Comprehensive characterization of CAG-hACE2 transgenic mice to define the role of the ACE2 receptor

RAS represents a critical regulatory hub not only for peripheral homeostasis, encompassing physiological functions such as the regulation of cardiovascular and vascular homeostasis, but also for cerebral homeostasis. Within this framework, ACE2 plays a central role as a fine modulator of the balance between neurotoxic and potentially neuroprotective peptides. In light of these premises, the present thesis employed the CAG-hACE2 transgenic mouse model, characterized by ubiquitous overexpression of hACE2, with the aim of providing a systematic behavioral characterization of this model, which is currently lacking in the literature, thereby laying the groundwork for future studies seeking to use this animal model to investigate the role of the RAS in neurobiological contexts. Behavioral characterization, conducted using a comprehensive battery of tests, revealed a complex and sexually dimorphic phenotype. These results indicate that ACE2 does not act as a simple on/off switch for behavior, but rather as a fine regulator of neurobehavioral homeostasis, with effects that vary according to biological sex and the functional domain under investigation. Taken together, these observations open new perspectives for the development of pharmacological strategies based on selective modulation of the RAS, within a precision medicine framework for the treatment of anxiety-related disorders, mnemonic deficits, and neurodegenerative diseases characterized by pathological RAS remodeling.