Effects of the Immunomodulatory Oligonucleotide IMT504 on Learning and Memory in an Alzheimer’s Disease Rat Model

Neuroinflammation and immune dysfunction are increasingly recognized as major contributors to Alzheimer’s disease (AD), suggesting that restoration of immune homeostasis may represent a promising therapeutic approach. IMT504 is an immunomodulatory oligonucleotide that promotes protective and reparative responses in experimental models involving chronic inflammation and tissue damage. We therefore investigated whether IMT504 could ameliorate cognitive alterations in the McGill-R-Thy1-APP rat (TG), a model that expresses human amyloid precursor protein with the Swedish and Indiana mutations and develops progressive amyloid pathology and memory impairment. Twelve-month-old TG rats received either physiological saline or IMT504 (20 mg/kg, s.c.) once daily for five consecutive days. Seventy-two hours later, animals were evaluated using open-field, novel object recognition, novel object location, and inhibitory avoidance tasks. Treatment with IMT504 enhanced novel object recognition performance and improved associative memory in the inhibitory avoidance task. In the latter, treatment response differed according to sex: females exhibiting a more marked improvement in performance than males. Overall, these results show that a short systemic treatment with IMT504 benefits specific cognitive domains in TG rats and highlight sex as a relevant biological variable when assessing its therapeutic potential for AD.