TLR4 Cross-Talk With NLRP3 Inflammasome and Complement Signaling Pathways in Alzheimer's Disease

Abstract

Amyloid plaques, mainly composed of abnormally aggregated amyloid β-protein (Aβ) in the brain parenchyma, and neurofibrillary tangles (NFTs), consisting of hyperphosphorylated tau protein aggregates in neurons, are two pathological hallmarks of Alzheimer's disease (AD). Aβ fibrils and tau aggregates in the brain are closely associated with neuroinflammation and synapse loss, characterized by activated microglia and dystrophic neurites. Genome-wide genetic association studies revealed important roles of innate immune cells in the pathogenesis of late-onset AD by recognizing a dozen genetic risk loci that modulate innate immune activities. Furthermore, microglia, brain resident innate immune cells, have been increasingly recognized to play key, opposing roles in AD pathogenesis by either eliminating toxic Aβ aggregates and enhancing neuronal plasticity or producing proinflammatory cytokines, reactive oxygen species, and synaptotoxicity. Aggregated Aβ binds to toll-like receptor 4 (TLR4) and activates microglia, resulting in increased phagocytosis and cytokine production. Complement components are associated with amyloid plaques and NFTs. Aggregated Aβ can activate complement, leading to synapse pruning and loss by microglial phagocytosis. Systemic inflammation can activate microglial TLR4, NLRP3 inflammasome, and complement in the brain, leading to neuroinflammation, Aβ accumulation, synapse loss and neurodegeneration. The host immune response has been shown to function through complex crosstalk between the TLR, complement and inflammasome signaling pathways. Accordingly, targeting the molecular mechanisms underlying the TLR-complement-NLRP3 inflammasome signaling pathways can be a preventive and therapeutic approach for AD.

The good, the bad, and the opportunities of the complement system in neurodegenerative disease

“…The presence of the MAC demonstrates that complete activation of the cascade does occur within the AD brain and thus is evidence for the generation of C5a and C3a. While complement activation products C5a and C3a may bind to their receptors and recruit phagocytic cells to the plaque (the source of the generated C3a and C5a), the intracellular signaling of C5a (and C3a) on microglia is predicted to synergize with plaque fAβ ligation of the TLRs inducing a chronic inflammatory state mediated substantially by locally produced pro-inflammatory cytokines as well as other neurotoxic species (reviewed in [ 161 ]). Ablation of C1q in the transgenic hAPP Tg2576 mouse model supported such a scenario as the absence of C1q, and thus inability to generate the downstream classical complement pathway products C3a and C5a, resulted in significant and substantial decreases in microgliosis and astrocytosis and prevention of synaptophysin and MAP2 loss in the CA3 region of the hippocampus [ 91 ].…”

“…C5a was found to increase the release of IL-1β and IL-6 when added to Aβ-primed human monocytes in vitro [ 179 ] and C5aR1 antagonists have been found to reduce proinflammatory cytokines (IL-1β) in periodontal disease [ 180 ]. Thus, it is possible that in the CNS, as in the periphery, C5a via C5aR1 signaling synergizes with TLR/NFκB and the NLRP3 inflammasome activity to trigger potent detrimental inflammatory responses [ 161 ]. If so, it would add further value to the use of a C5aR1 antagonist in AD, avoiding the systematic suppression of NLRP3, which could lead to susceptibility to infection.…”

Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

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Complex Interaction between Resident Microbiota and Misfolded Proteins: Role in Neuroinflammation and Neurodegeneration

“…These findings were confirmed by Ou et al who found that increasing A. muciniphila resulted in a reduction in Aβ 40 and Aβ 42 levels in the cerebral cortex of AD model mice (APP/PS1), and improved learning and completion rates in maze tests [ 176 ]. A possible pathway could be via the involvement of TLR4 in AD as aggregated Aβ can bind TLR4 and subsequently activate microglia, resulting in increased cytokine production (reviewed by [ 177 ]). Furthermore, several studies by Ashrafian et al demonstrated that A. muciniphila OMVs have the ability to decrease TLR4, resulting in decreased inflammation [ 178 , 179 ].…”