Role of pro-inflammatory cytokines released from microglia in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain, which is characterized by the formation of extracellular amyloid plaques (or senile plaques) and intracellular neurofibrillary tangles. However, increasing evidences demonstrated that neuroinflammatory changes, including chronic microgliosis are key pathological components of AD. Microglia, the resident immune cells of the brain, is constantly survey the microenvironment under physiological conditions. In AD, deposition of β-amyliod (Aβ) peptide initiates a spectrum of cerebral neuroinflammation mediated by activating microglia. Activated microglia may play a potentially detrimental role by eliciting the expression of pro-inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor-α (TNF-α) influencing the surrounding brain tissue. Emerging studies have demonstrated that up-regulation of pro-inflammatory cytokines play multiple roles in both neurodegeneration and neuroprotection. Understanding the pro-inflammatory cytokines signaling pathways involved in the regulation of AD is crucial to the development of strategies for therapy. This review will discuss the mechanisms and important role of pro-inflammatory cytokines in the pathogenesis of AD, and the ongoing drug targeting pro-inflammatory cytokine for therapeutic modulation.

Keywords: Alzheimer’s disease (AD); amyloid-β; microglia; neurodegeneration; pro-inflammatory cytokines; therapy.

Figure 1

The role of different inflammatory cytokines released from different subtypes of microglia in AD. AD, Alzheimer’s disease.

Figure 2

Possible mechanisms underlying microglial activation Aβ deposition and subsequent pro-inflammatory cytokine release contribute to AD. In the early stages of AD microglial activation can promote Aβ clearance via microglia’s SRs. The persistent microglial activation stimulated by Aβ via the receptor for CD36, Fc receptors, TLRs and RAGE, creating a vicious circle between microglia activation, neuroinflammation, and Aβ accumulation. A crucial role on pathogenesis of AD is an absolute culprit for both amyloid plaque and other pathologic change such as the neuronal damage. Aβ, amyloid-β; AD, Alzheimer’s disease; SRs, scavenger receptors; TLRs, toll-like receptors; RAGE, complement receptors advanced glycation end products; NO, nitric oxide; ROS, reactive oxygen species.

Figure 3

Speculative model of dysregulation of pro-inflammatory cytokines in the AD brain. (I) A vicious circle between microglia activation, pro-inflammatory cytokines production, and Aβ, tau accumulation in AD brain; (II) AD cerebral microvessels participates in a destructive cycle of events where inflammation precedes Aβ deposition and Aβ in turn promotes release of proinflammatory cytokines; (III) pro-inflammatory cytokines and Aβ could across the BBB from the periphery into brain, the latter is mediated by RAGE. AD, Alzheimer’s disease; Aβ, amyloid-β; RAGE, complement receptors advanced glycation end products; BBB, blood-brain barrier.

Figure 4

A hypothetical model linking the IL-1β activation to AD pathogenesis. AD, Alzheimer’s disease; oAβ, oligomeric amyloidβ; GSK3, glycogen synthase kinase 3; LTP, inhibiting long-term potentiation; BBB, blood-brain barrier; pro-IL-1β, pro forms IL-1β; ROS, reactive oxygen species; ↑↓, increase or decrease.