{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T16:47:12Z","timestamp":1770310032532,"version":"3.49.0"},"reference-count":42,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T00:00:00Z","timestamp":1691452800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 109-2221-E-037-001-MY3"],"award-info":[{"award-number":["MOST 109-2221-E-037-001-MY3"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["MOST 111-2314-B-075B-006"],"award-info":[{"award-number":["MOST 111-2314-B-075B-006"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["KMU-TC111B01"],"award-info":[{"award-number":["KMU-TC111B01"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology","doi-asserted-by":"publisher","award":["NPUST-KMU-111-P002"],"award-info":[{"award-number":["NPUST-KMU-111-P002"]}],"id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Kaohsiung Medical University","award":["MOST 109-2221-E-037-001-MY3"],"award-info":[{"award-number":["MOST 109-2221-E-037-001-MY3"]}]},{"name":"Kaohsiung Medical University","award":["MOST 111-2314-B-075B-006"],"award-info":[{"award-number":["MOST 111-2314-B-075B-006"]}]},{"name":"Kaohsiung Medical University","award":["KMU-TC111B01"],"award-info":[{"award-number":["KMU-TC111B01"]}]},{"name":"Kaohsiung Medical University","award":["NPUST-KMU-111-P002"],"award-info":[{"award-number":["NPUST-KMU-111-P002"]}]},{"name":"NPUST-KMU JOINT RESEARCH PROJECT","award":["MOST 109-2221-E-037-001-MY3"],"award-info":[{"award-number":["MOST 109-2221-E-037-001-MY3"]}]},{"name":"NPUST-KMU JOINT RESEARCH PROJECT","award":["MOST 111-2314-B-075B-006"],"award-info":[{"award-number":["MOST 111-2314-B-075B-006"]}]},{"name":"NPUST-KMU JOINT RESEARCH PROJECT","award":["KMU-TC111B01"],"award-info":[{"award-number":["KMU-TC111B01"]}]},{"name":"NPUST-KMU JOINT RESEARCH PROJECT","award":["NPUST-KMU-111-P002"],"award-info":[{"award-number":["NPUST-KMU-111-P002"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Two types of angiotensin-converting enzyme (ACE) inhibitors, lisinopril and benazepril HCl, were tested in neuroblastoma cells and found to upregulate low-density lipoprotein-receptor-related protein 1B (LRP1B) and 14-3-3 protein zeta\/delta. Additionally, benazepril HCl was found to increase the expression of calreticulin. The upregulation of these proteins by ACE inhibitors may contribute to the amelioration of cognitive deficits in Alzheimer\u2019s disease\/dementia, as well as the clinically observed deceleration of functional decline in Alzheimer\u2019s patients. This discovery suggests that the supplementation of ACE inhibitors may promote neuronal cell survival independently of their antihypertensive effect. Overall, these findings indicate that ACE inhibitors may be a promising avenue for developing effective treatments for Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.3390\/molecules28165938","type":"journal-article","created":{"date-parts":[[2023,8,8]],"date-time":"2023-08-08T12:45:53Z","timestamp":1691498753000},"page":"5938","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Utilizing Proteomic Approaches to Uncover the Neuroprotective Effects of ACE Inhibitors: Implications for Alzheimer\u2019s Disease Treatment"],"prefix":"10.3390","volume":"28","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5856-0498","authenticated-orcid":false,"given":"Ming-Hui","family":"Yang","sequence":"first","affiliation":[{"name":"Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Laboratory Science and Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tzu-Chuan","family":"Ho","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chin-Chuan","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuh-Shan","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cheng-Hui","family":"Yuan","sequence":"additional","affiliation":[{"name":"Mass Spectrometry Laboratory, Department of Chemistry, National University of Singapore, Singapore 119077, Singapore"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3973-8390","authenticated-orcid":false,"given":"Kuo-Pin","family":"Chuang","sequence":"additional","affiliation":[{"name":"School of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"International Degree Program in Animal Vaccine Technology, International College, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"},{"name":"Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"},{"name":"Companion Animal Research Center, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1917-5893","authenticated-orcid":false,"given":"Yu-Chang","family":"Tyan","sequence":"additional","affiliation":[{"name":"Department of Medical Imaging and Radiological Sciences, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Nuclear Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Graduate Institute of Animal Vaccine Technology, College of Veterinary Medicine, National Pingtung University of Science and Technology, Pingtung 912, Taiwan"},{"name":"Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan"},{"name":"Center for Tropical Medicine and Infectious Disease Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,8]]},"reference":[{"key":"ref_1","unstructured":"Patterson, C. (2018). World Alzheimer Report 2018, Alzheimer\u2019s Disease International."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Passeri, E., Elkhoury, K., Morsink, M., Broersen, K., Linder, M., Tamayol, A., Malaplate, C., Yen, F.T., and Arab-Tehrany, E. (2022). Alzheimer\u2019s Disease: Treatment Strategies and Their Limitations. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232213954"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2911","DOI":"10.1096\/fj.11-182873","article-title":"Perindopril, a centrally active angiotensin-converting enzyme inhibitor, prevents cognitive impairment in mouse models of Alzheimer\u2019s disease","volume":"25","author":"Dong","year":"2011","journal-title":"FASEB J."