Palmitate Is Increased in the Cerebrospinal Fluid of Humans with Obesity and Induces Memory Impairment in Mice via Pro-inflammatory TNF-α

Abstract

Graphical Abstract Highlights d CSF palmitate is increased in overweight or obese humans with cognitive impairment d CSF palmitate inversely correlates with cognitive performance in overweight humans d Palmitate impairs synaptic plasticity and memory in mice d Activated microglia and TNF-a mediate palmitate-induced impairments in memory In Brief Obesity has been associated with cognitive decline. Melo et al. show that palmitate levels are increased in the CSF of overweight and obese humans. In mice, intracerebroventricular infusion of palmitate impairs synaptic plasticity and memory. Microglial-derived TNF-a mediates the deleterious actions of palmitate in the brain.

The role of innate immunity in Alzheimer's disease

“…166 They further report that increased levels of palmitate in the CSF of aged mice provoke pro-inflammatory TNF-α cytokine production and that this can lead to memory deficits. 166 Indeed, they showed that TNF-α receptor-deficient mice treated with palmitate perform better on memory tests compared with palmitate-treated wildtype controls. 166 In addition, an intracerebroventricular injection of infliximab, a TNF-α-neutralizing antibody, was also found to improve memory and ameliorate microgliosis in mice on a high-fat diet.…”

“…161,162 In this section, we will discuss the double-edged nature of inflammation in AD. [163][164][165][166][167][168][169][170] Resting levels of pro-inflammatory cytokines are found to be higher in the blood and cerebrospinal fluid (CSF) of AD patients, suggesting a role for them in disease pathogenesis. 171 The deposition of Aβ and resultant neuronal damage provide ligands to activate microglial phagocytosis of Aβ while also promoting microglia-mediated production of pro-inflammatory cytokines.…”

“…228 Obesity and exercise have also been implicated in AD prevalence and severity. 166,[229][230][231][232] Researchers have shown that obese individuals have high levels of the short-chain fatty acid known as palmitate in the CSF and that this can lead to impaired neuronal insulin signaling. 166 They further report that increased levels of palmitate in the CSF of aged mice provoke pro-inflammatory TNF-α cytokine production and that this can lead to memory deficits.…”

“…166,[229][230][231][232] Researchers have shown that obese individuals have high levels of the short-chain fatty acid known as palmitate in the CSF and that this can lead to impaired neuronal insulin signaling. 166 They further report that increased levels of palmitate in the CSF of aged mice provoke pro-inflammatory TNF-α cytokine production and that this can lead to memory deficits. 166 Indeed, they showed that TNF-α receptor-deficient mice treated with palmitate perform better on memory tests compared with palmitate-treated wildtype controls.…”

“…166 Indeed, they showed that TNF-α receptor-deficient mice treated with palmitate perform better on memory tests compared with palmitate-treated wildtype controls. 166 In addition, an intracerebroventricular injection of infliximab, a TNF-α-neutralizing antibody, was also found to improve memory and ameliorate microgliosis in mice on a high-fat diet. 166 Routine exercise, on the other hand, has been shown to help limit AD development and progression.…”