{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T08:53:14Z","timestamp":1789203194803,"version":"build-2803163510"},"reference-count":124,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,20]],"date-time":"2021-09-20T00:00:00Z","timestamp":1632096000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>The activation of the brain renin-angiotensin system (RAS) plays a pivotal role in the pathophysiology of cognition. While the brain RAS has been studied before in the context of hypertension, little is known about its role and regulation in relation to neuronal function and its modulation. Adequate blood flow to the brain as well as proper clearing of metabolic byproducts become crucial in the presence of neurodegenerative disorders such as Alzheimer\u2019s disease (AD). RAS inhibition (RASi) drugs that can cross into the central nervous system have yielded unclear results in improving cognition in AD patients. Consequently, only one RASi therapy is under consideration in clinical trials to modify AD. Moreover, the role of non-genetic factors such as hypercholesterolemia in the pathophysiology of AD remains largely uncharacterized, even when evidence exists that it can lead to alteration of the RAS and cognition in animal models. Here we revise the evidence for the function of the brain RAS in cognition and AD pathogenesis and summarize the evidence that links it to hypercholesterolemia and other risk factors. We review existent medications for RASi therapy and show research on novel drugs, including small molecules and nanodelivery strategies that can target the brain RAS with potential high specificity. We hope that further research into the brain RAS function and modulation will lead to innovative therapies that can finally improve AD neurodegeneration.<\/jats:p>","DOI":"10.3390\/ijms221810139","type":"journal-article","created":{"date-parts":[[2021,9,21]],"date-time":"2021-09-21T08:04:23Z","timestamp":1632211463000},"page":"10139","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Brain Renin\u2013Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"22","author":[{"given":"Ra\u00fal","family":"Loera-Valencia","sequence":"first","affiliation":[{"name":"Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Eroli","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Garcia-Ptacek","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Clinical Geriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden"},{"name":"Aging and Inflammation Theme, Aging Brain Theme, Karolinska University Hospital, 141 57 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9577-0803","authenticated-orcid":false,"given":"Silvia","family":"Maioli","sequence":"additional","affiliation":[{"name":"Center for Alzheimer Research, Department of Neurobiology Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 171 64 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1152\/physrev.00036.2005","article-title":"Physiology of local renin-angiotensin systems","volume":"86","author":"Paul","year":"2006","journal-title":"Physiol. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1161\/HYPERTENSIONAHA.117.09167","article-title":"No Brain Renin-Angiotensin System: Deja vu All Over Again?","volume":"69","author":"Sigmund","year":"2017","journal-title":"Hypertension"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1136","DOI":"10.1161\/HYPERTENSIONAHA.116.08922","article-title":"Brain Renin-Angiotensin System: Does It Exist?","volume":"69","author":"Severs","year":"2017","journal-title":"Hypertension"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1038\/s41586-020-2179-y","article-title":"Structural basis of receptor recognition by SARS-CoV-2","volume":"581","author":"Shang","year":"2020","journal-title":"Nature"},{"key":"ref_5","unstructured":"Douaud, G., Lee, S., Alfaro-Almagro, F., Arthofer, C., Wang, C., Lange, F., Andersson, J.L.R., Griffanti, L., Duff, E., and Jbabdi, S. (2021). Brain imaging before and after COVID-19 in UK Biobank. medRxiv."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1126\/science.aaa1934","article-title":"Brain structure. Cell types in the mouse cortex and hippocampus revealed by single-cell RNA-seq","volume":"347","author":"Zeisel","year":"2015","journal-title":"Science"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1016\/0006-8993(87)91637-4","article-title":"Presence of renin in primary neuronal and glial cells from rat brain","volume":"437","author":"Hermann","year":"1987","journal-title":"Brain Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/0304-3940(80)90292-X","article-title":"Renin-like immunocytochemical activity in the rat and mouse brain","volume":"18","author":"Fuxe","year":"1980","journal-title":"Neurosci. Lett."