ACE2: Friend or Foe in Post-COVID-19 Neurodegeneration?

Figures

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  Figure 1. A simplified diagram of the renin–angiotensin system and its interactions with the kallikrein–kinin system. ACE promotes the conversion of angiotensin (Ang) I to Ang II, transforms Ang (1–9) into Ang (1–7), and inactivates bradykinin from the kinin–kallikrein system (KKS). ACE2 facilitates the transformation of Ang I into Ang (1–9) and Ang II into Ang (1–7), as well as breaking down metabolites such as (Des-Arg9)-bradykinin (DEABK) and Lys-(Des-Arg9)-bradykinin (LDEABK). The interaction of Ang (1–7) with the Mas receptor (MASR) can result in vasodilation and antioxidant, antiproliferative, anti-inflammatory, and anti-remodeling effects. Binding of Ang II to angiotensin receptor type 2 (AT2R) can lead to vasodilation, anti-inflammatory and antifibrotic effects, and apoptosis. The binding of Angiotensin II (Ang II) to angiotensin receptor type 1 (AT1R) triggers vasoconstriction, inflammation, fibrosis, and apoptosis, whereas the ACE2/Ang II/bradykinin receptor 1 (B1R) axis contributes to inflammation and oxidative stress [2,12,14,23,25]. The blue arrows represent the reactions occurring in the RAS, while the green arrows illustrate those in the KKS. Additionally, the blue and brown…

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  Figure 2. Diagram of ACE2 gene. The 18 initially identified exons, E1 to E18, are shown in gray, and exon 1 of the truncated ACE2 variant, dE, is highlighted in dark green. Additionally, the predicted exons associated with alternative splicing are depicted in light green [37,38,39,40,41]. Regulation of ACE2 expression at the transcriptional level is controlled by different transcription factors depending on the tissue. The localization of transcription factor binding sites is indicated by arrows [13,39,40,41,42]. This figure was designed using BioRender (https://www.biorender.com).

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  Figure 3. ACE2 protein’s structure. (A) A comprehensive diagram of the ACE2 protein’s domain structure, emphasizing its forms and isoforms [39]. (B) A schematic representation of the ACE2 protein, indicating sites of sheddase cleavage, post-translational modifications, and its protein interactions. SP—signal peptide. This figure was designed using BioRender (https://www.biorender.com). Panel A was adopted from Stocker et al. (2023) [39] (CC BY4.0).

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  Figure 4. SARS-CoV-2 infection may cause damage in neurotransmitter systems in a similar manner to Alzheimer’s disease. The marked decline in the enzymatic activity of mACE2, fueled by heightened ADAM17 and TMPRSS2 activation, together with SARS-CoV-2, could aggravate RAS imbalance (Ang II/ACE2/Ang(1–7)) in patients suffering from particular comorbidities, including neurodegenerative (including Alzheimer’s/Parkinson’s diseases) and cardiovascular diseases, diabetes, and chronic lung illnesses. High CHI3L1, ADAM17, and TMPRSS2 activity is characteristic of these comorbidities. SARS-CoV-2 virions attach to host receptors, triggering clathrin-mediated endocytosis (CME), where proteases like TMPRSS2 process the S-protein (SP) and mACE2. This process helps the virus fuse with the mucus membranes of mainly the olfactory system (OS) and lungs. The virus can spread through the OS and bloodstream, allowing it to infect the choroid plexus and brain cells that carry ACE2, along with the proteases TMPRSS2, CTSL, and FURIN. Virus attachment also triggers a change in the cytoplasmic ACE2 tail that enhances ADAM17 activation. When ADAM17 is activated, it releases sACE2, which can either prevent or…