Curcumin supplementation in the rhesus monkey: effects on cognitive decline and neuroinflammation

Abstract

Human and non-human primates (NHP) undergo age-related cognitive decline beginning as early as middle-age, even in the absence of an underlying pathology or disease. Growing evidence indicates that an increase in white mater pathology related to rising chronic levels of inflammation may be key contributors to age related cognitive decline. Curcumin (CUR), the active ingredient in turmeric, is a polyphenol nutraceutical with potent anti-inflammatory and antioxidative effects. Several ongoing research studies are underway to explore this potential anti-aging compound. For the first time in a rhesus monkey model of aging, we studied the effects of CUR supplementation on cognition and inflammation. Baseline MRI, blood, CSF and cognitive data were collected for all monkeys. Monkeys were fed daily doses of 500mg of CUR or a vehicle control over 18-months during which three rounds of a battery of cognitive testing was performed along with regular collection of blood, CSF and MRI. Following completion of this testing and specific to this thesis, monkeys were further tested on object discrimination, object and spatial reversal tasks. No significant differences were observed between groups in object discrimination task performance. CUR treatment improved performance on object reversal testing, with treated monkeys making fewer perseverative type errors. At the completion of behavioral testing, serum samples from two-year post treatment onset and brain tissue were harvested for post-mortem analysis of markers of inflammation. The density and morphology of microglia, the resident immune cells of the brain, were examined using immunohistochemistry on serial coronal sections through frontal cortical gray (A46, A25) and while matter (FWM, CC, and CngB) regions that are implicated in cognitive aging. We demonstrated that CUR treatment did not significantly alter the density of presumably immune-activated microglia expressing the MHC class II marker LN3. However, treatment did affect morphological features of microglia specifically within the while matter. Within the white matter, CUR treatment was associated with a significant increase in microglial ramification, evidenced by greater process length, number of nodes and convex-hull area and volume. Increased microglial ramification suggests greater likelihood of microglial surveillance within the white matter associated with CUR treatment. No significant group differences however were observed in the select serum cytokine levels quantified using multiplex ELISA, or in inflammatory gene expression in brain tissue measured with qRT-PCR. While our findings show the benefit of CUR supplementation on cognitive performance and its effects on microglial morphology, further study is needed to understand the precise changes that CUR supplementation may have on inflammation.