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Review
. 2021 Dec 7;10(1):49.
doi: 10.1186/s40035-021-00273-y.

Gram-negative bacteria and their lipopolysaccharides in Alzheimer's disease: pathologic roles and therapeutic implications

Hyeon Soo Kim #  1 , Sujin Kim #  1   2 , Soo Jung Shin #  1 , Yong Ho Park #  1 , Yunkwon Nam  1 , Chae Won Kim  1 , Kang Won Lee  1 , Sung-Min Kim  3 , In Duk Jung  3 , Hyun Duk Yang  4 , Yeong-Min Park  5   6 , Minho Moon  7   8
Affiliations
Review

Gram-negative bacteria and their lipopolysaccharides in Alzheimer's disease: pathologic roles and therapeutic implications

Hyeon Soo Kim et al. Transl Neurodegener. .

Abstract

Alzheimer's disease (AD) is the most serious age-related neurodegenerative disease and causes destructive and irreversible cognitive decline. Failures in the development of therapeutics targeting amyloid-β (Aβ) and tau, principal proteins inducing pathology in AD, suggest a paradigm shift towards the development of new therapeutic targets. The gram-negative bacteria and lipopolysaccharides (LPS) are attractive new targets for AD treatment. Surprisingly, an altered distribution of gram-negative bacteria and their LPS has been reported in AD patients. Moreover, gram-negative bacteria and their LPS have been shown to affect a variety of AD-related pathologies, such as Aβ homeostasis, tau pathology, neuroinflammation, and neurodegeneration. Moreover, therapeutic approaches targeting gram-negative bacteria or gram-negative bacterial molecules have significantly alleviated AD-related pathology and cognitive dysfunction. Despite multiple evidence showing that the gram-negative bacteria and their LPS play a crucial role in AD pathogenesis, the pathogenic mechanisms of gram-negative bacteria and their LPS have not been clarified. Here, we summarize the roles and pathomechanisms of gram-negative bacteria and LPS in AD. Furthermore, we discuss the possibility of using gram-negative bacteria and gram-negative bacterial molecules as novel therapeutic targets and new pathological characteristics for AD.

Keywords: Alzheimer’s disease; Amyloid beta; Exotoxin; Gram-negative bacteria; Lipopolysaccharide; Tau.

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Conflict of interest statement

Authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Mechanisms of gram-negative bacteria penetration to the central nervous system. ① The gram-negative bacteria-derived exotoxins provoke detachment of endothelial cells, and the gram-negative bacteria-induced inflammatory cytokines induce disruption of the tight junction at the blood-brain barrier (BBB). These impairments of BBB allow the gram-negative bacteria to pass through the brain in the paracellular pathway. ② The gram-negative bacteria-derived exotoxins directly influence endothelial necrosis. ③ The gram-negative bacteria are transported to the brain via vesicular transport of macromolecules, such as outer membrane protein A (OmPA), invasion of the brain endothelium protein A (IbeA), endothelial receptors beta-form of the heat-shock gp96 (Ecgp96), and contactin-associated protein 1 (CaspR1). ④ The cranial nerve can be a pathway for gram-negative bacteria to enter the brain without penetrating the BBB. CNS: Central nervous system; iNOS: Inducible nitric oxide synthase; PNS: peripheral nervous system
Fig. 2
Fig. 2
The pathological mechanisms underlying the effect of gram-negative bacteria in Alzheimer’s disease. The gram-negative bacteria produce a variety of exotoxins, such as gingipain, methylglyoxal (MG), bacterial amyloid, vacuolating cytotoxin (VacA), bacterial amino-acid, heme carrier protein (Hcp1), matrix metalloproteinase-8 (MMP8), phosphorylcholine, short-chain fatty acid (SCFA), and tryptophan. The gram-negative bacteria and exotoxins can penetrate the BBB and affect the AD-related pathology. Concerning Aβ aggregation, MG and gingipain are involved in the increase of Aβ production; bacterial amyloid and gram-negative bacteria can induce Aβ aggregation. Concerning hyperphosphorylated tau and neurofibrillary tangles, gingipain, MG, and gram-negative bacteria can provoke the hyperphosphorylation of tau; gingipain and gram-negative bacteria can also promote the aggregation of phosphorylated tau. Concerning neuroinflammation, the Aβ-induced activation of microglia and astrocytes contributes to a neuroinflammatory response, affecting neurodegeneration. The gram-negative bacteria and gingipain can increase the release of inflammatory cytokines. Concerning neurodegeneration, gingipain, MG, and gram-negative bacteria can induce neuronal death. The gram-negative bacteria provoke neuronal loss through the activation of the neuronal TLR4 signaling pathway. Hcp1: Heme carrier protein; IL-6: Interleukin 6; IL-1β: Interleukin 1β; IL-18: Interleukin 18; MMP8: Matrix metalloproteinase-8; NLRP1: Nod-like receptor protein 1; RAGE: Receptor for advanced glycation end products; SCFA: Short-chain fatty acid; TNF-α: Tumor necrosis factor α; VacA: Vacuolating cytotoxin A
Fig. 3
Fig. 3
Mechanisms of lipopolysaccharide (LPS) penetration to the central nervous system. LPS produced in the peripheral system penetrates the BBB and enters the brain. ① LBP is a soluble acute-phase protein that binds to bacterial LPS to elicit immune responses. LBP facilitates LPS penetration of the BBB through various receptors, such as Scavenger reception class B type 1 (SR-B1) and apolipoprotein E receptor 2 (ApoER2). ② LPS is transported to BBB by peripheral immune cells. ③ LPS enters the brain via damaged BBB caused by high concentrations of LPS and LPS-induced pro-inflammatory cytokines. ④ LPS is directly recognized by the cell surface pattern recognition receptor CD14/TLR 14 complex, resulting in penetration to the BBB. ⑤ LPS is transported into the brain through gram-negative bacteria transporters, such as OMV. CD14: Cluster of differentiation 14; CNS: Central nervous system; LBP: Lipopolysaccharide-binding protein; OMV: Outer membrane vesicle; PNS: Peripheral nervous system; TLR4: Toll-like receptor 4; VCAM1: Vascular cell adhesion molecules-1
Fig. 4
Fig. 4
Pathogenic mechanisms of lipopolysaccharides (LPS) in Alzheimer’s disease. LPS is a characteristic component in the cell wall of gram-negative bacteria and plays a key role in triggering inflammatory response and initiating and promoting AD pathology. LPS promotes the production of Aβ through the increase of β- and γ-secretases and decrease of α-secretase, and stimulates the accumulation of Aβ. LPS induces the impairment of low-density lipoprotein receptor-related protein-1 (LRP-1), which plays a pivotal role in Aβ clearance. LPS is involved in tau phosphorylation, and accelerates the aggregation of phosphorylated tau. LPS activates the microglial TLR4, RAGE, and TREM2 receptors, inducing release of pro-inflammatory cytokines. LPS activation of the TLR4 signaling pathway and LPS entry in the brain through OMV can induce neuronal cell death. ApoER2: apolipoprotein E receptor 2; BBB: blood–brain barrier; IL-6: interleukin 6; IL-1β: interleukin 1 β; LRP-1: low-density lipoprotein receptor-related protein 1; MBP: myelin basic protein; MMP8: matrix metalloproteinase-8; MyD88: myeloid differentiation primary response 88; NF-κβ: nuclear factor kappa β; NFT: neurofibrillary tangles; NLRP1: Nod-like receptor protein 1; OMV: outer membrane vesicle; PHF: paired helical filament; RAGE: receptor for advanced glycation end products; SCFA: short-chain fatty acid; SR-B1: scavenger reception class B type 1; TLR4: Toll-like receptor 4; TNF-α: tumor necrosis factor α; TREM2: triggering receptor expressed on myeloid cells 2; TRIF: Toll/interleukin-1 receptor-domain-containing adapter-inducing interferon-β; VacA: vacuolating cytotoxin A; VCAM1: vascular cell adhesion molecules-1
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