Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice
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...
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| Veröffentlicht in: | Neuropsychopharmacology (New York, N.Y.) N.Y.), 2024-02, Vol.49 (3), p.620-630 |
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| creator | Qian, Zhengjiang Li, Bowei Meng, Xin Liao, Jianming Wang, Guangxing Li, Yanjiao Luo, Qian Ye, Keqiang |
| description | 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. |
| doi_str_mv | 10.1038/s41386-023-01774-2 |
| format | Article |
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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.</description><identifier>ISSN: 0893-133X</identifier><identifier>EISSN: 1740-634X</identifier><identifier>DOI: 10.1038/s41386-023-01774-2</identifier><identifier>PMID: 38030711</identifier><language>eng</language><publisher>England: Nature Publishing Group</publisher><subject>Alzheimer Disease - pathology ; Alzheimer's disease ; Amyloid beta-Peptides ; Animals ; Asparagine ; Bioavailability ; Cognitive ability ; Cysteine Endopeptidases ; Disease Models, Animal ; Legumain ; Mice ; Mice, Transgenic ; Movement disorders ; Neurodegenerative Diseases ; Oral administration ; Pharmacodynamics ; Pharmacokinetics ; Presenilin 1 ; Secretase ; Tau protein ; tau Proteins ; Transgenic mice ; β-Amyloid</subject><ispartof>Neuropsychopharmacology (New York, N.Y.), 2024-02, Vol.49 (3), p.620-630</ispartof><rights>2023. The Author(s), under exclusive licence to American College of Neuropsychopharmacology.</rights><rights>The Author(s), under exclusive licence to American College of Neuropsychopharmacology 2023. 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.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-f05ea5498b9bf4201065fa1c92805312e2d26a61f46a9adb5d110d1729bd1ff3</citedby><cites>FETCH-LOGICAL-c375t-f05ea5498b9bf4201065fa1c92805312e2d26a61f46a9adb5d110d1729bd1ff3</cites><orcidid>0000-0002-7657-8154</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38030711$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Qian, Zhengjiang</creatorcontrib><creatorcontrib>Li, Bowei</creatorcontrib><creatorcontrib>Meng, Xin</creatorcontrib><creatorcontrib>Liao, Jianming</creatorcontrib><creatorcontrib>Wang, Guangxing</creatorcontrib><creatorcontrib>Li, Yanjiao</creatorcontrib><creatorcontrib>Luo, Qian</creatorcontrib><creatorcontrib>Ye, Keqiang</creatorcontrib><title>Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice</title><title>Neuropsychopharmacology (New York, N.Y.)</title><addtitle>Neuropsychopharmacology</addtitle><description>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.</description><subject>Alzheimer Disease - pathology</subject><subject>Alzheimer's disease</subject><subject>Amyloid beta-Peptides</subject><subject>Animals</subject><subject>Asparagine</subject><subject>Bioavailability</subject><subject>Cognitive ability</subject><subject>Cysteine Endopeptidases</subject><subject>Disease Models, Animal</subject><subject>Legumain</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>Movement disorders</subject><subject>Neurodegenerative Diseases</subject><subject>Oral administration</subject><subject>Pharmacodynamics</subject><subject>Pharmacokinetics</subject><subject>Presenilin 1</subject><subject>Secretase</subject><subject>Tau protein</subject><subject>tau Proteins</subject><subject>Transgenic mice</subject><subject>β-Amyloid</subject><issn>0893-133X</issn><issn>1740-634X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkTtPHDEUhS0UBMvjD6SILKWAFAP32vOwyxXaECQkKLbYzvKMr4PRvGLPRtr8emazJAXVbb5zdHQ_xj4j3CBIdZtylKrMQMgMsKryTByxBVY5ZKXMN5_YApSWGUq5OWVnKb0CYFGV6oSdSgUSKsQFcw_9S6jDFIaeD57bNNpof4aeOPVuGGmcgrOJ-PVy9fyNk_fUTOE3tTs-RbJT4mkconWh4cv2zwuFjuJV4i4k2qdCz7vQ0AU79rZNdPl-z9n6-2p99yN7fLp_uFs-Zo2siinzUJAtcq1qXftcAEJZeIuNFgoKiYKEE6Ut0eel1dbVhUMEh5XQtUPv5Tm7PtSOcfi1pTSZLqSG2tb2NGyTEUoXFYICNaNfP6Cvwzb28zgjNOa6nGeImRIHqolDSpG8GWPobNwZBLNXYA4KzKzA_FVg9qEv79XbuiP3P_Lv5_INZzqBMQ</recordid><startdate>20240201</startdate><enddate>20240201</enddate><creator>Qian, Zhengjiang</creator><creator>Li, Bowei</creator><creator>Meng, Xin</creator><creator>Liao, Jianming</creator><creator>Wang, Guangxing</creator><creator>Li, Yanjiao</creator><creator>Luo, Qian</creator><creator>Ye, Keqiang</creator><general>Nature Publishing Group</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7TK</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-7657-8154</orcidid></search><sort><creationdate>20240201</creationdate><title>Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice</title><author>Qian, Zhengjiang ; 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| subjects | Alzheimer Disease - pathology Alzheimer's disease Amyloid beta-Peptides Animals Asparagine Bioavailability Cognitive ability Cysteine Endopeptidases Disease Models, Animal Legumain Mice Mice, Transgenic Movement disorders Neurodegenerative Diseases Oral administration Pharmacodynamics Pharmacokinetics Presenilin 1 Secretase Tau protein tau Proteins Transgenic mice β-Amyloid |
| title | Inhibition of asparagine endopeptidase (AEP) effectively treats sporadic Alzheimer's disease in mice |
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