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.brainres.2010.07.006","article-title":"Effect of a centrally active angiotensin-converting enzyme inhibitor, perindopril, on cognitive performance in a mouse model of Alzheimer\u2019s disease","volume":"1352","author":"Yamada","year":"2010","journal-title":"Brain Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"16917","DOI":"10.3390\/ijms140816917","article-title":"ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer\u2019s disease","volume":"14","author":"AbdAlla","year":"2013","journal-title":"Int. J. Mol. Sci."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"S251","DOI":"10.3233\/JAD-2012-111376","article-title":"The renin-angiotensin system and antihypertensive drugs in Alzheimer\u2019s disease: Current standing of the angiotensin hypothesis?","volume":"30","author":"Kehoe","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e002881","DOI":"10.1136\/bmjopen-2013-002881","article-title":"Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia","volume":"3","author":"Gao","year":"2013","journal-title":"BMJ Open"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"595","DOI":"10.3233\/JAD-131694","article-title":"Effects of centrally acting angiotensin converting enzyme inhibitors on functional decline in patients with Alzheimer\u2019s disease","volume":"40","author":"Healy","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"S321","DOI":"10.3233\/JAD-132189","article-title":"Brain-penetrating angiotensin-converting enzyme inhibitors and cognitive change in patients with dementia due to Alzheimer\u2019s disease","volume":"42","author":"Bertolucci","year":"2014","journal-title":"J. Alzheimers Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1195","DOI":"10.1001\/archinternmed.2009.175","article-title":"Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: Results from the Cardiovascular Health Study","volume":"169","author":"Sink","year":"2009","journal-title":"Arch. Intern. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1111\/jgs.12415","article-title":"Angiotensin-converting enzyme inhibitors and Alzheimer\u2019s disease progression in older adults: Results from the R\u00e9seau sur la Maladie d\u2019Alzheimer Fran\u00e7ais cohort","volume":"61","author":"Soto","year":"2013","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"37644","DOI":"10.1074\/jbc.M508460200","article-title":"Amyloid veta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor","volume":"280","author":"Hemming","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"47863","DOI":"10.1074\/jbc.M104068200","article-title":"Angiotensin-converting enzyme degrades Alzheimer amyloid \u03b2-peptide (A\u03b2); Retards A beta 48 aggregation, deposition, fibril formation; and inhibits cytotoxicity","volume":"276","author":"Hu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1111\/j.1460-9568.2005.03912.x","article-title":"The N-terminal active centre of human angiotensin-convertingenzyme degrades Alzheimer amyloid beta-peptide","volume":"21","author":"Oba","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"32","DOI":"10.2174\/1567205012666141218140953","article-title":"Amyloid-beta protein clearance and degradation (ABCD) pathways and their role in Alzheimer\u2019s disease","volume":"12","author":"Baranello","year":"2015","journal-title":"Curr. Alzheimer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1172\/JCI66541","article-title":"Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer\u2019s-like cognitive decline","volume":"124","author":"Bernstein","year":"2014","journal-title":"J. Clin. Investig."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.jns.2010.09.030","article-title":"Higher activity of peripheral blood angiotensin-converting enzyme is associated with later-onset of Alzheimer\u2019s disease","volume":"300","author":"Akatsu","year":"2011","journal-title":"J. Neurol. Sci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3233\/JAD-131496","article-title":"Angiotensin-converting enzyme in cerebrospinal fluid and risk of brain atrophy","volume":"44","author":"Jochemsen","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/alzrt257","article-title":"The association of angiotensin-converting enzyme with biomarkers for Alzheimer\u2019s disease","volume":"6","author":"Jochemsen","year":"2014","journal-title":"Alzheimers Res. Ther."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.brainres.2011.09.016","article-title":"Effect of a centrally active angiotensin converting enzyme inhibitor, perindopril, on cognitive performance in chronic cerebral hypo-perfusion rats","volume":"1421","author":"Yamada","year":"2011","journal-title":"Brain Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1016\/S0887-2333(03)00110-3","article-title":"Tribromophenol induces the differentiation of SH-SY5Y human neuroblastoma cells in vitro","volume":"17","author":"Repetto","year":"2003","journal-title":"Toxicol. Vitr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1378","DOI":"10.1016\/j.tiv.2006.06.001","article-title":"Effect of selected insecticides on growth rate and stress protein expression in cultured human A549 and SH-SY5Y cells","volume":"20","author":"Skandrani","year":"2006","journal-title":"Toxicol. Vitr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.semcdb.2008.10.005","article-title":"Lipoprotein receptors and cholesterol in APP trafficking and proteolytic processing, implications for Alzheimer\u2019s disease","volume":"20","author":"Marzolo","year":"2009","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"29639","DOI":"10.1074\/jbc.M313893200","article-title":"The low density lipoprotein receptor-related protein 1B retains beta-amyloid