P4‐304: Effects of elevated plasma cholesterol on CSF lipids and Alzheimer's disease CSF biomarkers in African green monkeys

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Mounting genetic, biochemical and epidemiological evidence suggests that abnormalities in cholesterol metabolism play an important role in the pathogenesis of Alzheimer's disease (AD). It has been previously shown that high-fat/high-cholesterol diet exacerbates brain amyloid burden and memory deficits in amyloid model mice, and induces phosphorylation of the microtubule-associate protein tau in apolipoprotein E (apoE)-deficient mice. However, the mechanism by which plasma cholesterol contributes to the pathogenesis of AD still remains unknown. Furthermore, little is known about how plasma cholesterol impacts lipids in the central nervous system (CNS), apolipoproteins, and amyloid/tau levels in more clinically relevant species such as non-human primates. Here we investigated the impact of diet-induced elevated plasma cholesterol levels on cerebrospinal fluid (CSF) and brain lipids and apolipoproteins, as well as CSF AD biomarkers β-amyloid (Aβ) peptides and tau in African Green Monkeys (AGMs). We fed AGMs with regular diet or fat/cholesterol-enriched diet (38.3% of energy from fat) for 6 months (n = 5 per group). Plasma samples were analyzed for total cholesterol, low density lipoprotein (LDL), and high density lipoprotein (HDL) cholesterol, triglyceride, cholesteryl ester transfer protein (CETP) and apolipoproteins (apoE, apoAI, and clusterin/apoJ). Corresponding CSF samples were characterized for Aβ40, Aβ42, total tau, phosphorylated tau (p-tau), cholesterol and apolipoproteins. Cholesterol and triglyceride levels in the brain and the liver were determined with respective biochemical assays. Animals fed with fat/cholesterol-enriched diet showed an increase in plasma total cholesterol, LDL and HDL cholesterol, along with increases in CETP and apoAI when compared to animals fed with regular diet. In contrast, we found that CSF apolipoproteins, apoE and clusterin/apoJ, as well as cholesterol levels in CSF and brain tissue were decreased in animals fed with the fat/cholesterol-enriched diet. These changes were accompanied by a decrease in CSF AD biomarkers Aβ40, Aβ42, total tau, and p-tau, and led to a significant increase in p-tau/total tau ratio. Our findings in AGMs suggest that alterations in cholesterol metabolism in the CNS associated with a fat/cholesterol-enriched diet can directly impact levels of amyloid and tau, the key pathological players in AD.

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