Targeting the i2 imidazoline receptorsthe neuroprotective role of selective ligands in alzheimer’s disease

Resum

he identification of imidazoline receptors (IR) as a novel class of receptors has posed manifold research questions regarding their pharmacological and potential therapeutic properties. Among them, I2-IR receptors are widely distributed in the central nervous system (CNS) with predominant localization in glial cells. Remarkably, their activation has been shown to exhibit neuroprotective properties, yet through not fully understood molecular mechanisms. Furthermore, alterations of I2-IR density have been detected in patients with different brain disorders, including Alzheimer’s Disease (AD), suggesting a potential therapeutic value of I2-IR in AD. The latter suggestion is of special clinical significance since AD is an irreversible neurodegenerative disease and the most common form of dementia that affects millions of people worldwide. The consequences of AD range from detrimental outcomes for both the patients and their caregivers to a wide socioeconomic footprint, and unfortunately, there is still no cure for the disease. At the same time, AD prevalence is rapidly growing due to an increase in life expectancy in developed countries, further highlighting the urgency to identify new targets for halting disease progression and providing effective treatment. In this context, this doctoral dissertation aims to contribute to the scientific knowledge of I2-IR pharmacological possibilities in neurodegenerative diseases with unmet medical needs, such as AD. More concretely, during this thesis, we evaluate the neuroprotective properties of both well-established and structurally novel selective I2-IR ligands in lateonset AD (LOAD) and early-onset AD (EOAD) mouse models, with the aim to point out I2-IR as a novel potential therapeutic target for AD. In summary, we demonstrate that chronic treatment with potent and highly selective I2-IR ligands prevents cognitive decline and ameliorates behavioural and psychological symptoms of dementia (BPSD) -related phenotypes such as anxiety-, depressive-like behaviours and social deficits in the AD mouse models used. Furthermore, the prevention of the generalized cognitive downfall of the mice delivered by I2-IR treatments is consistent with favourable alterations at a molecular level. Notably, we provide evidence for beneficial effects on the AD classical hallmarks, namely A pathology and tau hyperphosphorylation, as well as mitigation of neuroinflammation and oxidative damage, processes with a pivotal role in AD initiation and progression. Remarkably, we detected alterations in Ca2+ related key enzymes induced by selective I2-IR treatment, providing insights into processes involved in the mechanism of neuroprotective action of I2-IR ligands. Ultimately, in our hands, I2-IR treatment exerted greater beneficial effects than donepezil under the neurodegenerative process. We conclude that I2-IR modulation by selective ligands can be a novel therapeutic strategy for AD therapy.