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

Chen, Jin; Wang, Jiaoni; Wang, Yumeng; Jia, Bojun; Guo, Xuefei; Yang, Guanghui; Xu, Peng; Greengard, Paul; Zhou, Rui; Shi, Yigong

doi:10.1073/pnas.2122292119

Cited by 11 publications

(6 citation statements)

References 63 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Gsap deletion in cells and mice attenuates the production of both Aβ 40 and Aβ 42 and also increases cellular respiration important for cell survival. Cognitive function is improved in Gsap knockout animal models of Alzheimer’s disease, consistent with the amyloid hypothesis of neurodegeneration ( 1 , 2 , 4 , 6 , 8 ). Although GSAP is best known for its influence on Aβ production in the brain, its contributions to subcellular signal transduction and protein trafficking promotes cell survival, illustrating its physiological role extends beyond the production of Aβ ( 5 ).…”

Section: Introductionsupporting

confidence: 67%

“…The 16-kDa GSAP interacts with the adaptor protein Fe65 and presenilin-1, which are components of the gamma-secretase enzyme complex, in the mitochondria-associated membrane, where it also binds to amyloid precursor protein ( 4 , 5 ). GSAP thus localizes the gamma-secretase enzyme complex with amyloid precursor protein important to produce beta-amyloid (Aβ) variants, including Aβ 40 and Aβ 42 ( 4 , 6 , 7 ). However, GSAP has an additional subcellular function(s).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Gwin

Alexeyev

Geurts

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

Pneumonia elicits the production of cytotoxic beta amyloid (Ab) that contributes to end-organ dysfunction, yet the mechanism(s) linking infection to activation of the amyloidogenic pathway that produces cytotoxic Ab is unknown. Here, we tested the hypothesis that g-secretase activating protein (GSAP), which contributes to the amyloidogenic pathway in the brain, promotes end-organ dysfunction following bacterial pneumonia. First-in-kind GSAP knockout rats were generated. Wild type and knockout rats possessed similar body weights, organ weights, circulating blood cell counts, arterial blood gases, and cardiac indices at baseline. Intratracheal Pseudomonas aeruginosa infection caused acute lung injury and a hyperdynamic circulatory state. Whereas infection led to arterial hypoxemia in wild type rats, the alveolar-capillary barrier integrity was preserved in GSAP knockout rats. Infection potentiated myocardial infarction following ischemia-reperfusion injury, and this potentiation was abolished in knockout rats. In the hippocampus, GSAP contributed to both pre- and postsynaptic neurotransmission, increasing the presynaptic action potential recruitment, decreasing neurotransmitter release probability, decreasing the postsynaptic response, and preventing postsynaptic hyperexcitability, resulting in greater early long-term potentiation but reduced late long-term potentiation. Infection abolished early and late long-term potentiation in wild type rats, whereas the late long-term potentiation was partially preserved in GSAP knockout rats. Furthermore, hippocampi from knockout rats, and both the wild type and knockout rats following infection, exhibited a GSAP-dependent increase in neurotransmitter release probability and postsynaptic hyperexcitability. These results elucidate an unappreciated role for GSAP in innate immunity and highlight the contribution of GSAP to end-organ dysfunction during infection.

show abstract

Section: Introductionsupporting

confidence: 67%

Section: Introductionmentioning

confidence: 99%

Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Gwin

Alexeyev

Geurts

et al. 2023

American Journal of Physiology-Lung Cellular and Molecular Phys

View full text Add to dashboard Cite

show abstract

“…According to our in vivo experiments, the depressive state caused by CUMS is connected with the pathological feature of AD, Aβ. APP is hydrolyzed to Aβ1-40 and Aβ1-42 by γ-secretase [ 36 ], of which Aβ1-42 is the main component in the formation of senile plaques and causes neuronal death and cognitive decline [ 37 ]. Aβ25-35 is the active peptide fragment of Aβ1-42, and its oligomeric form is the main active site causing neurotoxicity [ 38 ].…”

