Brain Renin–Angiotensin System as Novel and Potential Therapeutic Target for Alzheimer’s Disease

Figure 1. Genes of the RAS system in mouse brain cells. The figure shows genes expressed in the main cell types of the mouse brain, obtained by single-cell sequencing. Genes in black show increased expression (both copy number and number of expressing single cells) in that cell type. Agt-Angiotensinogen. Ace-Angiotensin-converting enzyme. Ace2 Angiotensin-converting enzyme 2. Agtr2-Type-2 angiotensin II receptor. Agtr1a-Type-1A angiotensin II receptor. Agtr1b-Type-1B angiotensin II receptor. Agtrap-Type-1 angiotensin II receptor-associated protein. Atp6ap2-Renin receptor. Ren1-Renin-1. MasR-Mas-related G-protein coupled receptor. AP-A-Aminopeptidase A (also known as Enpep). AP-N-Aminopeptidase N (also known as Anpep). Rnpep is the gene for aminopeptidase B (Also known as AP-B). Lnpep is the gene coding for the angiotensin IV receptor. Note that expression data were obtained from a WT animal and the lack of expression of genes in certain cell types could mean that such genes are expressed in a particular situation, such as inflammation or AD. Expression information extracted from http://linnarssonlab.org/cortex/ (accessed on 28 June 2021). Original article: [6].

Figure 2. Components of the brain RAS. From the cell types in the brain, neurons are the ones that express the genes that comprise the classical angiotensin pathway, from the generation of angiotensinogen (AGT), which is converted by renin into Angiotensin I (AngI), which is then converted to Angiotensin II (AngII) by the angiotensin-converting enzyme (ACE). Renin can signal the renin receptors (RENR), for which neurons have a high expression level (marked in blacks). AngII can signal the receptors AT1R and AT2R, which are present in neurons. The binding of AngII to AT1Rs is usually considered detrimental (red arrows), while binding to AT2R has neuroprotective effects (blue arrows). AngII can be converted to Ang1-7 by the angiotensin-converting enzyme 2 (ACE2), and its binding to the Mas receptor (MASR) is often related to vasodilation, anti-inflammatory effects, and reduction of oxidation (also blue arrows). For the novel RAS pathways, aminopeptidases A and B (AP-A/AP-B) can convert AngII into angiotensin III (AngIII), which is then converted to angiotensin IV (AngIV) by aminopeptidase B. It is noteworthy that the next aminopeptidase in the pathway, aminopeptidase-N (AP-N) is only…