Alzheimer's disease (AD) is a progressive neurodegenerative disorder, accounting for 60–80% of all worldwide dementia cases (Williams et al., 2010). It is characterized by a decline in learning and cognition, increased amyloid β burden, tau hyperphosphorylation, altered neurotransmitter level that finally lead to neural atrophy (DeTure and Dickson, 2019; Kehoe et al., 2016). Neuroinflammation is a primary barrier that protects the brain by abolishing or restraining varied pathogens (Ransohoff, 2016; Wyss-Coray and Mucke, 2002). Apart from transgenic models, studies revealed that intracerebroventricular (ICV) streptozotocin (STZ) induced a preclinical sporadic Alzheimer's disease (SAD) model leading to cognitive deficits along with reduced cholinergic neurotransmitter level leading to generation of plaques and glial cell activation in both mouse/rat models (Grieb, 2016; Liu et al., 2011; Salkovic-Petrisic and Hoyer, 2007; Salkovic-Petrisic et al., 2009). STZ is a glucosamine-nitrosourea compound which was originally identified as an antibiotic. STZ administration, through routes such as intracebroventricular or intraperitoneal injection, produces impaired learning and memory, increased cerebral aggregated Aβ fragments (Long-Smith et al., 2013), total tau protein (Chen et al., 2014), and Aβ deposits in rodents. These changes were accompanied by a decreased glycogen synthase kinase (GSK-3) alpha/beta ratio (phosphorylated/total) in the brain. Administration of STZ in a rodent's brain has been shown to produce neuroinflammation (Rai et al., 2013), oxidative stress and biochemical alterations (Long-Smith et al., 2013), and is considered a valid experimental model to study the early pathophysiological changes in neurodegenerative disease. STZ-induced spatial learning deficit in Morris water maze test and tau phosphorylation in rodent's brain produces sporadic AD like pathology (Chen et al., 2013; Gao et al., 2014; Gaspar et al., 2021; Kosaraju et al., 2013; Rai et al., 2014). Another resemblance to AD patient is the enhanced reactive oxygen species (ROS) generation that leads to mitochondrial anomalies causing neurodegeneration (Chen et al., 2013; Saxena et al., 2011; Tiwari et al., 2009). A number of factors have been linked to the pathophysiology of AD, including cholinergic system dysfunction, amyloid/tau toxicity, and oxidative stress/mitochondrial dysfunctions (Tiwari et al., 2019), implying that the pathology of AD is multifactorial and that more research is needed to determine the exact mechanism of disease progression.

Furthermore, previous reports have also suggested the involvement of renin-angiotensin system (RAS) i.e., Angiotensin Converting Enzyme/Angiotensin II (Ang II)/Angiotensin Receptor Type-1 (ACE/Ang II/AT1R) axis in AD progression (Abiodun and Ola, 2020; Feng et al., 2020; Jiang et al., 2016; Kamel et al., 2018; Ribeiro et al., 2020). Horiuchi et al., have reviewed the role of brain angiotensin in cognitive functioning and dementia. Horiuchi and colleagues hypothesized that RAS components could play a future therapeutic role in preventing AD progression. There is evidence that acute or subacute Ang II exposure improves memory and reduces cognitive impairment (Iwai and Horiuchi, 2009; Mogi et al., 2012). Interestingly, telmisartan, an Ang II receptor blocker, improved cognitive deficit in Aβ injected mice (Tsukuda et al., 2009), implying a role for RAS components in AD progression or dementia. Ang II plays role in pathophysiology of AD, including increased amyloid-β precursor protein (APP) formation and cognitive impairment (Wright and Harding, 2019). Another study revealed that oral ingestion of Perindopril (an ACE inhibitor) improved cognitive memory via NFκB downregulation in SHRs, suggesting decreasing level of Ang II was neuroprotective (Goel et al., 2015). Studies also showed that decreased acetylcholine (ACh) level in brain with respect to increased angiotensin levels (Barnes et al., 1992; Bartus et al., 1982). Clinical as well as preclinical studies have revealed that RAS inhibition protect against memory impairment, cholinergic dysfunction, oxidative stress, and β-amyloid deposition (Hou et al., 2008; Tota et al., 2012a, 2012b, 2013).

However, the deleterious effect of ACE/Ang II/AT1R is countered by another axis of RAS, that is Angiotensin converting enzyme2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang-(1–7)/Mas receptor) axis, an important component of the brain. The presence of ACE2 has been observed in diverse brain areas and cell types, including neurons (Doobay et al., 2007), astrocytes (Gallagher et al., 2006), and cerebral arteries (Hamming et al., 2004). ACE2 cleaves Ang II to produce Ang (1-7) independently. The Ang (1-7) is found in different brain regions including the hypothalamus, cerebellar cortex, hippocampus, substantia nigra, medulla oblongata, and amygdala (Gironacci et al., 2018). It has been shown that ACE2 counters Aβ mediated neurotoxic effect in APP transgenic mice as well as in vitro studies (Liu et al., 2014). Recent studies have shown that Mas receptor activation improve cognition deficits in a rat model of cerebral ischemia (Jiang et al., 2012; Xie et al., 2014).

However, the role of ACE2/Ang (1-7)/Mas receptor axis in the progression of AD is still unclear. Therefore, in the current study, we aimed to understand the functional significance of ACE2/Ang (1-7)/Mas receptor axis in the pathophysiology of AD in both in vitro and in vivo models. Using STZ induced toxicant model, we have shown that small dose of STZ is sufficient to reduce ACE2/Mas receptor levels, antioxidant content, mitochondrial membrane potential (MMP). Additionally, STZ treatment potentially induces inflammation, oxidative stress, amyloid beta deposition, NFκB activation and impairment in learning and memory. In contrast, ACE2 inhibitor (DIZE) treatment significantly restored STZ induced impairments in in-vitro and in-vivo models by reducing NFκB and inflammatory cascade.