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ABSTRACT
Introduction
Microglia, the primary immune cells in the brain, play multifaceted roles in Alzheimer’s disease (AD). Microglia can potentially mitigate the pathological progression of AD by clearing amyloid beta (Aβ) deposits in the brain and through neurotrophic support. In contrast, disproportionate activation of microglial pro-inflammatory pathways, as well as excessive elimination of healthy synapses, can exacerbate neurodegeneration in AD. The challenge, therefore, lies in discerning the precise regulation of the contrasting microglial properties to harness their therapeutic potential in AD.
Areas covered
This review examines the evidence relevant to the disease-modifying effects of microglial manipulators in AD preclinical models. The deleterious pro-inflammatory effects of microglia in AD can be ameliorated via direct suppression or indirectly through metabolic manipulation, epigenetic targeting, and modulation of the gut-brain axis. Furthermore, microglial clearance of Aβ deposits in AD can be enhanced via strategically targeting microglial membrane receptors, lysosomal functions, and metabolism.
Expert opinion
Given the intricate and diverse nature of microglial responses throughout the course of AD, therapeutic interventions directed at microglia warrant a tactical approach. This could entail employing therapeutic regimens, which concomitantly suppress pro-inflammatory microglial responses while selectively enhancing Aβ phagocytosis.
Article highlights
Microglia play a critical role in the progression of AD.
Microglia can potentially mitigate AD pathology by clearing amyloid beta (Aβ) deposits in the brain and through neurotrophic support.
Uncontrolled and exaggerated activation of microglia can exacerbate neurodegeneration in AD via neuroinflammation and excessive elimination of healthy synapses.
Microglial inflammatory responses can be repressed via direct pharmacological and genetic targeting or indirectly through modulation of microglial metabolism, epigenetic pathways, or the microbiome-gut-brain axis.
Microglial phagocytosis of Aβ can be enhanced by selective manipulation of microglial phagocytic receptors, lysosomal functions, as well as control of microglial metabolism.
Enhancing the activity of TREM2, NF-κB, and mitochondrial oxidative phosphorylation (OXPHOS) constitute strategies that hold tremendous promise in AD therapeutics owing to their dual and specific regulation of microglial inflammation and Aβ phagocytosis.
Abbreviations
| AD | = | Alzheimer’s disease |
| ADAM | = | A disintegrin and metalloproteinases |
| Aβ | = | Amyloid beta |
| BACE | = | β-secretase site amyloid precursor protein cleaving enzyme |
| BDNF | = | Brain-derived neurotrophic factor |
| CD | = | Cluster of differentiation |
| CNS | = | Central nervous system |
| CSF | = | Cerebrospinal fluid |
| CSF1 | = | Colony-stimulating factor 1 |
| CSF1R | = | colony-stimulating factor 1 receptor |
| DAM | = | Disease-associated microglia |
| EGCG | = | Epigallocatechin-3-gallate |
| ERK | = | Extracellular signal-regulated kinase |
| FDA | = | Food and Drug Administration |
| GDNF | = | Glial cell line-derived neurotrophic factor |
| GWAS | = | A genome-wide association study |
| HATs | = | Histone acetyltransferases |
| HDACs | = | Histone deacetylases |
| HK2 | = | Hexokinase-2 |
| IFN | = | Interferon |
| IGF-1 | = | Insulin-like growth factor-1 |
| IL | = | Interleukin |
| iNOS | = | Inducible nitric oxide synthase |
| JAK/STAT | = | Janus kinase/signal transducer and activator of transcription |
| LPS | = | Lipopolysaccharide |
| LTP | = | long-term potentiation |
| MAPKs | = | Mitogen-activated protein kinases |
| MCSFs | = | Macrophage colony-stimulating factors |
| miRNA | = | microRNA |
| NFTs | = | Neurofibrillary tangles |
| NF-κB | = | Nuclear factor kappa-light-chain-enhancer of activated B cells |
| NLRP3 | = | NLR family pyrin domain containing 3 |
| NO | = | Nitric oxide |
| OSTM1 | = | osteopetrosis-associated transmembrane protein 1 |
| OXPHOS | = | Oxidative phosphorylation |
| PBR | = | mitochondrial peripheral benzodiazepine receptor |
| PET | = | Positron emission tomography |
| PSEN1 | = | Presenilin 1 |
| RIPK1 | = | Receptor/interacting protein kinase 1 |
| Siglec | = | Sialic acid-binding Ig-like lectin |
| SIRTs | = | Sirtuins |
| SNAP | = | Single nucleotide polymorphism |
| TFEB | = | Transcription factor EB |
| TGF-β | = | Transforming growth factor-β |
| TNFR1 | = | Tumour necrosis factor receptor 1 |
| TNF-α | = | Tumour necrosis factor alpha |
| TRADD | = | Tumour necrosis factor receptor 1-associated death domain protein |
| TRAF2 | = | Tumour necrosis factor receptor-associated factor |
| TREM2 | = | Triggering receptor expressed on myeloid cells 2 |
| TSPO | = | Translocator protein |
| βAPP | = | β-amyloid precursor protein |
Declaration of interest
The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.