Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

Kounnas, Maria Z.; Danks, Anne M.; Cheng, Soan; Tyree, Curtis M.; Ackerman, Elizabeth; Zhang, Xulun; Ahn, Kwangwook; Nguyen, Phuong D.; Comer, Dan; Long, Mark D.; Yu, Chenguang; Pleynet, David; DiGregorio, Paul J.; Veliçelebi, Gönül; Stauderman, Kenneth A.; Comer, W. T.; Mobley, William C.; Li, Yueming; Sisodia, Sangram S.; Tanzi, Rudolph E.; Wagner, Steven L.

doi:10.1016/j.neuron.2010.08.018

Cited by 231 publications

(333 citation statements)

References 37 publications

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“…The precise mechanism of GSM activity is still debated, and different mechanisms have been proposed, including allosteric modulation of PS1 (45), binding to Pen-2 (18), or binding to a portion of the A␤ domain within APP (16,17). Our current observation that mutation of Lys-28 can mimic the effect of GSMs (shifting the site of ␥ cleavage) supports but does not prove that these compounds work by binding to APP.…”

Section: Discussionmentioning

confidence: 58%

Lysine 624 of the Amyloid Precursor Protein (APP) Is a Critical Determinant of Amyloid β Peptide Length

Kukar

Ladd

Robertson

et al. 2011

Journal of Biological Chemistry

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Background: ␥-Secretase modulators (GSMs) bind APP near lysine 624. Results: Mutation of lysine 624 shifts cleavage toward smaller A␤ with no effect on ⑀ cleavage. Conclusion:The amino acid at 624 in substrates affects the final ␥-secretase cut. Significance: ␥-Secretase cleavage likely begins at ⑀ and proceeds up the transmembrane until A␤ is released, and GSMs may modulate this process through lysine 624.

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Section: Discussionmentioning

confidence: 58%

Lysine 624 of the Amyloid Precursor Protein (APP) Is a Critical Determinant of Amyloid β Peptide Length

Kukar

Ladd

Robertson

et al. 2011

Journal of Biological Chemistry

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“…Taken together, these studies confirm that this reconstituted system recapitulates the major characteristics of γ-secretase in in vivo settings. Finally, to assess the specific activity of reconstituted ΔE9-C290S, we compared the activity of this preparation to a purified preparation of γ-secretase obtained from HEK293 cells that coexpress a TAP epitope-tagged human PS1 together with NCT, APH-1, and PEN2 (36). We quantified the amount of PS1 present in both the purified γ-secretase complex and the reconstituted liposomes using Western blot analysis using the PS1-specific N-terminal antibody and then measured the γ-secretase activity of both preparations.…”

Section: Resultsmentioning

confidence: 99%

Activation and intrinsic γ-secretase activity of presenilin 1

Ahn

Shelton

Tian

et al. 2010

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

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133

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A complex composed of presenilin (PS), nicastrin, PEN-2, and APH-1 is absolutely required for γ-secretase activity in vivo. Evidence has emerged to suggest a role for PS as the catalytic subunit of γ-secretase, but it has not been established that PS is catalytically active in the absence of associated subunits. We now report that bacterially synthesized, recombinant PS (rPS) reconstituted into liposomes exhibits γ-secretase activity. Moreover, an rPS mutant that lacks a catalytic aspartate residue neither exhibits reconstituted γ-secretase activity nor interacts with a transition-state γ-secretase inhibitor. Importantly, we demonstrate that rPS harboring mutations that cause early onset familial Alzheimer's disease (FAD) lead to elevations in the ratio of Aβ42 to Aβ40 peptides produced from a wild-type APP substrate and that rPS enhances the Aβ42∕ Aβ40 peptide ratio from FAD-linked mutant APP substrates, findings that are entirely consistent with the results obtained in in vivo settings. Thus, γ-secretase cleavage specificity is an inherent property of the polypeptide. Finally, we demonstrate that PEN2 is sufficient to promote the endoproteolysis of PS1 to generate the active form of γ-secretase. Thus, we conclusively establish that activated PS is catalytically competent and the bimolecular interaction of PS1 and PEN2 can convert the PS1 zymogen to an active protease.intermembrane-cleaving proteases | notch | presenilinase | reconstitution

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“…This ability is very important, because our imaging method would enable a quick evaluation of the efficacy of some categories of drug candidates, such as BACE-1 inhibitors, gamma-secretase inhibitors/modulators, and others (62,71).…”

Section: Discussionmentioning

confidence: 99%

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

Zhang

Tian

Zhang

et al. 2015

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

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199

180

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Near-infrared fluorescence (NIRF) molecular imaging has been widely applied to monitoring therapy of cancer and other diseases in preclinical studies; however, this technology has not been applied successfully to monitoring therapy for Alzheimer's disease (AD). Although several NIRF probes for detecting amyloid beta (Aβ) species of AD have been reported, none of these probes has been used to monitor changes of Aβs during therapy. In this article, we demonstrated that CRANAD-3, a curcumin analog, is capable of detecting both soluble and insoluble Aβ species. In vivo imaging showed that the NIRF signal of CRANAD-3 from 4-mo-old transgenic AD (APP/PS1) mice was 2.29-fold higher than that from age-matched wild-type mice, indicating that CRANAD-3 is capable of detecting early molecular pathology. To verify the feasibility of CRANAD-3 for monitoring therapy, we first used the fast Aβ-lowering drug LY2811376, a well-characterized beta-amyloid cleaving enzyme-1 inhibitor, to treat APP/PS1 mice. Imaging data suggested that CRANAD-3 could monitor the decrease in Aβs after drug treatment. To validate the imaging capacity of CRANAD-3 further, we used it to monitor the therapeutic effect of CRANAD-17, a curcumin analog for inhibition of Aβ cross-linking. The imaging data indicated that the fluorescence signal in the CRANAD-17-treated group was significantly lower than that in the control group, and the result correlated with ELISA analysis of brain extraction and Aβ plaque counting. It was the first time, to our knowledge, that NIRF was used to monitor AD therapy, and we believe that our imaging technology has the potential to have a high impact on AD drug development.Alzheimer's | amyloid | imaging | fluorescence | curcumin

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Modulation of γ-Secretase Reduces β-Amyloid Deposition in a Transgenic Mouse Model of Alzheimer's Disease

Cited by 231 publications

References 37 publications

Lysine 624 of the Amyloid Precursor Protein (APP) Is a Critical Determinant of Amyloid β Peptide Length

Lysine 624 of the Amyloid Precursor Protein (APP) Is a Critical Determinant of Amyloid β Peptide Length

Activation and intrinsic γ-secretase activity of presenilin 1

Near-infrared fluorescence molecular imaging of amyloid beta species and monitoring therapy in animal models of Alzheimer’s disease

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