Vasilopoulou_2021_Br.J.Pharmacol__

BACKGROUND AND PURPOSE: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I2 Imidazoline receptors (I2-IR) ligands have a neuroprotective role in AD. Moreover, co-treatment of acetylcholinesterase inhibitors with neuroprotective agents has shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I2-IR ligand LSL60101, donepezil, and their combination in 5XFAD mice. EXPERIMENTAL APPROACH: 5XFAD female mice were treated with low doses of LSL60101 (1 mg kg(-1) day(-1) ), donepezil (1 mg kg (-1) day(-1) ), and donepezil plus LSL60101 (1+1 mg kg(-1) day(-1) ), during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze, and three-chamber tests were employed to evaluate the cognitive and behavioural status after treatment. The effects of the treatments on AD-like pathology were assessed with immunohistochemistry, Western blot, ELISA and qPCR. KEY RESULTS: Chronic low-dose treatment with LSL60101 and donepezil reversed cognitive deficits and impaired social behaviour. LSL60101 treatment did not affect anxiety-like behaviour in contrast to donepezil. In the 5XFAD brains, LSL60101 and donepezil/LSL60101 treatments attenuated Abeta-pathology by decreasing Abeta40, Abeta42 levels and beta plaques number, and Tau hyperphosphorylation. These alterations were accompanied by reduced microglia marker Iba-1 levels and increased Trem2 gene expression. LSL60101 and donepezil decreased glial fibrillary acidic protein (GFAP) astrocytic marker reactivity. However, only LSL60101 and donepezil/LSL60101 treatments significantly increased the synaptic markers' levels post-density 95 (PSD95) and synaptophysin (SYN). CONCLUSION AND IMPLICATIONS: Our results suggest that chronic low dose treatment with selective I2-IR ligands can be an effective treatment for AD and provide insights into combination treatments of symptomatic and disease-modifying drugs.