Biomarkers and therapeutic strategies targeting microglia in neurodegenerative diseases: current status and future directions

Abstract

Recent advances in our understanding of non-cell-autonomous mechanisms in neurodegenerative diseases (NDDs) have highlighted microglial dysfunction as a core driver of disease progression. Conditions such as Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and frontotemporal dementia (FTD) share features of impaired microglial phagocytosis, chronic neuroinflammation, and metabolic dysregulation. These insights have prompted new therapeutic strategies targeting microglial function and emphasized the need for reliable biomarkers to monitor disease progression and treatment response. Well-established therapeutic targets, such as triggering receptor expressed on myeloid cells 2 (TREM2), progranulin (PGRN), and sortilin (SORT1), along with emerging candidates including LILRB4, P2Y6R, TAM receptors, and neuroinflammation-related markers, are discussed alongside novel blood, cerebrospinal fluid (CSF), and imaging biomarkers. Despite notable progress, many of these biomarkers remain restricted to preclinical studies and face translational challenges due to species-specific differences, lack of standardization, and clinical heterogeneity. Emerging technologies-including single-cell omics, spatial transcriptomics, and artificial intelligence (AI)-driven integration of multimodal data-offer new opportunities to align biomarker profiles with evolving disease states and improve patient stratification. Building on the model of companion diagnostics (CDx) in oncology, integrating multimodal biomarker strategies holds promise for guiding personalized interventions, improving clinical outcomes, and deepening our mechanistic understanding of microglial contributions across the neurodegenerative spectrum.

Keywords: AD; ALS; Companion diagnostics; FTD; Microglia-targeting therapy; Microglial dysfunction; Neurodegenerative diseases; PD; Precision medicine.

Fig. 1

Therapeutic Strategies Targeting Microglia in Neurodegenerative Diseases. This figure illustrates therapeutic strategies targeting microglia in neurodegenerative diseases (NDDs), broadly categorized into two primary approaches: (Left)-Targeting Disease-Associated Genes: Therapies focused on modulating microglial genes such as TREM2, CD33, and PGRN. These pathways are critical in regulating microglial signaling, receptor activation, and cellular response to disease-related stressors. (Right)-Restoring Dysfunctional Microglial Functions: Interventions aimed at key microglial functions—phagocytosis, metabolism, and neuroinflammation—to repair dysfunction. The phagocytosis process, essential for clearing abnormal protein aggregates, apoptotic cells, myelin debris, synapses, and degenerated neurites, unfolds in four key steps: Step 1: Recognition via phagocytic receptors and engagement with find-me signals. Step 2: Engulfment facilitated by cytoskeletal rearrangement and phagocytic cup formation. Step 3: Digestion through the endolysosomal network. Step 4: Response involving activation of transcriptional programs and cytokine release. Microglial metabolism is tightly linked to both inflammatory responses and phagocytosis, highlighting its central role in maintaining microglial homeostasis. This interplay between genetic pathways and functional modulation provides a foundation for innovative therapeutic strategies. For detailed lists of investigational agents and specific targets, refer to Table 1 and Supplementary Table 1. Abbreviations: AAV; Adeno-associated virus, acetyl-S565 COX2: acetylation of serine 565 residues of cyclooxygenase-2, ApoE; Apoprotein E, ASO; Antisense oligonucleotide, Aβ; Amyloid beta, C1q; Complement component 1q, C3; Complement component 3, C5; Complement component 5, CSF: Cerebrospinal fluid, CSF1R; Colony stimulating factor 1 receptor, EP2; E-prostanoid receptor type 2, FcγR; Fc-gamma receptors, Gal-3; Galectin-3, GLP-1; Glucagon-like peptide-1, GLUTs; Glucose transporters, GPNMB; Glycoprotein NMB, GRN; Granulin, H4K12la; Histone H4 lysine 12 lactylation, HIF-1α; Hypoxia inducible factor 1 subunit alpha, HK2; Hexokinase 2, IL-1β; Interleukin-1 beta, JAK; Janus kinase, LILRB4; Leukocyte Ig-like receptor B4, miRNA; microRNA, NCKAP1; NCK associated protein 1, NDDs: Neurodegenerative diseases, NF-kB; Nuclear Factor Kappa B, NLRP3; NLR family pyrin domain containing 3, P2Y6R; P2Y6 receptor, PD-L1; Programmed death-ligand 1, PGE2; Prostaglandin E2, PGRN; Progranulin, PI3K; phosphatidylinositol 3-kinase, Piezo 1; Piezo type mechanosensitive ion channel component 1, PTV; Protein transfer vehicle, RIPK1; Receptor-interacting serine/threonine-protein kinase 1, SHP-1; Src-homology 2-domain-containing protein tyrosine phosphatase-1, SORT1; Sortilin, SPMs; Specialized pro-resolving mediators, sTREM2; Soluble TREM2, SYK; Spleen tyrosine kinase, TAM receptors; Tyro3, Axl and MerTK, TDP-43; TAR DNA-binding protein 43, TF; Transcription factor, TLR2; Toll-like receptor 2, TNF-α; Tumor necrosis factor-alpha, TREM2; Triggering receptor expressed on myeloid cells 2, WRC complex; WAVE regulatory complex

