β-secretase (BACE1) and γ-secretase. Initially, APP is cleaved by BACE1 to produce a C99 fragment, which is further cleaved by γ-secretase [1]. γ-secretase cleaves the C99 fragment at several sites, including the ɛ site and the subsequent γ site [2]. Cleavage at the ɛ site produces Aβ49 or Aβ48, depending on which side of the site cleavage occurs. Aβ49 is processed to Aβ40 via the release of three tripeptides (ITL, VIV, and IAT), while Aβ48 is processed to Aβ42 via the release of two tripeptides (VIT and TVI) [3], indicating tripeptidylcarboxypeptidase activity of γ-secretase. Aβ in the human brain consists mainly of Aβ40 and Aβ42 at a ratio of approximately 9:1. Aβ42 is more prone to aggregate [4], and an increase in the Aβ42-to-Aβ40 ratio (Aβ42/Aβ40), observed in familial AD patients, is believed to lead to AD pathology [5]. Furthermore, Aβ43 is another neurotoxic Aβ species and PS with familial AD mutations causes higher Aβ43/Aβ40 ratios [6]. Because the Aβ42(43)/Aβ40 ratio is determined by γ-secretase, investigation of γ-secretase may help elucidate the pathogenesis of AD.