Top

Published in:

Open Access 01-12-2023 | Research

Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease

Authors: Louise Reveret, Manon Leclerc, Vincent Emond, Cyntia Tremblay, Andréanne Loiselle, Philippe Bourassa, David A. Bennett, Sébastien S. Hébert, Frédéric Calon

Published in: Acta Neuropathologica Communications | Issue 1/2023

Abstract

Cognitive decline due to Alzheimer’s disease (AD) is frequent in the geriatric population, which has been disproportionately affected by the COVID-19 pandemic. In this study, we investigated the levels of angiotensin-converting enzyme 2 (ACE2), a regulator of the renin-angiotensin system and the main entry receptor of SARS-CoV-2 in host cells, in postmortem parietal cortex samples from two independent AD cohorts, totalling 142 persons. Higher concentrations of ACE2 protein (p < 0.01) and mRNA (p < 0.01) were found in individuals with a neuropathological diagnosis of AD compared to age-matched healthy control subjects. Brain levels of soluble ACE2 were inversely associated with cognitive scores (p = 0.02) and markers of pericytes (PDGFRβ, p = 0.02 and ANPEP, p = 0.007), but positively correlated with concentrations of soluble amyloid-β peptides (Aβ) (p = 0.01) and insoluble phospho-tau (S396/404, p = 0.002). However, no significant differences in ACE2 were observed in the 3xTg-AD mouse model of tau and Aβ neuropathology. Results from immunofluorescence and Western blots showed that ACE2 protein is predominantly localized in microvessels in the mouse brain whereas it is more frequently found in neurons in the human brain. The present data suggest that higher levels of soluble ACE2 in the human brain may contribute to AD, but their role in CNS infection by SARS-CoV-2 remains unclear.

Available only for authorised users

Abdi A, Jalilian M, Sarbarzeh PA, Vlaisavljevic Z (2020) Diabetes and COVID-19: a systematic review on the current evidences. Diabetes Res Clin Pract 1(166):108347CrossRef

Abiodun OA, Ola MS (2020) Role of brain renin angiotensin system in neurodegeneration: an update. Saudi J Biol Sci 27(3):905PubMedPubMedCentralCrossRef

Alnefeesi Y, Siegel A, Lui LMW, Teopiz KM, Ho RCM, Lee Y, Nasri F, Gill H, Lin K, Cao B et al (2020) Impact of SARS-CoV-2 infection on cognitive function: a systematic review. Front Psychiatry 11:621773. https://doi.org/10.3389/fpsyt.2020.621773CrossRefPubMed

Badawi S, Ali BR (2021) ACE2 nascence, trafficking, and SARS-CoV-2 pathogenesis: the saga continues. Hum Genom 15:8. https://doi.org/10.1186/s40246-021-00304-9CrossRef

Barron AM, Rosario ER, Elteriefi R, Pike CJ (2013) Sex-specific effects of high fat diet on indices of metabolic syndrome in 3xTg-AD mice: implications for Alzheimer’s disease. PLoS ONE 8(10):e78554PubMedPubMedCentralCrossRef

Bártová E, Legartová S, Krejčí J, Arcidiacono OA (2020) Cell differentiation and aging accompanied by depletion of the ACE2 protein. Aging 12:22495–22508. https://doi.org/10.18632/aging.202221CrossRefPubMedPubMedCentral

Bennett DA, Schneider JA, Arvanitakis Z, Wilson RS (2012) Overview and findings from the religious orders study. Curr Alzheimer Res 9(6):628–645PubMedPubMedCentralCrossRef

Bennett DA, Buchman AS, Boyle PA, Barnes LL, Wilson RS, Schneider JA (2018) Religious orders study and rush memory and aging project. J Alzheimer’s Dis 64(s1):S161–S189CrossRef

Bennett DA, Wilson RS, Schneider JA, Evans DA, Beckett LA, Aggarwal NT, Barnes LL, Fox JH, Bach J (2002) Natural history of mild cognitive impairment in older persons. Neurology 59:198–205PubMedCrossRef

10.

Bennion DM, Haltigan E, Regenhardt RW, Steckelings UM, Sumners C (2015) Neuroprotective mechanisms of the ACE2-angiotensin-(1–7)-mas axis in stroke. Curr Hypertens Rep 17:3. https://doi.org/10.1007/s11906-014-0512-2CrossRefPubMedPubMedCentral

11.

