Basic Science and Pathogenesis.

Background: Microglia play an important role in immune memory. Lipopolysaccharide (LPS) triggers immune memory and primes microglia, resulting in brain pathologies and brain dysfunction following a second stimulus (1, 2). An increase in the C1q/ PSD95 expressions within microglia and excessively synaptic pruning were observed in mouse model of Alzheimer's disease (3). However, the effects of microglial priming induced by high-fat diet (HFD) on microglial function, synaptic plasticity, cognition, and depressive-like behavior after the secondary LPS stimulation have not been investigated.

Method: Twenty-four male Wistar rats were randomly assigned to be three primed conditions to receive either normal saline (NSS: intraperitoneal injection (i.p., as single dose)), LPS (0.5 mg/kg, i.p. as a single dose), or 4 weeks of 60% HFD consumption. Then at week 8, rats in each condition were divided into 2 groups. Each group was received the single dose of second stimulus of either NSS (i.p.) or LPS (0.5 mg/kg, i.p.). After 12-16 hrs from second stimulus, the cognitive function and depressive-like behavior were determined in all rats. Then animals were euthanized, and brains were removed for further analysis.

Result: All rats receiving LPS injection as the second stimulation with or without primed condition, equally increased microglial numbers, when compared to rats without any LPS stimulation or control rats (p<0.05, Figure 1). Interestingly, rats receiving second LPS injection increased C1q/PSD95 colocalized with microglia, decreased dendritic spine density, and increased freezing duration, when compared to the control rats (p<0.05, Figure 1). LPS-stimulated rats with both LPS and HFD-primed conditions showed the highest levels of these parameters (p<0.05, Figure 1). In addition, All LPS-stimulated rats with or without primed conditions exhibited cognitive decline, when compared to the control rats (p<0.05, Figure 1).

Conclusion: Our findings suggest that only 4-week HFD consumption effectively primed microglia to a similar extent as primed with a single dose of LPS injection, leading to excessive synaptic engulfment, as well as cognitive decline and depressive-like behavior in the second LPS stimulation after 4-week of HFD withdrawal period.