Evaluation of biomarker, behavioral, and immunostimulatory profiles following treatment with Class C CpG ODN in a non‐human primate model of sporadic CAA

Abstract

AbstractBackgroundInnate immunomodulation has shown potential to be an effective therapeutic approach in ameliorating pathological features of Alzheimer’s Disease (AD). Our recently published study showed a reduction in cognitive deficits and AD‐related pathology in a squirrel monkey model (SQM) of sporadic cerebral amyloid angiopathy (CAA) following treatment with TLR9 agonist, Class B CpG ODN. Subsequently, we commenced a chronic treatment study evaluating the efficacy and safety of Class C CpG ODN in geriatric SQMs. Here, we further explore the efficacy of Class C CpG ODN by evaluating fluid biomarkers and implementing automated cognitive tests. Moreover, we assess the immunostimulatory profiles induced by Class B and Class C CpG ODNs using RNA‐Seq genome‐wide transcriptome analysis of SQM PBMCs.MethodGeriatric SQMs received monthly injections of CpG ODN‐C or saline (VEH) over three years. Fluid biomarkers for cerebrovascular dysfunction, neurodegeneration, and neuroinflammation were assessed by Luminex and SIMOA. Touchscreen‐based Automated Cognitive Testing System (ACTS) was applied among socially living SQMs to assess behavioral changes. RNA‐Seq analyses were performed using PBMCs isolated 24hrs following CpG ODN‐B and ‐C administrations in a separate cohort of elderly SQMs.ResultOur initial experiments confirmed the utility of SQMs for investigating plasma age‐associated neurodegeneration biomarkers, including NfL, GFAP, and neurogranin. Preliminary evaluation of cerebrovascular dysfunction‐related plasma biomarkers, such as MMPs, albumin index, bFGF, and VCAM, revealed no differences between our treatment groups at earlier time points. Although not significant, higher levels of plasma sTREM2 and YKL‐40 were observed in VEH monkeys compared to CpG ODN‐treated group. Concluding assessments will be performed in plasma collected at the end of the treatment period. Characterization of additional plasma/CSF biomarkers related to AD/neurodegeneration is underway. ACTS‐based two‐choice discrimination learning task revealed that CpG ODN‐treated group performed with a greater correct response rate than the VEH group. As expected, RNA‐Seq analyses of SQM PBMCs revealed significantly altered pathways, including Th1/Th2, TLR signaling, phagocytosis, chemokine signaling, interferon signaling, and senescence pathways, in addition to pathways involved in infiltration, activation, and recruitment of various immune cells.ConclusionThe study highlights the potential of the SQM model for future translational research on CAA/AD and for advancing innovative therapeutic interventions.