Archives

  • 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04

    • Valproic acid br Gamma secretase trafficking GS activity for

    2021-09-18


    Gamma-secretase trafficking GS activity for APP can be influenced by sub-cellular trafficking, as APP cleavage differs depending on its localization. APP is synthesized in the ER and transported to the trans-Golgi network (Annaert et al., 1999, Pasternak et al., 2003, Ray et al., 1999a, Rechards et al., 2003, Vassar et al., 1999). If it is on the cell surface, it can be cleaved by α-secretase (Parvathy et al., 1999). APP can also be internalized and cleaved by β-secretase (BACE) and GS in the ER, Golgi, and the endosomal system. The goal of some therapeutics is to shift localization to the cell surface to decrease amyloidogenic processing. Therefore, it is important to understand what factors alter APP localization. Cholesterol and lipid metabolism can affect this trafficking. APP needs to interact with Valproic acid and associated proteins to change its localization. For example, LRP1 binds to APP and mediates Aβ clearance (Deane et al., 2004, Herz and Bock, 2002, Zerbinatti et al., 2006). It is found near plaques (Rebeck et al., 1993) and polymorphisms are linked with increased risk for AD(Kang et al., 1997, Kang et al., 2000). Disrupting the interaction between LRP1 and APP decreases Aβ production by increasing cell surface APP (Ulery et al., 2000). LRP1 is also a GS substrate (Lleo et al., 2005), so modulating GS cleavage of LRP1 can shift APP trafficking. SorLA is another GS substrate implicated in APP trafficking. SorLA is decreased in AD brains (Scherzer et al., 2004) and binds APP directly (Andersen et al., 2005). Its overexpression shifts the APP to the Golgi, thereby altering Aβ production (Offe et al., 2006). SorLA was also implicated as an AD risk gene through gene variants identified in a GWAS study (Rogaeva et al., 2007). Finally, GS activity itself is regulated by low levels of cholesterol (Grimm et al., 2005, Grimm et al., 2008). Shifting APP to lipid rafts increases Aβ, where GS is localized (Fuentealba et al., 2007). Cholesterol lowering drugs decrease this interaction (Ehehalt et al., 2003, Kojro et al., 2001). An increase in cholesterol shift PS1 to late endosomes and is associated with an increase in GS activity (Burns et al., 2003). However, the interplay between GS and cholesterol is still controversial. Modulating lipid metabolism and GS activity could provide a new therapeutic target for AD.
    Notch and neural stem cells Notch was the second GS substrate identified (De Strooper et al., 1999, Ray et al., 1999a, Ray et al., 1999b). Importantly, Notch can act as a proto-oncogene or tumor suppressor in some cancers (Lobry et al., 2011). It is also involved in neural differentiation, which is especially crucial during neural development. Notch must be cleaved to become active (Kopan and Goate, 2000). Ligand binding triggers the sequential cleavage, first by ADAM metalloproteases and then by GS. This releases the Notch intracellular domain (NICD), which acts as a transcription factor for a host of genes, many involved in cell survival and differentiation (Kopan and Ilagan, 2009). All four Notch receptors are GS substrates (Saxena et al., 2001), so any therapeutic that inhibits GS activity completely will also block the action of Notch. Neural stem cells exist in both the adult and the embryonic brain, defined as any cell that can both replicate and also has the potential to differentiate into neurons or glia (Altman and Das, 1965). These neural stem cells give rise to either other neural stem cells or neural progenitors cells, which have a limited ability to divide and cannot self-renew (Bonaguidi et al., 2011). Neural progenitor cells give rise to new adult neurons, and this is correlated with improved spatial memory (Sahay et al., 2011, Stone et al., 2011). In AD, there is a decrease in neurogenesis, so understanding the complex mechanisms that regulate this process may open a new therapeutic window for the treatment of AD (Lazarov et al., 2010). Strikingly, GS and its substrates are at the heart of these pathways.