Abstract
Alzheimer’s disease (AD) is a progressive neurodegenerative disease with cognitive dysfunction as its major clinical symptom. However, there is no disease-modifying small molecular medicine to effectively slow down progression of the disease. Here, we show an optimized asparagine endopeptidase (AEP, also known as δ-secretase) inhibitor, #11 A, that displays an orderly in vivo pharmacokinetics/pharmacodynamics (PK/PD) relationship and robustly attenuates AD pathologies in a sporadic AD mouse model. #11 A is brain permeable with great oral bioavailability. It blocks AEP cleavage of APP and Tau dose-dependently, and significantly decreases Aβ40 and Aβ42 and p-Tau levels in APP/PS1 and Tau P301S mice after oral administration. Notably, #11 A strongly inhibits AEP and prevents mouse APP and Tau fragmentation by AEP, leading to reduction of mouse Aβ42 (mAβ42), mAβ40 and mouse p-Tau181 levels in Thy1-ApoE4/C/EBPβ transgenic mice in a dose-dependent manner. Repeated oral administration of #11 A substantially decreases mAβ aggregation as validated by Aβ PET assay, Tau pathology, neurodegeneration and brain volume reduction, resulting in alleviation of cognitive impairment. Therefore, our results support that #11 A is a disease-modifying preclinical candidate for pharmacologically treating AD.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 13 print issues and online access
$259.00 per year
only $19.92 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Blennow K, de Leon MJ, Zetterberg H. Alzheimer’s disease. Lancet. 2006;368:387–403.
Akiyama H, Barger S, Barnum S, Bradt B, Bauer J, Cole GM, et al. Inflammation and Alzheimer’s disease. Neurobiol Aging. 2000;21:383–421.
Heneka MT, Carson MJ, El Khoury J, Landreth GE, Brosseron F, Feinstein DL, et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015;14:388–405.
Querfurth HW, LaFerla FM. MECHANISMS OF DISEASE Alzheimer’s disease. N. Engl J Med. 2010;362:329–44.
Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chételat G, Teunissen CE, et al. Alzheimer’s disease. Lancet. 2021;397:1577–90.
Cummings J, Lee G, Nahed P, Kambar M, Zhong K, Fonseca J, et al. Alzheimer’s disease drug development pipeline: 2022. Alzheimer’s Dement. 2022;8:e12295.
Athar T, Al Balushi K, Khan SA. Recent advances on drug development and emerging therapeutic agents for Alzheimer’s disease. Mol Biol Rep. 2021;48:5629–45.
van Dyck CH, Swanson CJ, Aisen P, Bateman RJ, Chen C, Gee M, et al. Lecanemab in early Alzheimer’s disease. N Engl J Med. 2023;388:9–21.
Mintun MA, Lo AC, Duggan Evans C, Wessels AM, Ardayfio PA, Andersen SW, et al. Donanemab in early Alzheimer’s disease. N Engl J Med. 2021;384:1691–704.
Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in early symptomatic Alzheimer disease: the TRAILBLAZER-ALZ 2 randomized clinical trial. Jama. 2023;330:512–27.
Liu Z, Jang SW, Liu X, Cheng D, Peng J, Yepes M, et al. Neuroprotective actions of PIKE-L by inhibition of SET proteolytic degradation by asparagine endopeptidase. Mol Cell. 2008;29:665–78.
Zhang Z, Song M, Liu X, Kang SS, Kwon IS, Duong DM, et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat Med. 2014;20:1254–62.
Zhang Z, Song M, Liu X, Su Kang S, Duong DM, Seyfried NT, et al. Delta-secretase cleaves amyloid precursor protein and regulates the pathogenesis in Alzheimer’s disease. Nat Commun. 2015;6:8762.
Xia Y, Wang ZH, Zhang Z, Liu X, Yu SP, Wang JZ, et al. Delta- and beta- secretases crosstalk amplifies the amyloidogenic pathway in Alzheimer’s disease. Prog Neurobiol. 2021;204:102113.
Blennow K, Chen C, Cicognola C, Wildsmith KR, Manser PT, Bohorquez SMS, et al. Cerebrospinal fluid tau fragment correlates with tau PET: a candidate biomarker for tangle pathology. Brain. 2020;143:650–60.
Leuzy A, Cicognola C, Chiotis K, Saint-Aubert L, Lemoine L, Andreasen N, et al. Longitudinal tau and metabolic PET imaging in relation to novel CSF tau measures in Alzheimer’s disease. Eur J Nucl Med Mol Imaging. 2019;46:1152–63.
