Research Article: Oral administration of Pantoea agglomerans-derived lipopolysaccharide prevents metabolic dysfunction and Alzheimer’s disease-related memory loss in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet

Date Published: June 1, 2018

Publisher: Public Library of Science

Author(s): Yutaro Kobayashi, Hiroyuki Inagawa, Chie Kohchi, Kimiko Kazumura, Hiroshi Tsuchiya, Toshiyuki Miwa, Katsuichiro Okazaki, Gen-Ichiro Soma, Keiko Abe.


The pathogenesis of Alzheimer’s disease (AD) remains unclear, but an imbalance between the production and clearance of amyloid-β (Aβ) peptides is known to play a critical role in AD progression. A promising preventative approach is to enhance the normal Aβ clearance activity of brain phagocytes such as microglia. In mice, the intraperitoneal injection of Toll-like receptor 4 agonist was shown to enhance Aβ clearance and exhibit a preventative effect on AD-related pathology. Our previous clinical study demonstrated that orally administered Pantoea agglomerans-derived lipopolysaccharide (LPSp) exhibited an LDL (low-density lipoprotein)-lowering effect in human volunteers with hyperlipidemia, a known risk factor for AD. In vitro studies have shown that LPSp treatment increases Aβ phagocytosis by microglial cells; however it is still unclear whether orally administered LPSp exhibits a preventive effect on AD progression. We show here that in senescence-accelerated prone 8 (SAMP8) mice fed a high-fat diet, oral administration of LPSp at 0.3 or 1 mg/kg body weight·day for 18 weeks significantly improved glucose metabolism and lipid profiles. The LPSp treatment also reduced pro-inflammatory cytokine expression and oxidative-burst activity in the peripheral blood. Moreover, LPSp significantly reduced brain Aβ burden and memory impairment as seen in the water maze test, although we could not confirm a significant enhancement of Aβ phagocytosis in microglia isolated from the brains after treatment. Taken together, our results show that LPSp holds promise as a preventative therapy for AD or AD-related diseases induced by impairment of metabolic functions.

Partial Text

Alzheimer’s disease (AD) is an age-dependent neurodegenerative pathology characterized by irreversible and progressive dysfunction of cognition and behavior. The primary pathological features of AD occur in brain parenchyma: progressive deposition of amyloid β (Aβ) peptides derived from Aβ protein precursor (APP) and aggregation of hyperphosphorylated tau protein [1]. The pathogenesis of AD remains unclear, but one widely accepted hypothesis, known as the amyloid cascade hypothesis, postulates that AD neurodegeneration is caused by an imbalance between production and clearance of Aβ peptides in the central nervous system [2]. β- and γ-Secretases have been identified as the proteases responsible for generating Aβ species by cleavage of APP, and are thus considered a prime therapeutic target in AD. Many secretase inhibitors have been designed and synthesized, but no efficient clinical drug has emerged until now due to the presence of side effects in humans [3].

The present study showed that oral administration of LPSp for 18 weeks significantly prevented a memory deficit in HFD-fed SAMP8 mice. This was associated with an improvement of glucose tolerance and lipid profiles. Although in vivo studies aimed at prevention or treatment of AD usually use transgenic mouse models of AD, these transgenic mice have been designed mainly for expressing specific gene mutations present in early-onset familial AD, which accounts for only a small percentage (< 1%) of AD patients. The majority of AD cases are termed late-onset, sporadic AD, which is caused by metabolic or non-genetic environmental factors [29]. A growing body of evidence indicates that SAMP8 mice exhibit AD-like pathology and cognitive decline that result from aging and oxidative stress without genetic factors that act proximally on AD etiology [30]. Considering that orally administered LPSp has a beneficial effect on glucose/lipid metabolism [16], the present study used SAMP8 mice as a mouse model of AD to evaluate LPSp effects on HFD-induced AD progression. Consistent with recent studies using an HFD-fed SAMP8 [21, 31], the present data demonstrated that chronic HFD feeding induces a significant increase in BW, caloric intake, fasting insulin level, HbA1c, and the glucose AUC in the OGTT, which is associated with an impairment of memory performance in the MWM test. Interestingly, when LPSp was orally administered to the HFD-fed mice, improvements in the glucose response, insulin levels, and HbA1c levels were seen, and prevention of the memory deficit was observed at the dose of 1 mg/kg BW·day. Although there were no significant differences in the escape latency between groups when the age of mice was 7 months at the present training trial, the initial escape latency of HFD-fed mice (52.2 ± 3.1s) was slightly longer than that of NC mice (45.2 ± 4.6 s) (S1 Table). Other study using SAMP8 mice (5 months of age) indicated that the memory performance of HFD-fed mice was declined in the probe test, whereas there was no significant difference in the escape latency between groups at the training [31]. Deficit of learning performance in SAMP8, as indicated by significant longer escape latency in training, is usually observed when the age was over 8 months [32], implying that the present HFD-fed SAMP8 mice might represent an early stage of cognitive dysfunction. In addition, biochemical analysis indicated that LPSp prevented the HFD-induced changes in plasma lipid profiles and accumulation of hepatic triacylglycerol, which seems to be associated with a reduction in the weight of the liver and EWAT. Other studies using non-transgenic rodent models of AD have observed a preventive effect on the HFD-induced cognitive deficit via an improvement of glucose/lipid metabolism by orally administered food compounds [33, 34]. These data suggest that orally administered LPSp might prevent the HFD-induced memory decline, at least in part by improvement of glucose/lipid metabolism.   Source:


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