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1161\/01.HYP.0000125143.73301.94","article-title":"Adjacent expression of renin and angiotensinogen in the rostral ventrolateral medulla using a dual-reporter transgenic model","volume":"43","author":"Lavoie","year":"2004","journal-title":"Hypertension"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1186\/s13059-020-02210-0","article-title":"Single-cell transcriptome profiling of an adult human cell atlas of 15 major organs","volume":"21","author":"He","year":"2020","journal-title":"Genome Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4183","DOI":"10.1038\/s41467-020-17876-0","article-title":"A single-cell atlas of the human substantia nigra reveals cell-specific pathways associated with neurological disorders","volume":"11","author":"Agarwal","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1038\/s41586-019-1654-9","article-title":"Organoid single-cell genomic atlas uncovers human-specific features of brain development","volume":"574","author":"Kanton","year":"2019","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1444","DOI":"10.1126\/science.3201232","article-title":"Astrocytes synthesize angiotensinogen in brain","volume":"242","author":"Stornetta","year":"1988","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/S0006-8993(98)01236-0","article-title":"The angiotensinogen gene is expressed in both astrocytes and neurons in murine central nervous system","volume":"817","author":"Yang","year":"1999","journal-title":"Brain Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/0014-2999(87)90473-0","article-title":"Exaggerated pressor response to centrally administered renin in freely moving, spontaneously hypertensive rats","volume":"138","author":"Kawasaki","year":"1987","journal-title":"Eur. J. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3975","DOI":"10.1073\/pnas.96.7.3975","article-title":"Blood pressure reduction and diabetes insipidus in transgenic rats deficient in brain angiotensinogen","volume":"96","author":"Schinke","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1161\/01.CIR.87.6.1816","article-title":"Molecular biology of the renin-angiotensin system","volume":"87","author":"Griendling","year":"1993","journal-title":"Circulation"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1042\/CS20130324","article-title":"Cerebroprotective action of angiotensin peptides in stroke","volume":"126","author":"Regenhardt","year":"2014","journal-title":"Clin. Sci. (Lond.)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"149","DOI":"10.7326\/0003-4819-137-3-200208060-00006","article-title":"Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease","volume":"137","author":"Kivipelto","year":"2002","journal-title":"Ann. Intern. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/S1474-4422(05)70141-1","article-title":"The age-dependent relation of blood pressure to cognitive function and dementia","volume":"4","author":"Qiu","year":"2005","journal-title":"Lancet Neurol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00401-004-0951-y","article-title":"Metabolic\/signal transduction hypothesis of Alzheimer\u2019s disease and other tauopathies","volume":"109","author":"Iqbal","year":"2005","journal-title":"Acta Neuropathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12292","DOI":"10.1073\/pnas.1606171113","article-title":"PPARgamma-coactivator-1alpha gene transfer reduces neuronal loss and amyloid-beta generation by reducing beta-secretase in an Alzheimer\u2019s disease model","volume":"113","author":"Katsouri","year":"2016","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1001\/archneurol.2009.27","article-title":"The role of metabolic disorders in Alzheimer disease and vascular dementia: Two roads converged","volume":"66","author":"Craft","year":"2009","journal-title":"Arch. Neurol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"699","DOI":"10.1084\/jem.20160534","article-title":"27-Hydroxycholesterol impairs neuronal glucose uptake through an IRAP\/GLUT4 system dysregulation","volume":"214","author":"Ismail","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1038\/s41588-019-0358-2","article-title":"Genetic meta-analysis of diagnosed Alzheimer\u2019s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing","volume":"51","author":"Kunkle","year":"2019","journal-title":"Nat. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"eaaz2541","DOI":"10.1126\/scitranslmed.aaz2541","article-title":"Abeta-accelerated neurodegeneration caused by Alzheimer\u2019s-associated ACE variant R1279Q is rescued by angiotensin system inhibition in mice","volume":"12","author":"Cuddy","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_27","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_28","doi-asserted-by":"crossref","unstructured":"Kauwe, J.S., Bailey, M.H., Ridge, P.G., Perry, R., Wadsworth, M.E., Hoyt, K.L., Staley, L.A., Karch, C.M., Harari, O., and Cruchaga, C. (2014). Genome-wide association study of CSF levels of 59 alzheimer\u2019s disease candidate proteins: Significant associations with proteins involved in amyloid processing and inflammation. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004758"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"669","DOI":"10.3233\/JAD-2011-101512","article-title":"Upregulation of brain renin angiotensin system by 27-hydroxycholesterol in Alzheimer\u2019s disease","volume":"24","author":"Mateos","year":"2011","journal-title":"J. Alzheimers Dis."