Beyrouti R, Adams ME, Benjamin L, Cohen H, Farmer SF, Goh YY, Humphries F, Jäger HR, Losseff NA, Perry RJ, Shah S, Simister RJ, Turner D, Chandratheva A, Werring DJ. Characteristics of ischaemic stroke associated with COVID-19. J Neurol Neurosurg Psychiatry. 2020 91(8):889–891. https://doi.org/10.1136/jnnp-2020-323586CrossRefPubMed

12.

Bories C, Guitton MJ, Julien C, Tremblay C, Vandal M, Msaid M, De Koninck Y, Calon F. Sex-dependent alterations in social behaviour and cortical synaptic activity coincide at different ages in a model of Alzheimer's disease. PLoS One. 2012;7(9):e46111. https://doi.org/10.1371/journal.pone.0046111CrossRefPubMedPubMedCentral

13.

Bourassa P, Alata W, Tremblay C, Paris-Robidas S, Calon F (2019) Transferrin receptor-mediated uptake at the blood-brain barrier is not impaired by Alzheimer’s disease neuropathology. Mol Pharm 16:583–594PubMedCrossRef

14.

Bourassa P, Tremblay C, Schneider JA, Bennett DA, Calon F (2019) Beta-amyloid pathology in human brain microvessel extracts from the parietal cortex: relation with cerebral amyloid angiopathy and Alzheimer’s disease. Acta Neuropathol 137:801–823PubMedPubMedCentralCrossRef

15.

Bourassa P, Tremblay C, Schneider JA, Bennett DA, Calon F (2020) Brain mural cell loss in the parietal cortex in Alzheimer’s disease correlates with cognitive decline and TDP-43 pathology. Neuropathol Appl Neurobiol 46:458–477PubMedPubMedCentralCrossRef

16.

Braak H, Braak E (1991) Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol 82(4):239–259PubMedCrossRef

17.

Carrillo-Larco RM, Altez-Fernandez C (2020) Anosmia and dysgeusia in COVID-19: a systematic review. Wellcome Open Res 5:94. https://doi.org/10.12688/wellcomeopenres.15917.1CrossRef

18.

Chen R, Wang K, Yu J, Howard D, French L, Chen Z, Wen C, Xu Z (2021) The spatial and cell-type distribution of SARS-CoV-2 receptor ACE2 in the human and mouse brains. Front Neurol. https://doi.org/10.3389/fneur.2020.573095CrossRefPubMedPubMedCentral

19.

Dal-Pan A, Dudonné S, Bourassa P, Bourdoulous M, Tremblay C, Desjardins Y, Calon F (2016) Cognitive-enhancing effects of a polyphenols-rich extract from fruits without changes in neuropathology in an animal model of Alzheimer’s disease. J Alzheimer’s Dis 55:115–135CrossRef

20.

Ding Q, Shults NV, Gychka SG, Harris BT, Suzuki YJ (2021) Protein expression of angiotensin-converting Enzyme 2 (ACE2) is upregulated in brains with Alzheimer’s disease. Int J Mol Sci. https://doi.org/10.3390/ijms22041687CrossRefPubMedPubMedCentral

21.

Ding Y, He LI, Zhang Q, Huang Z, Che X, Hou J, Wang H, Shen H, Qiu L, Li Z, Geng J (2004) Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways. J Pathol: J Pathol Soc Great Britain Ireland 203(2):622–630CrossRef

22.

Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE (2000) A novel angiotensin-converting enzyme–related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 87(5):e1-9PubMedCrossRef

23.

Doobay MF, Talman LS, Obr TD, Tian X, Davisson RL, Lazartigues E (2007) Differential expression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system. Am J Physiol-Regul, Int Comparat Physiol 292(1):R373–R381CrossRef

24.

Douaud G, Lee S, Alfaro-Almagro F, Arthofer C, Wang C, McCarthy P, Lange F, Andersson JLR, Griffanti L, Duff E et al (2022) SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 604:697–707. https://doi.org/10.1038/s41586-022-04569-5CrossRefPubMedPubMedCentral

25.