Simrén J, Brum WS, Ashton NJ, Benedet AL, Karikari TK, Kvartsberg H, et al. CSF tau368/total-tau ratio reflects cognitive performance and neocortical tau better compared to p-tau181 and p-tau217 in cognitively impaired individuals. Alzheimer’s Res Ther. 2022;14:192.
Wang ZH, Gong K, Liu X, Zhang Z, Sun X, Wei ZZ, et al. C/EBPβ regulates delta-secretase expression and mediates pathogenesis in mouse models of Alzheimer’s disease. Nat Commun. 2018;9:1784.
Xia Y, Wang ZH, Zhang J, Liu X, Yu SP, Ye KX, et al. C/EBPβ is a key transcription factor for APOE and preferentially mediates ApoE4 expression in Alzheimer’s disease. Mol Psychiatry. 2021;26:6002–22.
Wang ZH, Xia Y, Liu P, Liu X, Edgington-Mitchell L, Lei K, et al. ApoE4 activates C/EBPβ/δ-secretase with 27-hydroxycholesterol, driving the pathogenesis of Alzheimer’s disease. Prog Neurobiol. 2021;202:102032.
Huang YA, Zhou B, Nabet AM, Wernig M, Südhof TC. Differential signaling mediated by ApoE2, ApoE3, and ApoE4 in human neurons parallels Alzheimer’s disease risk. J Neurosci. 2019;39:7408–27.
Zalocusky KA, Najm R, Taubes AL, Hao Y, Yoon SY, Koutsodendris N, et al. Neuronal ApoE upregulates MHC-I expression to drive selective neurodegeneration in Alzheimer’s disease. Nat Neurosci. 2021;24:786–98.
Wang ZH, Xia Y, Wu Z, Kang SS, Zhang JC, Liu P, et al. Neuronal ApoE4 stimulates C/EBPβ activation, promoting Alzheimer’s disease pathology in a mouse model. Prog Neurobiol. 2022;209:102212.
Zhang Z, Obianyo O, Dall E, Du Y, Fu H, Liu X, et al. Inhibition of delta-secretase improves cognitive functions in mouse models of Alzheimer’s disease. Nat Commun. 2017;8:14740.
Lei K, Kang SS, Ahn EH, Chen C, Liao J, Liu X, et al. C/EBPβ/AEP signaling regulates the oxidative stress in malignant cancers, stimulating the metastasis. Mol Cancer Ther. 2021;20:1640–52.
Zhang Z, Kang SS, Liu X, Ahn EH, Zhang Z, He L, et al. Asparagine endopeptidase cleaves α-synuclein and mediates pathologic activities in Parkinson’s disease. Nat Struct Mol Biol. 2017;24:632–42.
Kang SS, Wu Z, Liu X, Edgington-Mitchell L, Ye K. Treating Parkinson’s disease via activation of BDNF/TrkB signaling pathways and inhibition of delta-secretase. Neurotherapeutics. 2022;19:1283–129.
Liao J, Chen C, Ahn EH, Liu X, Li H, Edgington-Mitchell LE, et al. Targeting both BDNF/TrkB pathway and delta-secretase for treating Alzheimer’s disease. Neuropharmacology. 2021;197:108737.
Xia Y, Wang ZH, Liu P, Edgington-Mitchell L, Liu X, Wang XC, et al. TrkB receptor cleavage by delta-secretase abolishes its phosphorylation of APP, aggravating Alzheimer’s disease pathologies. Mol Psychiatry. 2021;26:2943–63.
Qian Z, Li H, Yang H, Yang Q, Lu Z, Wang L, et al. Osteocalcin attenuates oligodendrocyte differentiation and myelination via GPR37 signaling in the mouse brain. Sci Adv. 2021;7:eabi5811.
Casali BT, Landreth GE. Abeta extraction from murine brain homogenates. Bio Protoc. 2016;6:e1787.
Sahara N, Kimura T. Biochemical properties of pathology-related tau species in tauopathy brains: an extraction protocol for tau oligomers and aggregates. Methods Mol Biol. 2018;1779:435–45.
Connor B, Young D, Yan Q, Faull RL, Synek B, Dragunow M. Brain-derived neurotrophic factor is reduced in Alzheimer’s disease. Brain Res Mol Brain Res. 1997;49:71–81.
Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al. Deficiency in BDNF/TrkB neurotrophic activity stimulates δ-secretase by upregulating C/EBPβ in Alzheimer’s disease. Cell Rep. 2019;28:655–69.e5.