},{"key":"ref_30","first-page":"163","article-title":"Angiotensin-converting enzyme levels and activity in Alzheimer\u2019s disease: Differences in brain and CSF ACE and association with ACE1 genotypes","volume":"1","author":"Miners","year":"2009","journal-title":"Am. J. Transl. Res."},{"key":"ref_31","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_32","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.3233\/JAD-171119","article-title":"The Coming of Age of the Angiotensin Hypothesis in Alzheimer\u2019s Disease: Progress Toward Disease Prevention and Treatment?","volume":"62","author":"Kehoe","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1007\/s11357-020-00231-y","article-title":"Brain angiotensin II and angiotensin IV receptors as potential Alzheimer\u2019s disease therapeutic targets","volume":"42","author":"Royea","year":"2020","journal-title":"Geroscience"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.neubiorev.2018.05.005","article-title":"Cognitive benefits of angiotensin IV and angiotensin-(1\u20137): A systematic review of experimental studies","volume":"92","author":"Ho","year":"2018","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5562","DOI":"10.1523\/JNEUROSCI.0329-17.2017","article-title":"Angiotensin IV Receptors Mediate the Cognitive and Cerebrovascular Benefits of Losartan in a Mouse Model of Alzheimer\u2019s Disease","volume":"37","author":"Royea","year":"2017","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"104644","DOI":"10.1016\/j.nbd.2019.104644","article-title":"Memory and cerebrovascular deficits recovered following angiotensin IV intervention in a mouse model of Alzheimer\u2019s disease","volume":"134","author":"Royea","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1523\/JNEUROSCI.3742-14.2015","article-title":"Biomarkers of traumatic injury are transported from brain to blood via the glymphatic system","volume":"35","author":"Plog","year":"2015","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1073\/pnas.1914017117","article-title":"Imaging the effect of the circadian light-dark cycle on the glymphatic system in awake rats","volume":"117","author":"Cai","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6365","DOI":"10.1523\/JNEUROSCI.1974-18.2019","article-title":"Impaired Glymphatic Transport in Spontaneously Hypertensive Rats","volume":"39","author":"Mortensen","year":"2019","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1111\/joim.12838","article-title":"Connecting the brain cholesterol and renin-angiotensin systems: Potential role of statins and RAS-modifying medications in dementia","volume":"284","author":"Petek","year":"2018","journal-title":"J. Intern. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2046","DOI":"10.1001\/archinte.162.18.2046","article-title":"The prevention of dementia with antihypertensive treatment: New evidence from the Systolic Hypertension in Europe (Syst-Eur) study","volume":"162","author":"Forette","year":"2002","journal-title":"Arch. Intern. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1727","DOI":"10.1212\/01.wnl.0000345062.86148.3f","article-title":"Duration of antihypertensive drug use and risk of dementia: A prospective cohort study","volume":"72","author":"Haag","year":"2009","journal-title":"Neurology"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1212\/WNL.56.1.42","article-title":"Cardiovascular risk factors and cognitive decline in middle-aged adults","volume":"56","author":"Knopman","year":"2001","journal-title":"Neurology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1080\/080370500453483999","article-title":"Study on COgnition and Prognosis in the Elderly (SCOPE): Baseline characteristics","volume":"9","author":"Hansson","year":"2000","journal-title":"Blood Press."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1007\/s11906-009-0047-0","article-title":"Hypertension, dementia, and antihypertensive treatment: Implications for the very elderly","volume":"11","author":"Peters","year":"2009","journal-title":"Curr. Hypertens. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"McGuinness, B., Todd, S., Passmore, P., and Bullock, R. (2009). Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia. Cochrane Database Syst. Rev., CD004034.","DOI":"10.1002\/14651858.CD004034.pub3"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1001\/archinte.163.9.1069","article-title":"Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease","volume":"163","author":"Tzourio","year":"2003","journal-title":"Arch. Intern. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.neulet.2016.05.003","article-title":"Renin-angiotensin system blockade use and risks of cognitive decline and dementia: A meta-analysis","volume":"624","author":"Zhuang","year":"2016","journal-title":"Neurosci. Lett."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1111\/j.1447-0594.2011.00746.x","article-title":"Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer\u2019s disease","volume":"12","author":"Kume","year":"2012","journal-title":"Geriatr. Gerontol. Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1111\/jgs.12100","article-title":"Antihypertensive therapy and cerebral hemodynamics in executive mild cognitive impairment: Results of a pilot randomized clinical trial","volume":"61","author":"Hajjar","year":"2013","journal-title":"J. Am. Geriatr. Soc."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"779","DOI":"10.3233\/JAD-150487","article-title":"Older Adults Taking AT1-Receptor Blockers Exhibit Reduced Cerebral Amyloid Retention","volume":"50","author":"Nation","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1632","DOI":"10.1001\/archneurol.2012.1010","article-title":"Impact of Angiotensin receptor blockers on Alzheimer disease neuropathology in a large brain autopsy series","volume":"69","author":"Hajjar","year":"2012","journal-title":"Arch. Neurol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"147","DOI":"10.3233\/JAD-2012-120763","article-title":"The effects of ramipril in individuals at risk for Alzheimer\u2019s disease: Results of a pilot clinical trial","volume":"32","author":"Wharton","year":"2012","journal-title":"J. Alzheimers Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.1001\/jamaneurol.2015.1001","article-title":"Association Between Angiotensin Receptor Blockers and Longitudinal Decline in Tau in Mild Cognitive Impairment","volume":"72","author":"Hajjar","year":"2015","journal-title":"JAMA Neurol."},{"key":"ref_55","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_56","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_57","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_58","doi-asserted-by":"crossref","first-page":"116","DOI":"10.3389\/fncel.2018.00116","article-title":"Microglial Activation Is Modulated by Captopril: In Vitro and in Vivo Studies","volume":"12","author":"Asraf","year":"2018","journal-title":"Front. Cell. Neurosci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1177\/0271678X16658489","article-title":"Losartan improves cerebrovascular function in a mouse model of Alzheimer\u2019s disease with combined overproduction of amyloid-beta and transforming growth factor-beta1","volume":"37","author":"Papadopoulos","year":"2017","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1016\/j.nbd.2014.04.018","article-title":"Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer\u2019s disease model","volume":"68","author":"Ongali","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3393","DOI":"10.1172\/JCI31547","article-title":"Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease","volume":"117","author":"Wang","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.bbrc.2008.08.032","article-title":"Telmisartan prevented cognitive decline partly due to PPAR-gamma activation","volume":"375","author":"Mogi","year":"2008","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Torika, N., Asraf, K., Danon, A., Apte, R.N., and Fleisher-Berkovich, S. (2016). Telmisartan Modulates Glial Activation: In Vitro and In Vivo Studies. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0155823"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1161\/HYPERTENSIONAHA.109.138586","article-title":"Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling","volume":"54","author":"Takeda","year":"2009","journal-title":"Hypertension"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"37644","DOI":"10.1074\/jbc.M508460200","article-title":"Amyloid beta-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_66","doi-asserted-by":"crossref","first-page":"47863","DOI":"10.1074\/jbc.M104068200","article-title":"Angiotensin-converting enzyme degrades Alzheimer amyloid beta-peptide (A beta ); retards A beta aggregation, deposition, fibril formation; and inhibits cytotoxicity","volume":"276","author":"Hu","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_67","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-converting enzyme degrades Alzheimer amyloid beta-peptide","volume":"21","author":"Oba","year":"2005","journal-title":"Eur. J. Neurosci."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"30471","DOI":"10.1074\/jbc.M605827200","article-title":"Regulation of steady-state beta-amyloid levels in the brain by neprilysin and endothelin-converting enzyme but not angiotensin-converting enzyme","volume":"281","author":"Eckman","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_69","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_70","doi-asserted-by":"crossref","first-page":"9760","DOI":"10.1074\/jbc.RA118.006420","article-title":"A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer\u2019s disease pathology in mice","volume":"294","author":"Liu","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1007\/s00401-019-02098-6","article-title":"ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"139","author":"Evans","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13195-016-0217-7","article-title":"Angiotensin-converting enzyme 2 is reduced in Alzheimer\u2019s disease in association with increasing amyloid-beta and tau pathology","volume":"8","author":"Kehoe","year":"2016","journal-title":"Alzheimers Res. