The Ambiguous Role of Microglia in Aβ Toxicity: Chances for Therapeutic Intervention

Abstract

Amyloid-β (Aβ) has long been shown to be critical in Alzheimer's disease pathophysiology. Microglia contributes to the earliest responses to Aβ buildup, by direct interaction through multiple receptors. Microglial cells operate Aβ clearance and trigger inflammatory/regenerative processes that take place in the long years of silent disease progression that precede symptomatic appearance. But in time and with aging, the fine balance between pro- and anti-inflammatory activity of microglia deranges, negatively impacting its Aβ-clearing ability. Furthermore, in recent years, microglial activation has proven to be much more complex than the mere dichotomic pro/antiinflammatory polarization previously accepted. Microglia can display a wide spectrum of phenotypes, which can even be mixed. On these bases, it is evident that while pharmacological intervention aiding microglia to prolong its ability to cope with Aβ buildup could be extremely relevant, its feasibility is hampered by such high complexity, which still needs to be completely understood.

Keywords: Alzheimer's disease; CD33; TREM2; microglial activation; neuroinflammation; β-amyloid receptors..

Fig. (1)

The microglial continuum. During Alzheimer’s disease progression, microglia dynamically change in a continuum from two different, but potentially overlapping states of activation (M2 and M1 phenotypes), that eventually converge towards a prevalent chronic inflammatory condition. This event leads to neurotoxic accumulation of Aβ peptide. (A higher resolution / colour version of this figure is available in the electronic copy of the article).

Fig. (2)

Microglial interactions with Aβ and epigenetic mechanisms controlling Aβ removal. At the microglial cell surface, aggregated Aβ interacts with the triggering receptor expressed on myeloid cells 2 (TREM2), Toll Like Receptors (TLRs) and Scavenger Receptors (SRs), which all mediate its uptake. CD33 negatively affects TREM2’s ability to bind Aβ. Soluble High Mobility Group Box 1 (sHMGB1) binds to Aβ in the extracellular compartment, preventing its uptake. Epigenetic mechanisms affect multiple steps involved in Aβ removal. NF-kB increases transcription of miRNA-34, which represses TREM2 production. A number of other miRNAs regulate the expression of TLRs and SRs. The transcription factor EB (TFEB) is activated by SIRT1-mediated deacetylation and upregulates genes involved in lysosome biogenesis and Aβ degradation. Histone (H) deacetylation by histone deacetylases (HDAC) 1 and 2 leads to upregulation of genes involved in Aβ uptake and downregulation of genes involved in inflammation and radical oxygen species (ROS) generation. (A higher resolution / colour version of this figure is available in the electronic copy of the article).