Disease-modifying treatment with I imidazoline receptor ligand LSL60101 in an Alzheimer's disease mouse model: a comparative study with donepezil.

Background And Purpose: The development of effective therapeutic strategies against Alzheimer's disease (AD) remains a challenge. I imidazoline receptor ligands have a neuroprotective role in AD. Moreover, co-treatment of AChE inhibitors with neuroprotective agents have shown better effects on the prevention of dementia. Here, we assessed the potential therapeutic effect of the I ligand, donepezil and their combination in 5XFAD mice.

Experimental Approach: 5XFAD female mice were treated with low doses (1 mg·kg ·day ) of LSL60101, donepezil and donepezil plus LSL60101, during 4 weeks per os. Novel object recognition, Morris water maze, open field, elevated plus maze and three-chamber tests were used to evaluate the cognitive and behavioural status after treatment. The effects 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 amyloid-β pathology by decreasing amyloid-β and amyloid-β levels, amyloid-β plaque 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 marker levels of post-synaptic density protein 95 and synaptophysin.

Conclusion And Implications: Chronic low-dose treatment with selective I - ligands can be an effective treatment for AD and provide insights into combination treatments for symptomatic and disease-modifying drugs.