Evans CE, Miners JS, Piva G, Willis CL, Heard DM, Kidd EJ, Good MA, Kehoe PG (2020) ACE2 activation protects against cognitive decline and reduces amyloid pathology in the Tg2576 mouse model of Alzheimer’s disease. Acta Neuropathol 139:485–502PubMedPubMedCentralCrossRef

26.

Eysert F, Coulon A, Boscher E, Vreulx A-C, Flaig A, Mendes T, Hughes S, Grenier-Boley B, Hanoulle X, Demiautte F et al (2020) Alzheimer’s genetic risk factor FERMT2 (Kindlin-2) controls axonal growth and synaptic plasticity in an APP-dependent manner. Mol Psychiatry. https://doi.org/10.1038/s41380-020-00926-wCrossRefPubMedPubMedCentral

27.

Fazal K, Perera G, Khondoker M, Howard R, Stewart R (2017) Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease. BJPsych Open 3:158–164. https://doi.org/10.1192/bjpo.bp.116.004184CrossRefPubMedPubMedCentral

28.

Fekih-Mrissa N, Bedoui I, Sayeh A, Derbali H, Mrad M, Mrissa R, Nsiri B (2017) Association between an angiotensin-converting enzyme gene polymorphism and Alzheimer’s disease in a Tunisian population. Ann General Psychiatry 16:1–8CrossRef

29.

Franceschi AM, Ahmed O, Giliberto L, Castillo M (2020) Hemorrhagic posterior reversible encephalopathy syndrome as a manifestation of COVID-19 infection. AJNR Am J Neuroradiol 14:1173–1176CrossRef

30.

Gebre AK, Altaye BM, Atey TM, Tuem KB, Berhe DF (2018) Targeting renin–angiotensin system against Alzheimer’s disease. Front Pharmacol 30(9):440CrossRef

31.

Gu J, Gong E, Zhang B, Zheng J, Gao Z, Zhong Y, Zou W, Zhan J, Wang S, Xie Z, Zhuang H (2005) Multiple organ infection and the pathogenesis of SARS. J Experiment Med 202(3):415–424CrossRef

32.

Hamming I, Timens W, Bulthuis ML, Lely AT, Navis GV, Van Goor H (2004) Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus A first step in understanding SARS pathogenesis. J Pathol: J Pathol Soc Great Br Ireland 203(2):631–637CrossRef

33.

Harmer D, Gilbert M, Borman R, Clark KL (2002) Quantitative mRNA expression profiling of ACE 2, a novel homologue of angiotensin converting enzyme. FEBS Lett 532(1–2):107–110PubMedCrossRef

34.

He L, Mäe MA, Muhl L, Sun Y, Pietilä R, Nahar K, Liébanas EV, Fagerlund MJ, Oldner A, Liu Jet al (2020) Pericyte-specific vascular expression of SARS-CoV-2 receptor ACE2 – implications for microvascular inflammation and hypercoagulopathy in COVID-19. bioRxiv, City, pp 2020.2005.2011.088500

35.

He L, Vanlandewijck M, Mäe MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Laviña B, Gouveia L et al (2018) Single-cell RNA sequencing of mouse brain and lung vascular and vessel-associated cell types. Sci Data 5:180160. https://doi.org/10.1038/sdata.2018.160CrossRefPubMedPubMedCentral

36.

Helms J, Kremer S, Merdji H, Schenck M, Severac F, Clere-Jehl R, Studer A, Radosavljevic M, Kummerlen C, Monnier A, Boulay C (2020) Delirium and encephalopathy in severe COVID-19: a cohort analysis of ICU patients. Critic Care 24(1):1–1CrossRef

37.

Heurich A, Hofmann-Winkler H, Gierer S, Liepold T, Jahn O, Pöhlmann S (2014) TMPRSS2 and ADAM17 cleave ACE2 differentially and only proteolysis by TMPRSS2 augments entry driven by the severe acute respiratory syndrome coronavirus spike protein. J Virol 88(2):1293–1307PubMedPubMedCentralCrossRef

38.

Hikmet F, Méar L, Edvinsson Å, Micke P, Uhlén M, Lindskog C (2020) The protein expression profile of ACE2 in human tissues. Mol Syst Biol 16:e9610PubMedPubMedCentralCrossRef

39.

Ho JK, Nation DA (2017) Memory is preserved in older adults taking AT1 receptor blockers. Alzheimer’s Res Therapy 9(1):1–4CrossRef

40.

Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A, Müller MA (2020) SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181(2):271–280PubMedPubMedCentralCrossRef

41.

Hosp JA, Dressing A, Blazhenets G, Bormann T, Rau A, Schwabenland M, Thurow J, Wagner D, Waller C, Niesen WD et al (2021) Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain 144:1263–1276. https://doi.org/10.1093/brain/awab009CrossRefPubMed

42.

Jackson L, Eldahshan W, Fagan SC, Ergul A (2018) Within the Brain: the renin angiotensin system. Int J Mol Sci. https://doi.org/10.3390/ijms19030876CrossRefPubMedPubMedCentral

43.

Jordan RE, Adab P, Cheng KK (2020) Covid-19: risk factors for severe disease and death. BMJ Publishing Group, City, The BMJ

44.

Julien C, Tremblay C, Phivilay A, Berthiaume L, Émond V, Julien P, Calon F (2010) High-fat diet aggravates amyloid-beta and tau pathologies in the 3xTg-AD mouse model. Neurobiol Aging 31(9):1516–1531PubMedCrossRef

45.

Kauwe JSK, Bailey MH, Ridge PG, Perry R, Wadsworth ME, Hoyt KL, Staley LA, Karch CM, Harari O, Cruchaga C et al (2014) Genome-wide association study of CSF levels of 59 Alzheimer’s disease candidate proteins: significant associations with proteins involved in amyloid processing and inflammation. Public Library of Science, City, PLoS Genetics

46.

Kehoe PG, Wong S, Al Mulhim N, Palmer LE, Miners JS (2016) Angiotensin-converting enzyme 2 is reduced in Alzheimer’s disease in association with increasing amyloid-β and tau pathology. Alzheimer’s Res Therapy 8:1CrossRef

47.

Korczyn AD (2020) Dementia in the COVID-19 period. J Alzheimer’s Dis 75(4):1071CrossRef

48.

Labandeira-Garcia JL, Rodríguez-Perez AI, Garrido-Gil P, Rodriguez-Pallares J, Lanciego JL, Guerra MJ (2017) Brain renin-angiotensin system and microglial polarization: implications for aging and neurodegeneration. Front Aging Neurosci 3(9):129CrossRef

49.

Lan J, Ge J, Yu, J et al (2020) Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor. Nature 581:215–220. https://doi.org/10.1038/s41586-020-2180-5CrossRefPubMed

50.

Lee DJ, Lockwood J, Das P, Wang R, Grinspun E, Lee JM (2020) Self-reported anosmia and dysgeusia as key symptoms of coronavirus disease 2019. Can J Emergency Med 22(5):595–602CrossRef

51.

Lim KH, Yang S, Kim SH, Joo JY (2020) Elevation of ACE2 as a SARS-CoV-2 entry receptor gene expression in Alzheimer’s disease. J Infect 81(3):e33–e34PubMedPubMedCentralCrossRef

52.

Love S, Chalmers K, Ince P, Esiri M, Attems J, Jellinger K, Yamada M, McCarron M, Minett T, Matthews F et al (2014) Development, appraisal, validation and implementation of a consensus protocol for the assessment of cerebral amyloid angiopathy in post-mortem brain tissue. Am J Neurodegener Dis 3:19–32PubMedPubMedCentral

53.

Mahammedi A, Saba L, Vagal A, Leali M, Rossi A, Gaskill M, Sengupta S, Zhang B, Carriero A, Bachir S, Crivelli P (2020) Imaging of neurologic disease in hospitalized patients with COVID-19: an Italian multicenter retrospective observational study. Radiology 297(2):E270–E273PubMedCrossRef

54.

Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, Chang J, Hong C, Zhou Y, Wang D, Miao X (2020) Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan. Chin JAMA Neurol 77(6):683–690CrossRef

55.

Martín-Jiménez P, Muñoz-García MI, Seoane D, Roca-Rodríguez L, García-Reyne A, Lalueza A, Maestro G, Folgueira D, Blanco-Palmero VA, Herrero-San Martín A et al (2020) Cognitive impairment is a common comorbidity in deceased COVID-19 patients: a hospital-based retrospective cohort study. J Alzheimers Dis 78:1367–1372. https://doi.org/10.3233/jad-200937CrossRefPubMed

56.

