Pen2 and Presenilin-1 Modulate the Dynamic Equilibrium of Presenilin-1 and Presenilin-2 γ-Secretase Complexes

Placanica, Lisa; Tarassishin, Leonid; Yang, Guangli; Peethumnongsin, Erica; Kim, Seong Hun; Zheng, Hui; Sisodia, Sangram S.; Li, Yueming

doi:10.1074/jbc.m807269200

Cited by 57 publications

(82 citation statements)

References 45 publications

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“…blue indicated CS-1 had little to no effect on cell viability up to 30 M. In addition, we found that CS-3 exhibited an identical inhibitory profile with a slightly increased EC 50 for A␤42 inhibition (approximately 5 M). Compound E inhibited the production of all 3 ␤-amyloid species with equal potency (Fig.…”

Section: Di-coumarin Compounds Are Selective Gsis In Cellsmentioning

confidence: 53%

“…The majority of mutations within each of these genes cause an increase in the ratio of A␤42 to A␤40 in biochemical, cellular, and animal models. Recent studies suggest that alteration of ␥-secretase complex dynamics and/or formation of ␥-secretase complexes with mutated components can affect the enzymatic cleavage specificity (30,31). Despite these advances in our understanding, little is known regarding the molecular mechanisms that control the specificity of ␥-secretase-mediated cleavage at the A␤40, A␤42, or Notch1 cleavage locations.…”

Section: Di-coumarin Inhibitors Alter the Sub-sites Of The ␥-Secretasmentioning

confidence: 99%

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Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Shelton

Zhu²,

Chau

et al. 2009

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

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␥-Secretase cleaves multiple substrates within the transmembrane domain that include the amyloid precursor protein as well as the Notch family of receptors. These substrates are associated with Alzheimer disease and cancer. Despite extensive investigation of this protease, little is known regarding the regulation of ␥-secretase specificity. To discover selective inhibitors for drug development and for probing the mechanisms of ␥-secretase specificity, we screened chemical libraries and consequently developed a di-coumarin family of inhibitors that preferentially inhibit ␥-secretase-mediated production of A␤42 over other cleavage activities. These coumarin dimerbased compounds interact with ␥-secretase by binding to an allosteric site. By developing a multiple photo-affinity probe approach, we demonstrate that this allosteric binding causes a conformational change within the active site of ␥-secretase at the S2 and S1 sub-sites that leads to selective inhibition of A␤42. In conclusion, by using these di-coumarin compounds, we reveal a mechanism by which ␥-secretase specificity is regulated and provide insights into the molecular basis by which familial presenilin mutations may affect the active site and specificity of ␥-secretase. Furthermore, this class of selective inhibitors provides the basis for development of Alzheimer disease therapeutic agents. affinity labeling ͉ Alzheimer disease ͉ allosteric regulation ͉ di-coumarin ␥ -Secretase is a multi-protein membrane-bound complex that is currently at the front line of basic and translational research. It is composed of at least 4 proteins that include presenilin, nicastrin, Aph-1, and Pen-2 (1). Presenilin is believed to contain the active site of ␥-secretase (2-4). It represents a novel class of protease that catalyzes peptide bond hydrolysis within the transmembrane hydrophobic environment and plays an essential role in a newly emerged signaling pathway known as regulated intramembrane proteolysis (5). ␥-Secretase cleaves a variety of type I membrane proteins that include the amyloid precursor protein (APP) and the Notch family of proteins despite limited primary sequence homology across targeted substrates (6). Elucidation of the mechanisms that control the specificity of ␥-secretase for these substrates has been hindered by technical difficulties associated with intramembrane enzymology. Determining the factors that contribute to ␥-secretase specificity is critical to understanding the biology of this unique protease and targeting it for therapeutic purposes.␥-Secretase has become an appealing drug target for Alzheimer disease (AD) and cancer because of its central role in the processing of APP and Notch (6). ␥-Secretase cleaves APP to generate neurotoxic A␤ peptides, ranging from 37 to 46 aa in length (7). Among them, A␤40 and A␤42 have been extensively investigated for their association with AD (7). Additionally, diseasecausing familial AD mutations within APP, presenilin-1 (PS-1), and presenilin-2 (PS-2) proteins result in an increase in the ratio of A␤42...

