Molecular Mechanisms of Neuroinflammation in Aging and Alzheimer's Disease Progression

Abstract

Aging is the most prominent risk factor for late-onset Alzheimer's disease. Aging associates with a chronic inflammatory state both in the periphery and in the central nervous system, the evidence thereof and the mechanisms leading to chronic neuroinflammation being discussed. Nonetheless, neuroinflammation is significantly enhanced by the accumulation of amyloid beta and accelerates the progression of Alzheimer's disease through various pathways discussed in the present review. Decades of clinical trials targeting the 2 abnormal proteins in Alzheimer's disease, amyloid beta and tau, led to many failures. As such, targeting neuroinflammation via different strategies could prove a valuable therapeutic strategy, although much research is still needed to identify the appropriate time window. Active research focusing on identifying early biomarkers could help translating these novel strategies from bench to bedside.

Keywords: Alzheimer’s disease; TNF signaling; TREM2; cellular senescence; inflammaging; microglia; neuroinflammation; oxidative stress; therapy.

Figure 1

The processing of APP. APP has a large N-terminal ectodomain and a shorter C-terminus domain. The Aβ peptide starts in the ectodomain and continues in the transmembrane region (pictured in red). Alpha-secretase cleaves APP within the Aβ domain and thus does not lead to generation of Aβ. The soluble sAPPα fragment is released into the extracellular space. Both α- and β-secretase (BACE-1) cleavage of APP is followed by γ-secretase processing of the C-terminal fragment (CTF) residue, resulting in an identical intracellular C-terminal fragment (AICD). BACE-1 cleavage leads to the release of sAPPβ, while further processing of the β-CTF will lead to generation of Aβ.

Figure 2

Aβ binds to Toll-like receptors (TLR) and TREM2, while both Aβ and tau fibrils (NFTs) can trigger the NLRP3 inflammasome assembly. Ligand binding to TREM2 activates DAP12 through charge interactions in their transmembrane domain, followed by recruitment of spleen tyrosine kinase (Syk) and activation of phospoinositide 3-kinase (PI3K), which targets Akt and activates mammalian target of rapamycin (mTOR), inhibiting autophagy and impairing Aβ clearance. Mitochondrial DNA (mtDNA) activates cGAS, which synthesizes cGAMP that binds to STING. Subsequently, STING translocates to the Golgi apparatus and is phosphorylated by TANK binding kinase 1 (TBK1), followed by binding to interferon regulatory factor 3 (IRF3), which is also phosphorylated and activated by TBK1. Phosphorylated IRF3 translocates to the nucleus, where it promotes the production of interferons (IFNs) and cytokines that enhance the inflammatory response. TLR signaling and phosphorylated STING can also activate IκB kinase (IKK), resulting in phosphorylation of the inhibitor of κB (IκB) and release of NF-κB, the master transcription factor regulating the production of pro-inflammatory cytokine precursors and the NLRP3 inflammasome assembly. Caspase-1, contained in the NLRP3 inflammasome, cleaves the precursors of pro-inflammatory cytokines, resulting in IL-1β and IL-18, which can damage neurons.

Figure 3

The various cytokines and chemokines released during neuroinflammatory states lead to synaptic loss, excitotoxicity, oxidative damage, and culminate with neuronal loss.