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Ding, Q., Shults, N.V., Gychka, S.G., Harris, B.T., and Suzuki, Y.J. (2021). Protein Expression of Angiotensin-Converting Enzyme 2 (ACE2) is Upregulated in Brains with Alzheimer\u2019s Disease. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22041687"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1149","DOI":"10.1093\/gerona\/gly219","article-title":"Chronic Treatment With the ACE Inhibitor Enalapril Attenuates the Development of Frailty and Differentially Modifies Pro- and Anti-inflammatory Cytokines in Aging Male and Female C57BL\/6 Mice","volume":"74","author":"Keller","year":"2019","journal-title":"J. Gerontol. A Biol. Sci. Med. Sci."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1161\/HYPERTENSIONAHA.119.14431","article-title":"AT2R\u2019s (Angiotensin II Type 2 Receptor\u2019s) Role in Cognitive and Cerebrovascular Deficits in a Mouse Model of Alzheimer Disease","volume":"75","author":"Royea","year":"2020","journal-title":"Hypertension"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/ajh\/hpu197","article-title":"Neuroprotective effects of angiotensin receptor blockers","volume":"28","author":"Villapol","year":"2015","journal-title":"Am. J. Hypertens."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"104230","DOI":"10.1016\/j.phrs.2019.04.014","article-title":"Improvements of symptoms of Alzheimer\u2018s disease by inhibition of the angiotensin system","volume":"154","author":"Quitterer","year":"2020","journal-title":"Pharmacol. Res."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1016\/j.expneurol.2013.10.014","article-title":"The angiotensin converting enzyme inhibitor captopril protects nigrostriatal dopamine neurons in animal models of parkinsonism","volume":"250","author":"Sonsalla","year":"2013","journal-title":"Exp. Neurol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2554","DOI":"10.1084\/jem.20180776","article-title":"Lupus antibodies induce behavioral changes mediated by microglia and blocked by ACE inhibitors","volume":"215","author":"Nestor","year":"2018","journal-title":"J. Exp. Med."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"573677","DOI":"10.3389\/fimmu.2020.573677","article-title":"Centrally Acting Angiotensin-Converting Enzyme Inhibitor Suppresses Type I Interferon Responses and Decreases Inflammation in the Periphery and the CNS in Lupus-Prone Mice","volume":"11","author":"Nocito","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"22082","DOI":"10.1038\/s41598-020-79096-2","article-title":"Chronically infused angiotensin II induces depressive-like behavior via microglia activation","volume":"10","author":"Park","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/0006-8993(90)90428-E","article-title":"Intracerebroventricularly infused [D-Arg1]angiotensin III, is superior to [D-Asp1]angiotensin II, as a pressor agent in rats","volume":"514","author":"Wright","year":"1990","journal-title":"Brain Res."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1161\/01.HYP.13.6.910","article-title":"Leucine aminopeptidase M-induced reductions in blood pressure in spontaneously hypertensive rats","volume":"13","author":"Wright","year":"1989","journal-title":"Hypertension"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1021\/acschemneuro.7b00326","article-title":"Higher Aminopeptidase Activity Determined by Electroosmotic Push-Pull Perfusion Contributes to Selective Vulnerability of the Hippocampal CA1 Region to Oxygen Glucose Deprivation","volume":"9","author":"Ou","year":"2018","journal-title":"ACS Chem. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1007\/s00401-021-02308-0","article-title":"Aminopeptidase A contributes to biochemical, anatomical and cognitive defects in Alzheimer\u2019s disease (AD) mouse model and is increased at early stage in sporadic AD brain","volume":"141","author":"Valverde","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"2950","DOI":"10.1021\/jm00044a016","article-title":"Differential inhibition of aminopeptidase A and aminopeptidase N by new beta-amino thiols","volume":"37","author":"Chauvel","year":"1994","journal-title":"J. Med. Chem."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"7775","DOI":"10.1073\/pnas.0402312101","article-title":"Brain renin-angiotensin system blockade by systemically active aminopeptidase A inhibitors: A potential treatment of salt-dependent hypertension","volume":"101","author":"Fassot","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"11968","DOI":"10.1073\/pnas.93.21.11968","article-title":"Identification of metabolic pathways of brain angiotensin II and III using specific aminopeptidase inhibitors: Predominant role of angiotensin III in the control of vasopressin release","volume":"93","author":"Zini","year":"1996","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1097\/HJH.0000000000001563","article-title":"Central antihypertensive effects of chronic treatment with RB150: An orally active aminopeptidase A inhibitor in deoxycorticosterone acetate-salt rats","volume":"36","author":"Marc","year":"2018","journal-title":"J. Hypertens."