Central inhibition of Stearoyl-CoA Desaturase has minimal effects on the peripheral metabolic symptoms of the 3xTg Alzheimer's disease mouse model

Abstract

Evidence from genetic and epidemiological studies point to lipid metabolism defects in both the brain and periphery being at the core of Alzheimers disease (AD) pathogenesis. Previously, we reported that central inhibition of the rate-limiting enzyme in monounsaturated fatty acid synthesis, Stearoyl-CoA Desaturase (SCD), improves brain structure and function in the 3xTg mouse model of AD (3xTg-AD). Here, we tested whether these beneficial central effects involve recovery of peripheral metabolic defects, such as fat accumulation and glucose and insulin handling. As early as 3 months of age, 3xTg-AD mice exhibited obesity-like phenotypes including increased body weight and visceral and subcutaneous white adipose tissue deposition, as well as diabetic-like peripheral gluco-regulatory abnormalities. Intracerebral infusion of an SCD inhibitor that normalizes brain fatty acid metabolism, synapse loss and learning and memory deficits in middle-aged symptomatic 3xTg-AD mice did not affect peripheral phenotypes. This suggests that the beneficial effects of central SCD inhibition on cognitive function are not mediated by recovery of peripheral metabolic abnormalities. Given the widespread side-effects of systemically administered SCD inhibitors, these data suggest that selective inhibition of SCD in the brain may represent a clinically safer and more effective strategy for AD.