Devi L, Ohno M. TrkB reduction exacerbates Alzheimer’s disease-like signaling aberrations and memory deficits without affecting β-amyloidosis in 5XFAD mice. Transl Psychiatry. 2015;5:e562.
Xiang J, Wang ZH, Ahn EH, Liu X, Yu SP, Manfredsson FP, et al. Delta-secretase-cleaved Tau antagonizes TrkB neurotrophic signalings, mediating Alzheimer’s disease pathologies. Proc Natl Acad Sci USA. 2019;116:9094–102.
Wang ZH, Wu W, Kang SS, Liu X, Wu Z, Peng J, et al. BDNF inhibits neurodegenerative disease-associated asparaginyl endopeptidase activity via phosphorylation by AKT. JCI Insight. 2018;3:e99007.
Murthy RV, Arbman G, Gao J, Roodman GD, Sun XF. Legumain expression in relation to clinicopathologic and biological variables in colorectal cancer. Clin Cancer Res. 2005;11:2293–9.
Liu C, Sun C, Huang H, Janda K, Edgington T. Overexpression of legumain in tumors is significant for invasion/metastasis and a candidate enzymatic target for prodrug therapy. Cancer Res. 2003;63:2957–64.
Chen G, Kang SS, Wang Z, Ahn EH, Xia Y, Liu X, et al. Netrin-1 receptor UNC5C cleavage by active δ-secretase enhances neurodegeneration, promoting Alzheimer’s disease pathologies. Sci Adv. 2021;7:eabe4499.
Cummings J, Zhou Y, Lee G, Zhong K, Fonseca J, Cheng F. Alzheimer’s disease drug development pipeline: 2023. Alzheimer’s Dement (N Y). 2023;9:e12385.
Xiong J, Kang SS, Wang Z, Liu X, Kuo TC, Korkmaz F, et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature. 2022;603:470–76.
Simonsen AH, McGuire J, Podust VN, Hagnelius NO, Nilsson TK, Kapaki E, et al. A novel panel of cerebrospinal fluid biomarkers for the differential diagnosis of Alzheimer’s disease versus normal aging and frontotemporal dementia. Dement Geriatr Cogn Disord. 2007;24:434–40.
Miller G, Matthews SP, Reinheckel T, Fleming S, Watts C. Asparagine endopeptidase is required for normal kidney physiology and homeostasis. FASEB J. 2011;25:1606–17.
Chan CB, Abe M, Hashimoto N, Hao C, Williams IR, Liu X, et al. Mice lacking asparaginyl endopeptidase develop disorders resembling hemophagocytic syndrome. Proc Natl Acad Sci USA. 2009;106:468–73.
Manoury B, Mazzeo D, Li DN, Billson J, Loak K, Benaroch P, et al. Asparagine endopeptidase can initiate the removal of the MHC class II invariant chain chaperone. Immunity. 2003;18:489–98.
Maehr R, Hang HC, Mintern JD, Kim YM, Cuvillier A, Nishimura M, et al. Asparagine endopeptidase is not essential for class II MHC antigen presentation but is required for processing of cathepsin L in mice. J Immunol. 2005;174:7066–74.
Funding
This work was supported by Start-up fund from SIAT and the National Natural Science Foundation of China (32330040) to KY, the Guangdong Basic and Applied Basic Research Foundation (2023A1515030296) and the Shenzhen Government Basic Research Program (JCYJ20220531100802005) to ZQ, and the National Natural Science Foundation of China (32200928) to YL, and the “Hundred, Thousand and Ten Thousand” Science and Technology Major Special Project of Heilongjiang Province (No. 2020ZX07B01) to QL.
Author information
Authors and Affiliations
Contributions
KY conceived the project, designed the experiments, analyzed the data, and wrote the manuscript. ZQ designed and performed most of the experiments, analyzed the data and wrote the manuscript. BL performed the SiMoA experiments. XM and GW performed the LC-MS/MS analysis. JL performed part of the immunofluorescence staining experiments. YL and QL assisted with data analysis and interpretation. All the authors approved the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Qian, Z., Li, B., Meng, X. et al. Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer’s disease in mice. Neuropsychopharmacol. 49, 620–630 (2024). https://doi.org/10.1038/s41386-023-01774-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41386-023-01774-2
This article is cited by
-
Thy1-ApoE4/C/EBPβ double transgenic mice act as a sporadic model with Alzheimer’s disease
Molecular Psychiatry (2024)