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Section: Di-coumarin Compounds Are Selective Gsis In Cellsmentioning

confidence: 53%

Section: Di-coumarin Inhibitors Alter the Sub-sites Of The ␥-Secretasmentioning

confidence: 99%

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Shelton

Zhu²,

Chau

et al. 2009

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

Self Cite

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“…1B). All three probes only photolabel PS1-NTF but not PS1-CTF or other subunits (18,22,23,25). Membranes isolated from N2a cells stably expressing WT, M146L, E280A, FIGURE 1.…”

Section: Ps1 Mutationsmentioning

confidence: 99%

“…The PS1 M146V knock-in mice have been well characterized for memory formation and A␤ production (18,27,28). Membranes isolated from the M146V knock-in and PS1 WT mouse brain were labeled with the photoprobes JC8 and L646.…”

Section: Ps1 Mutationsmentioning

confidence: 99%

“…Little is known about the molecular mechanism of these mutations in altering the specificity of ␥-secretase. A previous study showed that expression of PS1 FAD mutants in PS1-and PS2-null cells led to the formation of ␥-secretase complexes with different molecular weights (17), whereas another study showed that the overexpression of PS1 FAD mutants can also alter the equilibrium of wild-type PS1 and PS2 in ␥-secretase complexes (18). Furthermore, we have demonstrated that proteoliposomes containing PS1 mutants alone are sufficient to alter the specificity of ␥-secretase for the production of A␤40 and A␤42 (16).…”

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confidence: 99%

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Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase

Chau

Crump

Villa

et al. 2012

Journal of Biological Chemistry

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Background:The effect of PS1 mutations on the active site of ␥-secretase is unknown. Results: PS1 mutations reduce photoprobe interaction with the S2 subsite of ␥-secretase and Notch1 cleavage. Conclusion: Certain PS mutations specifically alter the S2 subsite of ␥-secretase active site that leads to changes in APP and Notch1 cleavage. Significance: It provides structural insights into the mechanism of PS1 mutations in regards to ␥-secretase regulation.

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Retracted: Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

Wang

et al. 2013

J of Neuroscience Research

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Evidence suggests that curcumin, the phytochemical agent in the spice turmeric, might be a potential therapy for Alzheimer's disease (AD). Its antioxidant, anti-inflammatory properties have been investigated extensively. Studies have also shown that curcumin can reduce amyloid pathology in AD. The underlying mechanism, however, is complex and is still being explored. In this study, we used the APPswe/PS1dE9 double transgenic mice, an AD model, to investigate the effects and mechanisms of curcumin in the prevention and treatment of AD. The water maze test indicated that curcumin can improve spatial learning and memory ability in mice. Immunohistochemical staining and Western blot analysis were used to test major proteins in β-amyloid aggregation, β-amyloid production, and β-amyloid clearance. Data showed that, 3 months after administration, curcumin treatment reduced Aβ40 , Aβ42 , and aggregation of Aβ-derived diffusible ligands in the mouse hippocampal CA1 area; reduced the expression of the γ-secretase component presenilin-2; and increased the expression of β-amyloid-degrading enzymes, including insulin-degrading enzymes and neprilysin. This evidence suggests that curcumin, as a potential AD therapeutic method, can reduce β-amyloid pathological aggregation, possibly through mechanisms that prevent its production by inhibiting presenilin-2 and/or by accelerating its clearance by increasing degrading enzymes such as insulin-degrading enzyme and neprilysin.

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Pen2 and Presenilin-1 Modulate the Dynamic Equilibrium of Presenilin-1 and Presenilin-2 γ-Secretase Complexes

Cited by 57 publications

References 45 publications

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Modulation of γ-secretase specificity using small molecule allosteric inhibitors

Familial Alzheimer Disease Presenilin-1 Mutations Alter the Active Site Conformation of γ-secretase

Retracted: Mechanisms and effects of curcumin on spatial learning and memory improvement in APPswe/PS1dE9 mice

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