McCracken IR, Saginc G, He L, Huseynov A, Daniels A, Fletcher S, Peghaire C, Kalna V, Andaloussi-Mäe M, Muhl L et al (2021) Lack of evidence of angiotensin-converting Enzyme 2 expression and replicative infection by SARS-CoV-2 in human endothelial cells. Circulation 143:865–868. https://doi.org/10.1161/circulationaha.120.052824CrossRefPubMedPubMedCentral

57.

Meng X, Deng Y, Dai Z, Meng Z (2020) COVID-19 and anosmia: a review based on up-to-date knowledge. Am J Otolaryngol 41(5):102581PubMedPubMedCentralCrossRef

58.

Miners JS, Schulz I, Love S (2018) Differing associations between Aβ accumulation, hypoperfusion, blood–brain barrier dysfunction and loss of PDGFRB pericyte marker in the precuneus and parietal white matter in Alzheimer’s disease. J Cerebral Blood Flow Metabol 38(1):103–115CrossRef

59.

Miners S, Kehoe PG, Love S (2020) Cognitive impact of COVID-19: looking beyond the short term. Alzheimer’s Res Ther 12(1):1–6CrossRef

60.

Mirra SS, Heyman A, McKeel D, Sumi SM, Crain BJ, Brownlee LM, Vogel FS, Hughes JP, Van Belle G, Berg L (1991) The consortium to establish a registry for Alzheimer’s disease (CERAD): part II standardization of the neuropathologic assessment of Alzheimer’s disease. Neurology 41(4):479PubMedCrossRef

61.

Hyman BT, Phelps CH, Beach TG, Bigio EH, Cairns NJ, Carrillo MC, Dickson DW, Duyckaerts C, Frosch MP, Masliah E, Mirra SS (2012) National Institute on aging–Alzheimer’s association guidelines for the neuropathologic assessment of Alzheimer’s disease. Alzheimer’s Dementia 8(1):1–3PubMedCrossRef

62.

Muhl L, He L, Sun Y, Andaloussi Mäe M, Pietilä R, Liu J, Genové G, Zhang L, Xie Y, Leptidis S et al (2022) The SARS-CoV-2 receptor ACE2 is expressed in mouse pericytes but not endothelial cells: Implications for COVID-19 vascular research. Stem Cell Reports 17:1089–1104. https://doi.org/10.1016/j.stemcr.2022.03.016CrossRefPubMedPubMedCentral

63.

Mukerji SS, Solomon IH (2021) What can we learn from brain autopsies in COVID-19? Neurosci Lett 742:135528. https://doi.org/10.1016/j.neulet.2020.135528CrossRefPubMed

64.

Oddo S, Caccamo A, Shepherd JD, Murphy MP, Golde TE, Kayed R, Metherate R, Mattson MP, Akbari Y, LaFerla FM (2003) Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Aβ and synaptic dysfunction. Neuron 39(3):409–421PubMedCrossRef

65.

Palau V, Riera M, Soler MJ (2020) ADAM17 inhibition may exert a protective effect on COVID-19. Nephrol Dial Trans 35(6):1071–1072CrossRef

66.

Patel S, Rauf A, Khan H, Abu-Izneid T (2017) Renin-angiotensin-aldosterone (RAAS): the ubiquitous system for homeostasis and pathologies. Biomed Pharmacother 94:317–325. https://doi.org/10.1016/j.biopha.2017.07.091CrossRefPubMed

67.

Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, Vivekanandam V (2020) The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain 143(10):3104–3120PubMedPubMedCentralCrossRef

68.

Perrotta F, Corbi G, Mazzeo G, Boccia M, Aronne L, D’Agnano V, Komici K, Mazzarella G, Parrella R, Bianco A (2020) COVID-19 and the elderly: insights into pathogenesis and clinical decision-making. Aging Clin Experiment Res 32:1599–1608CrossRef

69.

Pugazhenthi S, Qin L, Reddy PH (2017) Common neurodegenerative pathways in obesity, diabetes, and Alzheimer's disease. Biochimica et biophysica acta (BBA)-molecular basis of disease 1863(5): 1037-45

70.

Rhea EM, Logsdon AF, Hansen KM, Williams LM, Reed MJ, Baumann KK, Holden SJ, Raber J, Banks WA, Erickson MA (2021) The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24(3):368–378PubMedCrossRef

71.

