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Adv Biomed Res 2020,  9:36

Can infection of COVID-19 virus exacerbate Alzheimer's symptoms? Hypothetic possible role of angiotensin-converting enzyme-2/Mas/brain-derived neurotrophic factor axis and Tau hyper-phosphorylation

1 Razi Drug Research Center, Iran University of Medical Sciences, Tehran, Iran
2 Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

Date of Submission05-Apr-2020
Date of Acceptance16-May-2020
Date of Web Publication28-Aug-2020

Correspondence Address:
Dr. Majid Motaghinejad
Iran University of Medical Sciences, P. O. Box: 14496-14525, Sheykhfazloolah Highway, Tehran
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/abr.abr_72_20

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How to cite this article:
Kermanshahi S, Gholami M, Motaghinejad M. Can infection of COVID-19 virus exacerbate Alzheimer's symptoms? Hypothetic possible role of angiotensin-converting enzyme-2/Mas/brain-derived neurotrophic factor axis and Tau hyper-phosphorylation. Adv Biomed Res 2020;9:36

How to cite this URL:
Kermanshahi S, Gholami M, Motaghinejad M. Can infection of COVID-19 virus exacerbate Alzheimer's symptoms? Hypothetic possible role of angiotensin-converting enzyme-2/Mas/brain-derived neurotrophic factor axis and Tau hyper-phosphorylation. Adv Biomed Res [serial online] 2020 [cited 2021 Aug 3];9:36. Available from:

  Hypothesis Top

During the years of the 2019–2020 outbreak of infection, one of the members of coronavirus, coronavirus disease-19 (COVID-19), becomes a global concern and is a public health emergency.[1],[2] Infection by coronaviruses causes mild respiratory tract disorder, such as the common cold, but rare forms of infections with this family of viruses such as severe acute respiratory syndrome, Middle East respiratory syndrome coronavirus, and COVID-19 can be lethal and can remain long-term sequels.[2],[3] Unfortunately, there is no enough information on long-term sequels of infection by COVID-19 in an infected person.[3],[4] However, based on some indirect evidence and documents, it can be hypostatized that infection with coronavirus family, especially COVID-19, can cause neurological disorder or exacerbate existing disease in an infected person, but it is not proven yet.[4],[5] According to recent studies, angiotensin-converting enzyme 2 (ACE2) can be acts as functional and host receptor of COVID-19.[6],[7] It seems that some parts of the sequels of COVID-19 in the respiratory and cardiovascular system were mediated via the inhibition of ACE-2, but the mechanism of involvement of this ACE-2 was not exactly clarified.[8],[9] On the other way, it was suggested that ACE-2 is one of the main enzymes which by the mediation of some important proteins such as Mas protein regulates normal brain functions such as cognitive activity and release of neurotrophic factors such as brain-derived neurotrophic factor (BDNF).[10],[11] Furthermore, there are novel studies that indicate that the reduced activity of the ACE-2/Ang (1–7)/Mas axis is strongly linked to Tau hyper-phosphorylation (inactivation) and aggregation of neural internal microtubules and amyloid-β (Aβ) peptides.[12],[13] According to these data, it was established that the reduction of ACE-2 activity or expression can disturb normal brain cognition activity or can exacerbate Alzheimer's disease.[13],[14] Thus, according to the mentioned studies, it was hypothesized that infection with COVID-19 can target and reduce ACE-2 activity, and/or expression, and probably its downstream Mas/BDNF axis, in the brain cells, and according to these data, it can be expected that infection by COVID-19 may cause disturbances in cognition activity and also exacerbate cognitive impairment in infected person with Alzheimer's disease [Figure 1].
Figure 1: In the pathophysiology of Alzheimer's disease, some intrinsic and extrinsic triggers cause activation of some kinases which led to hyper-phosphorylation of Tau protein. This Tau hyper-phosphorylation causes disability of microtubules, which consequently causes aggregation of tau protein (Tau fibril) and neuro-filaments. On the other way, some intrinsic and extrinsic triggers cause activation of secretase family enzymes which initiate degradation of Amyloid precursor protein and led to production and formation of amyloid-beta. Amyloid-beta, Tau fibril/neuro-filament causes degeneration neural cells which cause Alzheimer's disease or dementia. As mentioned in the text, angiotensin-converting enzyme-2 causes inhibition of secretases family enzymes and kinases enzymes which can inhibit occurrences of Alzheimer's disease, dementia, or cognition impairment. According to some indirect evidence, it seems that infection with the COVID-19 virus can cause inhibition of the angiotensin-converting enzyme-2 signaling pathway, and it might be can have long-term neurological sequels such as activation of Alzheimer's or dementia triggers signaling pathway

