Evaluation of the Efficacy and Safety of TLR9 Stimulation in a Non-Human Primate Model of Sporadic Cerebral Amyloid Angiopathy 3879

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Abstract Description Squirrel Monkeys (SQMs) are a non-human primate model of sporadic Alzheimer’s disease (AD) pathology, characterized by abundant cerebral amyloid angiopathy. Previously, we demonstrated that chronic administration with TLR9 agonist class B CpG ODN in geriatric SQMs ameliorates AD-related pathology and behavioral deficits, without toxicity. In the present study, we evaluated the safety and efficacy of a class C CpG ODN (CpG-C) in another cohort of geriatric SQMs. We confirmed the upregulation of cytokine/chemokine (CXCL9, CCL2, and CXCL10) and IFN-inducible (GBP1, IFIT2, Mx2) genes associated with CpG-C immunostimulation at multiple intervals throughout the study, demonstrating that our treatment approach was not impeded by tolerance or senescence. Plasma Aβ40/42 IgG autoantibody levels were also measured throughout the treatment period. We found no differences between treatment groups, confirming that TLR9 stimulation did not lead to secondary activation of adaptive immunity. Additional histological assessments of treatment associated effect on brain astrocytes, microglia, and amyloid burden are ongoing. Furthermore, age related changes in plasma immune biomarkers were measured using Luminex magnetic bead panels. Significant alterations in plasma levels of S100B, sTrem2, YKL-40, and GFAP were observed with age. Hence, our findings enhance the translational value of SQMs for preclinical research while further demonstrating the safety and therapeutic efficacy of CpG ODNs. Funding Sources NIH grants- R01NS102845, R21NS127091 Topic Categories Translational and Interventional Immunology (TI)

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