**8. Role of ACE2 in adult neurogenesis in COVID-19**

SARS-CoV-2 entry into the cell through ACE2 is followed by the downregulation of ACE2. A decrease in ACE2 will lead to dysregulation of RAS and various other complications. A recent study has found that ACE2 is expressed in young neurons and in human-induced pluripotent stem cell-derived neural progenitor cells [90]. ACE2 is found to have various neuroprotective functions. It converts neurotoxic amyloid protein Aβ into neuroprotective one in transgenic mice [91]. ACE2 activator, diminazene increased CREB, BDNF, glutamate, and nicotinic receptor and decreased the levels of apoptotic and inflammatory proteins in the AD model of D-galactose-ovariectomized rats [92]. All these factors play a major role in adult neurogenesis. ACE2 deficiency in mice was found to be accompanied by significantly impaired learning and memory [93]. Exercise-induced neurogenesis in the dentate gyrus was abolished in ACE2 deficient mice. Ang II, Ang [1-7], and Mas receptors were not found to be responsible and hence the mediator of this effect is not identified yet [94].

ACE2 expression is stronger in the enterocytes of the small intestine and colon, which is even higher than in the lungs. Neural ganglia cells in the colon of the enteric nervous system also express ACE2 receptors. Intestinal ACE2 plays a major role in the transport of neutral amino acids via B0AT1, neutral amino acid transporter. ACE2/B0AT1 complex regulates the composition and function of gut microbiota. ACE2 knockout animals showed lower levels of serum neutral amino acid levels like tryptophan, and impaired gut microbiota composition along with reduced expression of small intestinal antimicrobial peptides [95]. Enteric infection is an important presentation of COVID-19. Faeces of COVID-19 patients were found to have Viral mRNA [96, 97]. SARS-CoV-2 entry via the enteric route into host cell leads to ACE2 shedding due to S priming which may lead to gut microbiota dysbiosis [98]. Depletion of gut microbiota by prolonged antibiotic treatment resulted in impairment in cognitive function and hippocampal neurogenesis in adult mice [99]. The existence of a strong link between gut microbiota and the development of mental disorders, depression, and anxiety which are associated with impaired adult neurogenesis has been explored in recent studies [100].

Neuroinflammation directly impairs adult hippocampal neurogenesis. Proinflammatory cytokine IL-1β, IL-6, IFN-α causes a reduction in neural cell proliferation and suppresses adult hippocampal neurogenesis [101–103]. SARS-CoV-2 entry into the brain triggers an immune response by activating microglia, astrocytes, and other immune cells. This leads to increased production of cytokines in the brain. Cytokine storm which is a deadly hyperinflammatory response is considered to be a hallmark feature of COVID-19 pathogenesis [104]. Hypercytokinemia of IL-6, IL-10, and TNF-α was observed in COVID-19 patients. Increased levels of IL-6 correlate with mortality and the need for ventilator support [105, 106].

Thus, there are different possible mechanisms through which SARS-CoV-2 affects adult neurogenesis via ACE2. This chapter, however, will focus on the role of ACE2 in possible alterations in adult neurogenesis in COVID-19 via neurotransmitters.