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  References Top

Chen H, Guo J, Wang C, Luo F, Yu X, Zhang W, et al. Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: A retrospective review of medical records. Lancet 2020;395:809-15.  Back to cited text no. 1
Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, et al. Pathological findings of COVID-19 associated with acute respiratory distress syndrome. Lancet Respir Med 2020;8:420-2.  Back to cited text no. 2
Paules CI, Marston HD, Fauci AS. Coronavirus infections – More than just the common cold. JAMA 2020;323:707-8.  Back to cited text no. 3
Li YC, Bai WZ, Hashikawa T. The neuroinvasive potential of SARS-CoV2 may be at least partially responsible for the respiratory failure of COVID-19 patients. J Med Virol 2020;92:552-555.  Back to cited text no. 4
Mao L, Jin H, Wang M, Hu Y, Chen S, He Q, et al. Neurological manifestations of hospitalized patients with COVID-19 in Wuhan, China: A retrospective case series study. JAMA Neurol 2020;1127:E1-E8.  Back to cited text no. 5
Kuhn JH, Radoshitzky SR, Wenhui Li, WongSK, Choe H, Farzan M. The SARS coronavirus receptor ACE 2 a potential target for antiviral therapy. In: New Concepts of Antiviral Therapy. Springer; 2006. p. 397-418.  Back to cited text no. 6
Cao Y, Li L, Feng Z, Wan S, Huang P, Sun X, et al. Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations. Cell Discov 2020;6:1-4.  Back to cited text no. 7
Chen L, Hao G. The role of angiotensin converting enzyme 2 in coronaviruses/influenza viruses and cardiovascular disease. Cardiovasc Res 2020. pii: cvaa093.  Back to cited text no. 8
Diao B, Feng Z, Wang C, Wang H, Liu L, Wang C, et al. Human Kidney is a Target for Novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection. medRxiv; 2020.  Back to cited text no. 9
Jiang T, Gao L, Lu J, Zhang YD. ACE2-Ang-(1-7)-mas axis in brain: A potential target for prevention and treatment of ischemic stroke. Curr Neuropharmacol 2013;11:209-17.  Back to cited text no. 10
Xia H, Lazartigues E. Angiotensin-converting enzyme 2 in the brain: Properties and future directions. J Neurochem 2008;107:1482-94.  Back to cited text no. 11
Jiang T, Zhang YD, Zhou JS, Zhu XC, Tian YY, Zhao HD, et al. Angiotensin-(1-7) is Reduced and Inversely Correlates with Tau Hyperphosphorylation in Animal Models of Alzheimer's Disease. Mol Neurobiol 2016;53:2489-97.  Back to cited text no. 12
Kehoe PG, Wong S, Al Mulhim N, Palmer LE, Miners JS. Angiotensin-converting enzyme 2 is reduced in Alzheimer's disease in association with increasing amyloid-β and tau pathology. Alzheimers Res Ther 2016;8:50.  Back to cited text no. 13
Bodiga VL, Bodiga S. Renin angiotensin system in cognitive function and dementia. Asian J Neurosci 2013;2013:1-18.  Back to cited text no. 14


  [Figure 1]

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