Ribeiro VT, de Souza LC, Simoes e Silva AC, (2020) Renin-angiotensin system and Alzheimer’s disease pathophysiology: from the potential interactions to therapeutic perspectives. Protein Peptide Lett 27(6):484–511CrossRef

72.

Rizzo MR, Paolisso G (2021) SARS-CoV-2 emergency and long-term cognitive impairment in older people. Aging Dis 12:345–352. https://doi.org/10.14336/ad.2021.0109CrossRefPubMedPubMedCentral

73.

Roca-Ho H, Riera M, Palau V, Pascual J, Soler MJ (2017) Characterization of ACE and ACE2 expression within different organs of the NOD mouse. Int J Mol Sci 18(3):563PubMedPubMedCentralCrossRef

74.

Rowland R, Brandariz-Nuñez A (2021) Analysis of the role of N-linked glycosylation in cell surface expression, function, and binding properties of SARS-CoV-2 receptor ACE2. Microbiol Spectr 9:e0119921. https://doi.org/10.1128/Spectrum.01199-21CrossRefPubMed

75.

Sah SK, Lee C, Jang JH, Park GH (2017) Effect of high-fat diet on cognitive impairment in triple-transgenic mice model of Alzheimer’s disease. Biochem Biophys Res Commun 493(1):731–736PubMedCrossRef

76.

Soto ME, Abellan van Kan G, Nourhashemi F, Gillette-Guyonnet S, Cesari M, Cantet C, Rolland Y, Vellas B (2013) Angiotensin-converting enzyme inhibitors and alzheimer’s disease progression in older adults: results from the Réseau sur la Maladie d’Alzheimer Français cohort. J Am Geriatrics Soc 61(9):1482–1488CrossRef

77.

St-Amour I, Paré I, Tremblay C, Coulombe K, Bazin R, Calon F (2014) IVIg protects the 3xTg-AD mouse model of Alzheimer’s disease from memory deficit and Aβ pathology. J Neuroinflamm 11(1):1–6CrossRef

78.

Stein SR, Ramelli SC, Grazioli A, Chung J-Y, Singh M, Yinda CK, Winkler CW, Sun J, Dickey JM, Ylaya K et al (2022) SARS-CoV-2 infection and persistence in the human body and brain at autopsy. Nature. https://doi.org/10.1038/s41586-022-05542-yCrossRefPubMedPubMedCentral

79.

Thal DR, Rüb U, Orantes M, Braak H (2002) Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58(12):1791–1800PubMedCrossRef

80.

Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ (2000) A human homolog of angiotensin-converting enzyme: cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 275(43):33238–33243PubMedCrossRef

81.

Tremblay C, François A, Delay C, Freland L, Vandal M, Bennett DA, Calon F (2017) Association of neuropathological markers in the parietal cortex with antemortem cognitive function in persons with mild cognitive impairment and Alzheimer disease. J Neuropathol Experiment Neurol 76(2):70–88CrossRef

82.

Tremblay C, St-Amour I, Schneider J, Bennett DA, Calon F (2011) Accumulation of transactive response DNA binding protein 43 in mild cognitive impairment and Alzheimer disease. J Neuropathol Exp Neurol 70(9):788–798PubMedCrossRef

83.

Vandal M, White PJ, Tremblay C, St-Amour I, Chevrier G, Emond V, Lefrançois D, Virgili J, Planel E, Giguere Y, Marette A (2014) Insulin reverses the high-fat diet–induced increase in brain Aβ and improves memory in an animal model of Alzheimer disease. Diabetes 63(12):4291–4301PubMedCrossRef

84.

Vanlandewijck M, He L, Mäe MA, Andrae J, Ando K, Del Gaudio F, Nahar K, Lebouvier T, Laviña B, Gouveia L et al (2018) A molecular atlas of cell types and zonation in the brain vasculature. Nature 554:475–480. https://doi.org/10.1038/nature25739CrossRefPubMed

85.

Wang J, Zhao H, An Y (2022) ACE2 shedding and the role in COVID-19. Front Cell Infect Microbiol. https://doi.org/10.3389/fcimb.2021.789180CrossRefPubMedPubMedCentral

86.

Wang Q, Davis PB, Gurney ME, Xu R (2021) COVID-19 and dementia: analyses of risk, disparity, and outcomes from electronic health records in the US. Alzheimer’s Dementia 17(8):1297–1306PubMedCrossRef

87.