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1161\/CIRCULATIONAHA.119.040070","article-title":"Efficacy and Safety of Firibastat, A First-in-Class Brain Aminopeptidase A Inhibitor, in Hypertensive Overweight Patients of Multiple Ethnic Origins","volume":"140","author":"Ferdinand","year":"2019","journal-title":"Circulation"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1300","DOI":"10.1161\/HYPERTENSIONAHA.118.12499","article-title":"NI956\/QGC006, a Potent Orally Active, Brain-Penetrating Aminopeptidase A Inhibitor for Treating Hypertension","volume":"73","author":"Keck","year":"2019","journal-title":"Hypertension"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1038\/nnano.2008.34","article-title":"Mesoporous silicon particles as a multistage delivery system for imaging and therapeutic applications","volume":"3","author":"Tasciotti","year":"2008","journal-title":"Nat. Nanotechnol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.21873\/anticanres.13285","article-title":"Delivery of Antisense Oligonucleotide LOR-2501 Using Transferrin-conjugated Polyethylenimine-based Lipid Nanoparticle","volume":"39","author":"Zheng","year":"2019","journal-title":"Anticancer Res."},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Soe, Z.C., Kwon, J.B., Thapa, R.K., Ou, W., Nguyen, H.T., Gautam, M., Oh, K.T., Choi, H.G., Ku, S.K., and Yong, C.S. (2019). Transferrin-Conjugated Polymeric Nanoparticle for Receptor-Mediated Delivery of Doxorubicin in Doxorubicin-Resistant Breast Cancer Cells. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11020063"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"7926","DOI":"10.1021\/acsnano.6b03858","article-title":"Neuron-Targeted Nanoparticle for siRNA Delivery to Traumatic Brain Injuries","volume":"10","author":"Kwon","year":"2016","journal-title":"ACS Nano"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1002\/smll.201201870","article-title":"Shuttle-mediated nanoparticle delivery to the blood-brain barrier","volume":"9","author":"Guarnieri","year":"2013","journal-title":"Small"},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1523\/JNEUROSCI.1211-20.2020","article-title":"Legumain Induces Oral Cancer Pain by Biased Agonism of Protease-Activated Receptor-2","volume":"41","author":"Tu","year":"2021","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"15281","DOI":"10.1073\/pnas.2000500117","article-title":"Endosomal signaling of delta opioid receptors is an endogenous mechanism and therapeutic target for relief from inflammatory pain","volume":"117","author":"Gong","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Jimenez-Vargas, N.N., Yu, Y., Jensen, D.D., Bok, D.D., Wisdom, M., Latorre, R., Lopez, C., Jaramillo-Polanco, J.O., Degro, C., and Guzman-Rodriguez, M. (2021). Agonist that activates the micro-opioid receptor in acidified microenvironments inhibits colitis pain without side effects. Gut.","DOI":"10.1136\/gutjnl-2021-324070"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1038\/nrd3024","article-title":"Teaching old receptors new tricks: Biasing seven-transmembrane receptors","volume":"9","author":"Rajagopal","year":"2010","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"745","DOI":"10.1038\/nrc2945","article-title":"The renin-angiotensin system and cancer: Old dog, new tricks","volume":"10","author":"George","year":"2010","journal-title":"Nat. Rev. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1161\/HYPERTENSIONAHA.119.12675","article-title":"Evolution of a New Class of Antihypertensive Drugs: Targeting the Brain Renin-Angiotensin System","volume":"75","author":"Touyz","year":"2020","journal-title":"Hypertension"},{"key":"ref_103","doi-asserted-by":"crossref","unstructured":"Pechanova, O., Barta, A., Koneracka, M., Zavisova, V., Kubovcikova, M., Klimentova, J., Trk, J., Zemancikova, A., and Cebova, M. (2019). Protective Effects of Nanoparticle-Loaded Aliskiren on Cardiovascular System in Spontaneously Hypertensive Rats. Molecules, 24.","DOI":"10.3390\/molecules24152710"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/hr.2013.155","article-title":"Targeting of hepatic angiotensinogen using chemically modified siRNAs results in significant and sustained blood pressure lowering in a rat model of hypertension","volume":"37","author":"Olearczyk","year":"2014","journal-title":"Hypertens. Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1210\/me.2004-0536","article-title":"Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II","volume":"20","author":"Hunyady","year":"2006","journal-title":"Mol. Endocrinol."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"(2012). Mateos L, Ismail MA, Winblad B, Cedazo-Minguez A: Side-chain-oxidized oxysterols upregulate ACE2 and Mas receptor in rat primary neurons. Neurodegener. Dis., 10, 313\u2013316.","DOI":"10.1159\/000333340"},{"key":"ref_107","doi-asserted-by":"crossref","unstructured":"Maioli, S., B\u00e5vner, A., Ali, Z., Heverin, M., Ismail, M.-A.