Imaging asparaginyl endopeptidase (AEP) in the live brain as a biomarker for Alzheimer's disease.

Publisher: BioMed Central Country of Publication: England NLM ID: 101152208 Publication Model: Electronic Cited Medium: Internet ISSN: 1477-3155 (Electronic) Linking ISSN: 14773155 NLM ISO Abbreviation: J Nanobiotechnology Subsets: MEDLINE

Original Publication: London : BioMed Central, 2003-

Cysteine Endopeptidases*/genetics; Alzheimer Disease/*metabolism ; Biomarkers/*metabolism ; Brain/*diagnostic imaging ; Brain/*metabolism; Amyloid beta-Peptides/metabolism ; Animals ; Cell Line, Tumor ; Cognitive Dysfunction/metabolism ; Disease Models, Animal ; Early Diagnosis ; Female ; Glioblastoma ; Glioma ; Gold/metabolism ; Humans ; Male ; Metal Nanoparticles/chemistry ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Plaque, Amyloid/metabolism

Background: Discovery of early-stage biomarkers is a long-sought goal of Alzheimer's disease (AD) diagnosis. Age is the greatest risk factor for most AD and accumulating evidence suggests that age-dependent elevation of asparaginyl endopeptidase (AEP) in the brain may represent a new biological marker for predicting AD. However, this speculation remains to be explored with an appropriate assay method because mammalian AEP exists in many organs and the level of AEP in body fluid isn't proportional to its concentration in brain parenchyma. To this end, we here modified gold nanoparticle (AuNPs) into an AEP-responsive imaging probe and choose transgenic APPswe/PS1dE9 (APP/PS1) mice as an animal model of AD. Our aim is to determine whether imaging of brain AEP can be used to predict AD pathology.
Results: This AEP-responsive imaging probe AuNPs-Cy5.5-A&C consisted of two particles, AuNPs-Cy5.5-AK and AuNPs-Cy5.5-CABT, which were respectively modified with Ala-Ala-Asn-Cys-Lys (AK) and 2-cyano-6-aminobenzothiazole (CABT). We showed that AuNPs-Cy5.5-A&C could be selectively activated by AEP to aggregate and emit strong fluorescence. Moreover, AuNPs-Cy5.5-A&C displayed a general applicability in various cell lines and its florescence intensity correlated well with AEP activity in these cells. In the brain of APP/PS1 transgenic mice , AEP activity was increased at an early disease stage of AD that precedes formation of senile plaques and cognitive impairment. Pharmacological inhibition of AEP with δ-secretase inhibitor 11 (10 mg kg ^-1 , p.o.) reduced production of β-amyloid (Aβ) and ameliorated memory loss. Therefore, elevation of AEP is an early sign of AD onset. Finally, we showed that live animal imaging with this AEP-responsive probe could monitor the up-regulated AEP in the brain of APP/PS1 mice.
Conclusions: The current work provided a proof of concept that assessment of brain AEP activity by in vivo imaging assay is a potential biomarker for early diagnosis of AD.
(© 2021. The Author(s).)

