CEREBRAL AMYLOID ANGIOPATHY TREATMENT VIA INNATE IMMUNITY STIMULATION IN AGED NON-HUMAN PRIMATES

Abstract

Immunotherapeutic approaches for Alzheimer's disease (AD) are hampered by complications related to ineffectual clearance of cerebral amyloid angiopathy (CAA). Given the independent correlation of the degree of CAA pathology with the severity of cognitive impairment, as well as the key role of CAA in the pathophysiology leading to development of amyloid-related imaging abnormalities, our studies were designed to determine whether stimulation of innate immunity with TLR9 agonist CpG oligodeoxynucleotides (ODNs) could have beneficial effects in a non-human primate model of sporadic CAA, squirrel monkey (Saimiri Boliviensis). Our prior work has shown that treatment with CpG ODN is effective at improving cognitive deficits in aged monkeys without inducing adverse events. Elderly female monkeys with expected CAA deposits were subcutaneously injected with either predetermined non-toxic dosages of the class B CpG ODN or saline for a 25 month period. Animals were continuously examined for signs of toxicity. Plasma taken at specific times in the course of treatment was analyzed to identify immune responses and AD biomarkers. Histological and biochemical brain analyses commenced upon completion of the behavioral protocols. Long term treatment with CpG ODN significantly reduced total amyloid burden (6E10/4G8 immunohistochemistry), which in this model corresponds primarily to CAA. Histological evaluation of CpG ODN effect on pyroglutamate levels (AβpE3 immunohistochemistry) revealed region specific reduction in AβpE3 burden in monkeys treated with CpG ODN. These favorable histological data will be corroborated by measurements of Aβ levels in the brain homogenates. Our initial biomarker analyses exhibited a noticeable increase in AβpE3 plasma levels in CpG ODN-treated animals. Subsequent evaluation showed no increase in the extent of Iba1 microgliosis and GFAP astrogliosis in CpG ODN group at the end of the treatment. Additionally, there was no evidence of increased microhemorrhages or T cell infiltration in association with CpG ODN treatment, further supporting the viability of our approach. Concluding assessment of microglia/macrophage activation is currently in progress. Overall, the present findings together with our earlier experimental evidence validate this novel concept of immunomodulation as a safe method to successfully ameliorate AD related pathology, suggesting CpG ODN would have a significant potential of achieving clinical efficacy.