precursor protein at the cell surface and reduces amyloid-beta peptide production","volume":"279","author":"Cam","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"654","DOI":"10.1074\/jbc.M112.400168","article-title":"C1q-induced LRP1B and GPR6 proteins expressed early in Alzheimer disease mouse models, are essential for the C1q-mediated protection against amyloid-\u03b2 neurotoxicity","volume":"288","author":"Benoit","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1489","DOI":"10.1172\/JCI10498","article-title":"Clearance of Alzheimer\u2019s amyloid-ss(1-40) peptide from brain by LDL receptor-related protein-1 at the blood-brain barrier","volume":"106","author":"Shibata","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1212\/WNL.50.6.1905","article-title":"Confirmation of an association between a polymorphism in exon 3 of the low-density lipoprotein receptor-related protein gene and Alzheimer\u2019s disease","volume":"50","author":"Hollenbach","year":"1998","journal-title":"Neurology"},{"key":"ref_28","first-page":"564534","article-title":"Neuroprotective Function of 14-3-3 Proteins in Neurodegeneration","volume":"79","author":"Shimada","year":"2013","journal-title":"BioMed Res. Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"12722","DOI":"10.1074\/jbc.M211491200","article-title":"14-3-3 connects glycogen synthase kinase-3 beta to tau within a brain microtubule-associated tau phosphorylation complex","volume":"278","author":"Qureshi","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.bbrc.2009.03.107","article-title":"Differential interaction and aggregation of 3-repeat and 4-repeat tau isoforms with 14-3-3zeta protein","volume":"383","author":"Sadik","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"26105","DOI":"10.1074\/jbc.M308298200","article-title":"14-3-3 binds to and mediates phosphorylation of microtubule-associated tau protein by Ser9-phosphorylated glycogen synthase kinase 3 beta in the brain","volume":"279","author":"Yuan","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"10831","DOI":"10.3390\/molecules170910831","article-title":"Protective effects of the key compounds isolated from Corni fructus against \u03b2-amyloid-induced neurotoxicity in PC12 cells","volume":"17","author":"Hong","year":"2012","journal-title":"Molecules"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3029","DOI":"10.1016\/j.bpj.2009.09.014","article-title":"Misfolded amyloid ion channels present mobile beta-sheet subunits in contrast to conventional ion channels","volume":"97","author":"Jang","year":"2009","journal-title":"Biophys. J."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1016\/S0197-4580(00)00247-5","article-title":"Calreticulin functions as a molecular chaperone for the beta-amyloid precursor protein","volume":"22","author":"Johnson","year":"2001","journal-title":"Neurobiol. Aging"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1083\/jcb.200302069","article-title":"Low density lipoprotein receptor-related protein is a calreticulin coreceptor that signals focal adhesion disassembly","volume":"161","author":"Orr","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"21740","DOI":"10.3390\/ijms151221740","article-title":"Serum calreticulin is a negative biomarker in patients with Alzheimer\u2019s disease","volume":"15","author":"Lin","year":"2014","journal-title":"Int. J. Mol. Sci."},{"key":"ref_37","first-page":"197","article-title":"Angiotensin II-inhibiting drugs have no effect on intraneuronal A\u03b2 or oligomeric A\u03b2 levels in a triple transgenic mouse model of Alzheimer\u2019s disease","volume":"3","author":"Ferrington","year":"2011","journal-title":"Am. J. Transl. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.nbd.2007.01.004","article-title":"Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease","volume":"26","author":"Hemming","year":"2007","journal-title":"Neurobiol. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.brainres.2005.08.019","article-title":"A new approach to the pharmacological regulation of memory: Sarsasapogenin improves memory by elevating the low muscarinic acetylcholine receptor density in brains of memory-deficit rat models","volume":"1060","author":"Hu","year":"2005","journal-title":"Brain Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1007\/s00702-014-1235-x","article-title":"Angiotensin-converting enzyme gene polymorphisms and risk for sporadic Alzheimer\u2019s disease: A meta-analysis","volume":"122","author":"Wang","year":"2015","journal-title":"J. Neural Transm."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Wang, X.B., Cui, N.H., Yang, J., Qiu, X.P., Gao, J.J., Yang, N., and Zheng, F. (2014). Angiotensin-converting enzyme insertion\/deletion polymorphism is not a major determining factor in the development of sporadic Alzheimer disease: Evidence from an updated meta-analysis. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0111406"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1007\/s00702-015-1368-6","article-title":"Angiotensin-converting enzyme gene insertion-deletion polymorphism is a risk marker for Alzheimer\u2019s disease in a Chinese population: A meta-analysis of case-control studies","volume":"122","author":"Yuan","year":"2015","journal-title":"J. Neural Transm."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/16\/5938\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:27:48Z","timestamp":1760128068000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/28\/16\/5938"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,8]]},"references-count":42,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2023,8]]}},"alternative-id":["molecules28165938"],"URL":"https:\/\/doi.org\/10.3390\/molecules28165938","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,8,8]]}}}