Bioorg Med Chem Lett. 2019 Oct 1;29(19):126629. (PMID: 31445852)
J Neurosci Methods. 2007 Mar 15;160(2):187-96. (PMID: 17049995)
Mol Cell. 2017 Sep 7;67(5):812-825.e5. (PMID: 28826672)
Br J Pharmacol. 2019 Aug;176(15):2691-2707. (PMID: 31034096)
Proc Natl Acad Sci U S A. 2019 Apr 30;116(18):9094-9102. (PMID: 31004063)
Nat Rev Neurol. 2018 Mar;14(3):133-150. (PMID: 29377008)
Nat Commun. 2017 Mar 27;8:14740. (PMID: 28345579)
Ann Neurol. 2010 Jan;67(1):114-21. (PMID: 20186856)
Transl Neurodegener. 2021 Mar 31;10(1):12. (PMID: 33789744)
Langmuir. 2005 Nov 8;21(23):10644-54. (PMID: 16262332)
Lancet. 2016 Jul 30;388(10043):505-17. (PMID: 26921134)
Exp Neurol. 2019 Jul;317:260-270. (PMID: 30926390)
Anal Chem. 2020 Sep 1;92(17):11627-11634. (PMID: 32867490)
ACS Chem Biol. 2010 Feb 19;5(2):233-43. (PMID: 20017516)
J Am Chem Soc. 2013 Jan 9;135(1):174-82. (PMID: 23215039)
Alzheimers Dement. 2018 Apr;14(4):535-562. (PMID: 29653606)
RSC Adv. 2019 Aug 13;9(44):25285-25302. (PMID: 35530057)
EMBO J. 2018 Jun 15;37(12):. (PMID: 29769405)
Biomaterials. 2015 Jan;37:425-35. (PMID: 25453970)
Lancet Neurol. 2016 Jun;15(7):673-684. (PMID: 27068280)
Nat Med. 2014 Nov;20(11):1254-62. (PMID: 25326800)
Adv Sci (Weinh). 2019 Aug 12;6(20):1900962. (PMID: 31637161)
J Neurol. 2014 Dec;261(12):2251-63. (PMID: 24627109)
Prog Neurobiol. 2020 Feb;185:101730. (PMID: 31778772)
Alzheimers Res Ther. 2020 Nov 19;12(1):155. (PMID: 33213489)
Org Biomol Chem. 2017 Oct 4;15(38):8018-8022. (PMID: 28920116)
Neurobiol Dis. 2006 Dec;24(3):516-24. (PMID: 17029828)
ACS Nano. 2016 Nov 22;10(11):10086-10098. (PMID: 27934068)
Nat Commun. 2015 Nov 09;6:8762. (PMID: 26549211)
PLoS Biol. 2010 Jun 29;8(6):e1000412. (PMID: 20613859)
Nat Commun. 2018 May 3;9(1):1784. (PMID: 29725016)
Radiology. 2014 Jun;271(3):831-8. (PMID: 24601752)
Neurology. 1998 Sep;51(3):728-33. (PMID: 9748017)
Anal Chem. 2018 Aug 7;90(15):8732-8735. (PMID: 30027744)
Lancet. 2020 Feb 15;395(10223):497-506. (PMID: 31986264)
J Natl Cancer Inst. 2020 Apr 1;112(4):343-355. (PMID: 31400201)
Nat Struct Mol Biol. 2017 Aug;24(8):632-642. (PMID: 28671665)
Bioorg Med Chem Lett. 2007 Feb 1;17(3):649-53. (PMID: 17189693)
Cell. 2019 Oct 3;179(2):312-339. (PMID: 31564456)
Transl Neurodegener. 2020 Jan 6;9:1. (PMID: 31911834)
Biochimie. 2016 Mar;122:126-50. (PMID: 26403494)
Lancet Oncol. 2014 Aug;15(9):e395-403. (PMID: 25079102)
Chem Biol Drug Des. 2019 Aug;94(2):1494-1503. (PMID: 31002467)
Neurotherapeutics. 2017 Jan;14(1):35-53. (PMID: 27738903)

91949116 National Natural Science Foundation of China; 81873807 National Natural Science Foundation of China; 81671375 National Natural Science Foundation of China

Keywords: Alzheimer’s disease; Asparagine endopeptidase; Biomarker; Click cycloaddition; Cy5.5; Early diagnosis; Fluorescent probe; Gold nanoparticle; Legumain; Live brain imaging

0 (Amyloid beta-Peptides)
0 (Biomarkers)
7440-57-5 (Gold)
EC 3.4.22.- (Cysteine Endopeptidases)
EC 3.4.22.34 (asparaginylendopeptidase)

Date Created: 20210820 Date Completed: 20220118 Latest Revision: 20240403

20240403

PMC8375181

10.1186/s12951-021-00988-0

34412639