Microglia in Alzheimer's Disease: A Target for Therapeutic Intervention

Abstract

Alzheimer's disease (AD) is one of the most common types of age-related dementia worldwide. In addition to extracellular amyloid plaques and intracellular neurofibrillary tangles, dysregulated microglia also play deleterious roles in the AD pathogenesis. Numerous studies have demonstrated that unbridled microglial activity induces a chronic neuroinflammatory environment, promotes β-amyloid accumulation and tau pathology, and impairs microglia-associated mitophagy. Thus, targeting microglia may pave the way for new therapeutic interventions. This review provides a thorough overview of the pathophysiological role of the microglia in AD and illustrates the potential avenues for microglia-targeted therapies, including microglial modification, immunoreceptors, and anti-inflammatory drugs.

Keywords: Alzheimer’s disease; microglia; neuroinflammation; tau; β-amyloid.

Figure 1

Microglia/Macrophage polarization subtypes. Traditionally, the M1 or M2 phenotype is considered as the extreme activation state of macrophages/microglia in response to different microenvironmental stimuli. Notably, novel observations have revealed the detailed macrophage subsets: Mhem, Mox, MHb, and M4. Moreover, the M2 macrophages have been further subdivided into the M2a, M2b, M2c, and M2d subtypes. MΦ, macrophages; LPS, lipopolysaccharide; IFN-γ, interferon-γ; IL, interleukin; TNF-α, tumor necrosis factor-α; NO, nitric oxide; ROS, reactive oxygen species; CCL17, CC chemokine ligand 17; IGF, insulin-like growth factor; TGF-β, transforming growth factor-β; VEGF, vascular endothelial growth factor; HMOX-1, heme oxygenase-1; COX2, cyclooxygenase-2; CXCL-4, chemokine (C-X-C motif) ligand (CXCL) 4; MMP7, matrix metalloproteinase 7.

Figure 2

Physiological functions of microglia. Scheme illustrating the diverse functions of microglia during development and microenvironmental stimuli. CSF1, colony stimulating factor 1; CSF1R, CSF1 receptor; IRF8, interferon regulatory factor 8.

Figure 3

The potential role of microglia in AD. (1) microglia and Aβ. (2) microglia and neuroinflammation. (3) microglia and tau pathology. (4) microglia and mitophagy. AD, Alzheimer’s disease; Aβ, β-amyloid; NFTs, neurofibrillary tangles; SRs, scavenger receptors; TREM2, triggering receptor expressed on myeloid cells 2; SOCS, suppressor of cytokine signaling; JAK, Janus kinase; STAT, signal transducer and activator of transcription; NF-κB, Nuclear Factor-κB; NLRP3, NOD-like receptor family pyrin domain containing 3.