Section: Resultsmentioning

confidence: 99%

Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells

Fan

Zheng

et al. 2023

Nutrients

View full text Add to dashboard Cite

Depression is often considered one of the prevalent neuropsychiatric symptoms of Alzheimer’s disease (AD). β-amyloid (Aβ) metabolism disorders and impaired microglia phagocytosis are potential pathological mechanisms between depression and AD. Folate deficiency (FD) is a risk factor for depression and AD. In this study, we used a chronic unpredictable mild stress (CUMS) rat model and a model of Aβ phagocytosis by BV2 cells to explore the potential mechanisms by which FD affects depression and AD. The results revealed that FD exacerbated depressive behavior and activated microglia in CUMS rats, leading to an increase in intracellular Aβ and phagocytosis-related receptors for advanced glycation end products (RAGE). Then, in vitro results showed that the expression of the RAGE receptor and M2 phenotype marker (CD206) were upregulated by FD treatment in BV2 cells, leading to an increase in Aβ phagocytosis. However, there was no significant difference in the expression of toll-like receptor 4 (TLR4) and clathrin heavy chain (CHC). Furthermore, when using the RAGE-specific inhibitor FPS-ZM1, there was no significant difference in Aβ uptake between folate-normal (FN) and FD BV2 cell groups. In conclusion, these findings suggest FD may promote microglia phagocytosis Aβ via regulating the expression of RAGE or microglia phenotype under Aβ treatment.

show abstract

“…GSAP-16 kDa condensates, and droplets isolate APP-C99, thereby, making it inaccessible to γ-secretase. Hence, the protease activity is lowered eventually . The proteins involved in the amyloid beta pathway such as APP, beta secretase, and gamma secretase complex, especially presenilin, are prone to mutations.…”

Section: Discussionmentioning

confidence: 99%

“…Hence, the protease activity is lowered eventually. 27 The proteins involved in the amyloid beta pathway such as APP, beta secretase, and gamma secretase complex, especially presenilin, are prone to mutations. Utilizing this evidence, the fit–stay–trim mechanism has been proposed where two major conformation states of APP-C99, a loose and a compact state have been identified.…”

Section: Discussionmentioning

confidence: 99%

To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides

et al. 2023

View full text Add to dashboard Cite

γ-Secretase activating protein (GSAP) is known to play an important role in the β-amyloid pathway. It acts as a modulator and accentuates the truncation of the amyloid precursor protein C-99 fragment through the γ-secretase complex. GSAP has four isoforms, out of which canonical isoform 1, a 16 kDa C-terminal portion, has been extensively studied, whereas the function of other three isoforms remains unknown. Here, we explore the GSAP isoform 4 (GSAP_I4) expression and purification from inclusion bodies followed by the refolding of the protein. The secondary structure of GSAP_I4 is predicted using circular dichroism. The protein is further characterized by western blotting and mass spectroscopy analysis. Additionally, biochemical assays and in silico molecular docking and molecular simulation are performed to investigate the binding of GSAP_I4 and APP-C99 peptide fragments. The results reflect that although GSAP_I1 and GSAP_I4 share high sequence similarity, the isoform 4 does not show any affinity toward APP-C99 peptide fragments. This hints toward the fact that GSAP_I4 might have a different role in the living system that is yet unexplored.

show abstract

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

Cited by 11 publications

References 63 publications

Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Gamma secretase activating protein promotes end-organ dysfunction after bacterial pneumonia

Folate Deficiency Increased Microglial Amyloid-β Phagocytosis via the RAGE Receptor in Chronic Unpredictable Mild-Stress Rat and BV2 Cells

To Explore the Binding Affinity of Human γ-Secretase Activating Protein (GSAP) Isoform 4 with APP-C99 Peptides

Contact Info

Product

Resources

About