GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

Jc, Chang; Xu, Peng; Wong, Eitan; Flajolet, Marc; Y, Li; Greengard, Paul

doi:10.1101/2020.11.12.379313

Cited by 4 publications

(15 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Previous studies have extensively shown that neuronal APP trafficking is regulated by protein phosphorylation, and represents one of the most essential pathways in AD pathogenesis (Haass et al, 2012). Recently, we observed that APP trafficking and partitioning in neuronal cells is regulated by GSAP (Chang et al, 2020), which may occur through the novel GSAP/Fe65/APP/PP1 protein complex described here. Since conflicting results have been reported with respect to the direct interaction of GSAP and APP, our current data favor a molecular model where Fe65 recruits GSAP:PP1 to dephosphorylate APP and regulate its trafficking and partitioning to lipid rafts (Angira et al, 2019; Deatherage et al, 2012; Savolainen et al, 2015).…”

Section: Resultsmentioning

confidence: 68%

“…2D, S1E). Since we observed that knockdown of GSAP decreased APP-CTF association with lipid-rafts (Chang et al, 2020), these results suggest that GSAP regulates APP phosphorylation and partioning through Fe65 interaction.…”

Section: Resultsmentioning

confidence: 78%

“…2F,G) (Xie et al, 2007). Since GSAP physically interacts with Fe65 and regulates APP intracellular trafficking (Chang et al, 2020), we hypothesized that Fe65 regulates APP intracellular trafficking in a manner similar to GSAP. We first characterized Fe65 and APP sub-cellular localization in CAD cells.…”

Section: Resultsmentioning

confidence: 99%

“…Specifically, MAM accumulation of APP-C99 triggers the up-regulation of Cer level, which leads to the mitochondrial oxidative phosphorylation defects in AD (Area-Gomez et al, 2018; Area-Gomez et al, 2019). Interestingly, we have observed that GSAP is enriched in lipid-raft microdomains; and knockdown of GSAP decreases APP-CTF association with lipid-rafts (Chang et al, 2020). Importantly, Cer level is significantly decreased after GSAP knockout (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Clinical AD trials have so far tested two γ-secretase inhibitors (GSI; Semagacestat and Avagacestat), the failure of which highlighted the importance of developing selective γ-secretase modulators (GSM) (Coric et al, 2012; Doody et al, 2013; Karran and Hardy, 2014; Mekala et al, 2020; Nie et al, 2020). We previously implicate GSAP as an attractive target for selective γ-secretase modulation based on two related mechanisms: 1) GSAP specifically regulates γ-secretase catalytic activity towards APP through modulating PS1 conformation, and 2) GSAP regulates APP trafficking and partitioning into lipid-raft microdomain, where γ-secretase is enriched (Chang et al, 2020; He et al, 2010; Wong et al, 2019). Using proteomics and sn-RNAseq, our current work unbiasedly uncovered potential molecular functions of GSAP in the regulation of protein phosphorylation, trafficking, lipid metabolism and mitochondrial function.…”

Section: Resultsmentioning

confidence: 99%

See 4 more Smart Citations

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Zhou

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Biochemical, pathogenic and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNA-seq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with Fe65:APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization, and lowering GSAP expression reduces pathological effects associated with AD.

show abstract

Section: Resultsmentioning

confidence: 68%

Section: Resultsmentioning

confidence: 78%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 3 more Smart Citations

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Zhou

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation

Chen

Wang

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Significance γ-secretase activating protein (GSAP) has emerged as a key regulator of γ-secretase. In cells, GSAP exists primarily in the form of a 16-kDa fragment known as GSAP-16K. In this study, we report the finding that GSAP-16K undergoes phase separation in vitro and in cells. Importantly, the outcome of GSAP-16K phase separation directly regulates the protease activity of human γ-secretase. Through direct interaction with the substrate amyloid precursor protein–C-terminal 99-residue fragment, GSAP-16K in dilute phase favors the production of β-amyloid peptide 42 (Aβ42) but not Aβ40. These observations not only explain how GSAP activates γ-secretase but also identify their interaction as a target of potential therapeutic intervention.

show abstract

GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease

Chang

Zhou

et al. 2021

Journal of Experimental Medicine

Self Cite

View full text Add to dashboard Cite

Biochemical, pathogenic, and human genetic data confirm that GSAP (γ-secretase activating protein), a selective γ-secretase modulatory protein, plays important roles in Alzheimer’s disease (AD) and Down’s syndrome. However, the molecular mechanism(s) underlying GSAP-dependent pathogenesis remains largely elusive. Here, through unbiased proteomics and single-nuclei RNAseq, we identified that GSAP regulates multiple biological pathways, including protein phosphorylation, trafficking, lipid metabolism, and mitochondrial function. We demonstrated that GSAP physically interacts with the Fe65–APP complex to regulate APP trafficking/partitioning. GSAP is enriched in the mitochondria-associated membrane (MAM) and regulates lipid homeostasis through the amyloidogenic processing of APP. GSAP deletion generates a lipid environment unfavorable for AD pathogenesis, leading to improved mitochondrial function and the rescue of cognitive deficits in an AD mouse model. Finally, we identified a novel GSAP single-nucleotide polymorphism that regulates its brain transcript level and is associated with an increased AD risk. Together, our findings indicate that GSAP impairs mitochondrial function through its MAM localization and that lowering GSAP expression reduces pathological effects associated with AD.

show abstract

GSAP Regulates Amyloid Beta Production through Modulation of Amyloid Precursor Protein Trafficking

Cited by 4 publications

References 70 publications

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

GSAP regulates mitochondrial function through the Mitochondria-associated ER membrane in the pathogenesis of Alzheimer’s disease

Modulation of amyloid precursor protein cleavage by γ-secretase activating protein through phase separation

GSAP regulates lipid homeostasis and mitochondrial function associated with Alzheimer’s disease

Contact Info

Product

Resources

About