-M., Puerta, E., Olin, M., Saeed, A., Shafaati, M., and Parini, P. (2013). Is It Possible to Improve Memory Function by Upregulation of the Cholesterol 24S-Hydroxylase (CYP46A1) in the Brain?. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068534"},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"4169","DOI":"10.1074\/jbc.RA118.005639","article-title":"24(S),25-Epoxycholesterol and cholesterol 24S-hydroxylase (CYP46A1) overexpression promote midbrain dopaminergic neurogenesis in vivo","volume":"294","author":"Theofilopoulos","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1016\/j.neuropharm.2017.06.026","article-title":"Cholesterol-metabolizing enzyme cytochrome P450 46A1 as a pharmacologic target for Alzheimer\u2019s disease","volume":"123","author":"Mast","year":"2017","journal-title":"Neuropharmacology"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"953","DOI":"10.1093\/brain\/awv384","article-title":"CYP46A1, the rate-limiting enzyme for cholesterol degradation, is neuroprotective in Huntington\u2019s disease","volume":"139","author":"Boussicault","year":"2016","journal-title":"Brain"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"5965","DOI":"10.1093\/hmg\/ddv268","article-title":"Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology","volume":"24","author":"Burlot","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3736","DOI":"10.1038\/s41598-021-83008-3","article-title":"High levels of 27-hydroxycholesterol results in synaptic plasticity alterations in the hippocampus","volume":"11","author":"Munoz","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1093\/cercor\/bhy274","article-title":"27-Hydroxycholesterol Induces Aberrant Morphology and Synaptic Dysfunction in Hippocampal Neurons","volume":"29","author":"Ismail","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"3112","DOI":"10.1093\/brain\/awx273","article-title":"Hereditary spastic paraplegia type 5: Natural history, biomarkers and a randomized controlled trial","volume":"140","author":"Schols","year":"2017","journal-title":"Brain"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"3810","DOI":"10.1074\/jbc.M505179200","article-title":"Studies on the transcriptional regulation of cholesterol 24-hydroxylase (CYP46A1): Marked insensitivity toward different regulatory axes","volume":"281","author":"Ohyama","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"4411","DOI":"10.1038\/s41467-020-18115-2","article-title":"Circadian control of brain glymphatic and lymphatic fluid flow","volume":"11","author":"Hablitz","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.brainres.2018.09.015","article-title":"Identification of insulin-regulated aminopeptidase (IRAP) in the rat pineal gland and the modulation of melatonin synthesis by angiotensin IV","volume":"1704","author":"Abrahao","year":"2019","journal-title":"Brain Res."},{"key":"ref_118","first-page":"4209","article-title":"Identification and characterization of a new cognitive enhancer based on inhibition of insulin-regulated aminopeptidase","volume":"22","author":"Albiston","year":"2008","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1111\/joim.12959","article-title":"Current and emerging avenues for Alzheimer\u2019s disease drug targets","volume":"286","author":"Kenigsberg","year":"2019","journal-title":"J. Intern. Med."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1016\/j.trci.2017.08.009","article-title":"Toward common mechanisms for risk factors in Alzheimer\u2019s syndrome","volume":"3","author":"Medina","year":"2017","journal-title":"Alzheimers Dement. (N. Y.)"},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1016\/S1474-4422(16)00062-4","article-title":"Defeating Alzheimer\u2019s disease and other dementias: A priority for European science and society","volume":"15","author":"Winblad","year":"2016","journal-title":"Lancet Neurol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1111\/joim.12192","article-title":"Pathways to Alzheimer\u2019s disease","volume":"275","author":"Hardy","year":"2014","journal-title":"J. Intern. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"602","DOI":"10.1016\/j.trci.2018.09.006","article-title":"Age stratification corrects bias in estimated hazard of APOE genotype for Alzheimer\u2019s disease","volume":"4","author":"Liu","year":"2018","journal-title":"Alzheimers Dement. (N. Y.)"},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1016\/j.jalz.2019.07.018","article-title":"Multicenter Alzheimer\u2019s and Parkinson\u2019s disease immune biomarker verification study","volume":"16","author":"Brosseron","year":"2020","journal-title":"Alzheimers Dement."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10139\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:02:33Z","timestamp":1760166153000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/18\/10139"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,20]]},"references-count":124,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms221810139"],"URL":"https:\/\/doi.org\/10.3390\/ijms221810139","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,20]]}}}