**4. Role of ACE2 in renin-angiotensin system [RAS]**

Both ACE and ACE2 play a major role in maintaining renin-angiotensin system [RAS] homeostasis. ACE2 acts like a negative regulator of ACE in RAS. RAS involves a variety of proteins and enzymes. Angiotensinogen is an inactive precursor that gets cleaved by renin to form angiotensin I. ACE acts on angiotensin I to convert into angiotensin II [Ang II] while ACE2 converts Ang II to Ang [1-7]. Ang [1-7] then binds to Mas receptors and causes attenuation of the signal cascade that was activated by Ang II (**Figure 2**). Thus, ACE2 not only inactivates Ang II but also generates the antagonistic peptide Ang [1-7] [33]. Ang [1-7] can also be formed from Ang I by neutral endopeptidases and neprilysin, but the most effective pathway of Ang [1-7] generation is through ACE2 [34]. The conversion of Ang II

**Figure 2.** *Renin-Angiotensin System.*

to Ang [1-7] by ACE2 is 70 folds more efficient than the conversion of Ang I to Ang [1-9] by ACE2. Thus, under physiological conditions, ACE2 mainly forms Ang [1-7] than Ang [1-9] [34].

While Ang II, which acts via angiotensin 1/AT1 [primary mediator] and angiotensin 2/AT2 receptors is a potent vasoconstrictor, a pro-fibrotic, and a pro-inflammatory agent, Ang [1-7] acts via Mas receptors and has vasodilator, anti-apoptotic and anti-proliferative effect. Mas receptors are G protein-coupled receptors and in the brain, they are highly expressed in the dentate gyrus of the hippocampus, a site-specific for adult neurogenesis and in blood vessels [35]. The ACE2/Ang [1-7]/Mas receptor axis of the RAS is considered to be the protective arm of the renin-angiotensin system. A balance in ACE/ACE2 is critical which implies a balance between the pro-inflammatory pro-oxidative arm and the anti-inflammatory and anti-oxidative arm of RAS. An increase in ACE/ ACE2 ratio was observed in many pathological conditions including cardiovascular pathology, renal dysfunction, pulmonary hypertension, in cigarette smokers, and Alzheimer's disease [36–39]. SARS-CoV-2 which enters the host cells via ACE2 also causes downregulation of ACE2 and the major targets of SARS-CoV-2 are those which express higher levels of ACE2 [26]. The fibrotic and inflammatory processes observed in various organs in COVID-19 patients could be attributed to the dysregulation of ACE2 and subsequently, RAS which is observed in endocrine, paracrine, and intracrine levels in several organs [40]. Dysregulation of RAS in the brain is associated with neuroinflammation and neurodegeneration [41].

### **5. Neurogenesis**

The old dogma that the production of functional neurons does not occur in adult life was refuted when Altman and Das published evidence to support the *Does COVID-19 Affect Adult Neurogenesis? A Neurochemical Perspective DOI: http://dx.doi.org/10.5772/intechopen.101179*

**Figure 3.** *Coronal section of the brain showing the sites of adult neurogenesis.*

continuation of neurogenesis in adult life in rodents [42]. Neurogenesis refers to the process of the generation of new neurons from neural stem cells. This process which plays a major role in brain development in embryonic life ceases to exist shortly after birth in the majority of brain areas except two. The subgranular zone [SGZ] of the dentate gyrus of the hippocampus and subventricular zone [SVZ], lining the lateral wall of the lateral ventricles are the two areas where neurogenesis persists well into adult life albeit declining slightly with ageing (**Figure 3**) [43, 44]. There is a complex microenvironment that nourishes and supports the neural progenitor cells and their progeny which is called the 'neurogenic niche'. There are various trophic factors, blood vessels, supporting glial cells, and hormones in the neurogenic niche that help to control and enhance neurogenesis [45]. The newborn neurons mature and get integrated into neural circuits and are involved in a variety of functions including learning and memory like temporal and pattern separation, high-resolution memory, synaptic plasticity, fear conditioning and emotions, and olfaction [46]. Incidentally altered neurogenesis is implicated in several neuropsychiatric diseases like Alzheimer's disease, Parkinson's disease, depression, Huntington's disease, and stroke, epilepsy, and demyelinating disease [46, 47].