Wright JW, Harding JW (2019) Contributions by the brain renin-angiotensin system to memory, cognition, and Alzheimer’s disease. J Alzheimer’s Dis 67(2):469–480CrossRef

88.

Wright JW, Kawas LH, Harding JW (2013) A role for the brain RAS in Alzheimer’s and Parkinson’s diseases. Front Endocrinol 25(4):158

89.

Xiao L, Sakagami H, Miwa N (2020) ACE2: the key molecule for understanding the pathophysiology of severe and critical conditions of COVID-19: demon or angel? Viruses 12(5):491PubMedPubMedCentralCrossRef

90.

Yang AC, Vest RT, Kern F, Lee DP, Agam M, Maat CA, Losada PM, Chen MB, Schaum N, Khoury N et al (2022) A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603:885–892. https://doi.org/10.1038/s41586-021-04369-3CrossRefPubMedPubMedCentral

91.

Yang F, Zhao H, Liu H, Wu X, Li Y (2021) Manifestations and mechanisms of central nervous system damage caused by SARS-CoV-2. Brain Res Bull 177:155–163. https://doi.org/10.1016/j.brainresbull.2021.09.015CrossRefPubMedPubMedCentral

92.

Yuki K, Fujiogi M, Koutsogiannaki S (2020) COVID-19 pathophysiology: a review. Clin Immunol 215:108427PubMedPubMedCentralCrossRef

93.

Zanin L, Saraceno G, Panciani PP, Renisi G, Signorini L, Migliorati K, Fontanella MM (2020) SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir 162:1491–1494PubMedCrossRef

94.

Zhang L, Zhou L, Bao L, Liu J, Zhu H, Lv Q, Liu R, Chen W, Tong W, Wei Q et al (2021) SARS-CoV-2 crosses the blood–brain barrier accompanied with basement membrane disruption without tight junctions alteration. Signal Transduct Target Ther 6:337. https://doi.org/10.1038/s41392-021-00719-9CrossRefPubMedPubMedCentral

95.

Zhang Y, Chen K, Sloan SA, Bennett ML, Scholze AR, Keeffe S, Phatnani HP, Guarnieri P, Caneda C, Ruderisch N et al (2014) An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. J Neurosci 34:11929. https://doi.org/10.1523/JNEUROSCI.1860-14.2014CrossRefPubMedPubMedCentral

96.

Zhou Y, Xu J, Hou Y, Leverenz JB, Kallianpur A, Mehra R, Liu Y, Yu H, Pieper AA, Jehi L et al (2021) Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment. Alzheimer’s Res Ther 13:110. https://doi.org/10.1186/s13195-021-00850-3CrossRef

97.

Zipeto D, Palmeira JdF, Argañaraz GA, Argañaraz ER (2020) ACE2/ADAM17/TMPRSS2 interplay may be the main risk factor for COVID-19. Front Immunol. https://doi.org/10.3389/fimmu.2020.576745CrossRefPubMedPubMedCentral

Title: Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease
Authors: Louise Reveret
Manon Leclerc
Vincent Emond
Cyntia Tremblay
Andréanne Loiselle
Philippe Bourassa
David A. Bennett
Sébastien S. Hébert
Frédéric Calon
Publication date: 01-12-2023
Publisher: BioMed Central
Published in: Acta Neuropathologica Communications / Issue 1/2023
Electronic ISSN: 2051-5960
DOI: https://doi.org/10.1186/s40478-023-01647-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Higher angiotensin-converting enzyme 2 (ACE2) levels in the brain of individuals with Alzheimer’s disease

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2023

Localized microglia dysregulation impairs central nervous system myelination in development

Rise and fall of peroxisomes during Alzheimer´s disease: a pilot study in human brains

A sellar presentation of a WNT-activated embryonal tumor: further evidence of an ectopic medulloblastoma

Spontaneous intracerebral haemorrhage associated with early-onset cerebral amyloid angiopathy and Alzheimer’s disease neuropathological changes five decades after cadaveric dura mater graft

Variant allelic frequencies of driver mutations can identify gliomas with potentially false-negative MGMT promoter methylation results

Sleep fragmentation affects glymphatic system through the different expression of AQP4 in wild type and 5xFAD mouse models