Targeting neuroinflammation in Alzheimer's disease: from mechanisms to clinical applications

Abstract

Alzheimer's disease is characterized by sustained neuroinflammation leading to memory loss and cognitive decline. The past decade has witnessed tremendous efforts in Alzheimer's disease research; however, no effective treatment is available to prevent disease progression. An increasing body of evidence suggests that neuroinflammation plays an important role in Alzheimer's disease pathogenesis, alongside the classical pathological hallmarks such as misfolded and aggregated proteins (e.g., amyloid-beta and tau). Firstly, this review summarized the clinical and pathological characteristics of Alzheimer's disease. Secondly, we outlined key aspects of glial cell-associated inflammation in Alzheimer's disease pathogenesis and provided the latest evidence on the roles of microglia and astrocytes in Alzheimer's disease pathology. Then, we revealed the double-edged nature of inflammatory cytokines and inflammasomes in Alzheimer's disease. In addition, the potential therapeutic roles of innate immunity and neuroinflammation for Alzheimer's disease were also discussed through these mechanisms. In the final section, the remaining key problems according to the current research status were discussed.

Keywords: Alzheimer’s disease; astrocytes; immune signaling; inflammatory cytokines; microglia; neuroinflammation; neurotoxicity; therapeutic strategies.

Figure 1

The Aβ and tau hypotheses in AD. Aβ is produced by β-secretase and γ-secretase cleavage from APP to form Aβ plaques. Hyperphosphorylated tau assembles and aggregates neurofibrillary tangles. AD: Alzheimer’s disease; APP: amyloid precursor protein; Aβ: amyloid-beta.

Figure 2

The difference between healthy brains and those of patients with AD. Compared with healthy brains, brains of patients with mild AD harbor moderate cortical shrinkage, enlarged ventricles, and hippocampus shrinkage. In the brains of patients with severe AD, severe cortical shrinkage, enlarged ventricles and hippocampus shrinkage can be observed. AD: Alzheimer’s disease.

Figure 3

The acute response during homeostasis and the chronic response in AD. The activation of microglia has both beneficial and detrimental roles. Acute microglial activation contributes to the decreased accumulation of Aβ via increased clearance or phagocytosis, whereas chronic microglial activation may provoke dysregulated neuroinflammatory responses and lead to neuronal distress, synapse loss, Aβ production, and neurotoxicity via multiple pro-inflammatory cascades. AD: Alzheimer’s disease; Aβ: amyloid-beta; NLRP3: NOD-like receptor thermal protein domain associated protein 3.

Figure 4

The activation of the NLRP3 inflammasome in AD. The NLRP3 inflammasome can be activated by Aβ/NAMPs/PAMPs/DAMPs. Inflammasome formation initiates a signaling cascade to active caspase-1, which induces the cleavage of inflammatory pro-IL-18 and pro-IL-1β into their mature forms. Meanwhile, active caspase-1 can cleave GSDMD, which translocates and forms pores on the cell membrane to promote the outflow of pro-inflammatory cytokines and cell lysis. AD: Alzheimer’s disease; ASC: adaptor protein apoptosis-associated specklike protein containing a CARD; Aβ: amyloid-beta; DAMPs: damage-associated molecular patterns; GSDMD: gasdermin-D; IL: interleukin; NAMPs: neurodegeneration-associated molecular patterns; NFκB: nuclear factor kappa B; NLRP3: NOD-like receptor thermal protein domain associated protein 3; PAMPs: pathogen-associated molecular patterns.