Fig. 2

Molecular Targets and Investigational Agents Modulating Microglial Functions in Preclinical Studies. The molecular targets linked to microglial key functions, including (A) phagocytosis, (B) TREM2 signaling, (C) phenotype switching, (D) metabolic pathways, and (E) neuroinflammation, are highlighted in this figure. In vitro/in vivo studies have demonstrated that the functional recovery of microglia can be achieved through the activation or inhibition of these targets. The comprehensive list and detailed descriptions of these targets are provided in supplementary Table 1. Abbreviations: AAV; Adeno-associated virus, AD; Alzheimer’s disease, AKAP8L; A-kinase anchor protein 8-like, ALS; Amyotrophic lateral sclerosis, ApoE; Apoprotein E, ASO; Antisense oligonucleotide, BACE1; Beta-site amyloid precursor protein cleaving enzyme1, C3; Complement component 3, CB2R; Cannabinoid receptor type 2, cGAMP; Cyclic guanosine monophosphate–adenosine monophosphate, COX-2 S565; serine 565 of Cyclooxygenase-2, FTD; Frontotemporal dementia, GRN; Granulin, H4K12la; Histone H4 lysine 12 lactylation, HCAR2; Hydroxycarboxylic acid receptor 2, HK2; Hexokinase 2, IGFBPL1; Insulin-like growth factor binding protein-like 1, LXA4; Lipoxin A4, LILRB4; Leukocyte Ig-like receptor B4, mAb; Monoclonal antibody, miRNA (miR); microRNA, NCKAP1; NCK associated protein 1, N-AS; N-acetyl sphingosine, NLRP3; NLR family pyrin domain containing 3, P2Y6R; P2Y6 receptor, PD; Parkinson’s disease, PGRN; Progranulin, Piezo 1; Piezo type mechanosensitive ion channel component 1, Pyk2; Protein tyrosine kinase 2-beta, RIPK1; Receptor-interacting serine/threonine-protein kinase 1, RvD1; Resolvin D1, SCAP; Sterol regulatory element-binding protein (SREBP) cleavage-activating protein, SOD1; Superoxide dismutase type 1, SPMs; Specialized pro-resolving mediators, TAM receptors; Tyro3, Axl and MerTK, TDP-43; TAR DNA-binding protein 43, TREM2; Triggering receptor expressed on myeloid cells 2

Fig. 3

Summary of Fluid and Image Biomarkers for Microglial Functions: Advantages and Limitations. Abbreviations: acetyl-S565 COX2; acetylation of serine 565 residues of cyclooxygenase-2, CAPG; Macrophage-capping protein, CB2R; Cannabinoid receptor type 2, CHIT1; Chitinase-1, CNS; Central nervous system, CSF-1R; Colony stimulating factor-1 receptor, CXCL1; Chemokine (C-X-C motif) ligand 1, DCI; Diffusion compartment imaging, DTI; Diffusion tensor imaging, FABP3; Fatty acid binding protein 3, FGFBP1; Fibroblast growth factor-binding protein 1, GDI1; GDP dissociation inhibitor1, GPNMB; Glycoprotein NMB, IL-6; Interleukin-6, LXA4; Lipoxin A4, MaR 1; Maresin1, MCP-1; Monocyte chemoattractant protein-1, MDH1; Malate dehydrogenase 1, miRNA (miR); microRNA, MRI; Magnetic resonance imaging, P2RY12; Purinergic receptor P2Y12, P2X7R; P2X7 receptor, PET; Positron emission tomography, PGRN; Progranulin, PKCδ; Protein kinase C delta, PROS1; Vitamin K-dependent protein S1, RvD1; Resolvin D1, sCD22; Soluble CD22, SPMs; Specialized pro-resolving mediators, sTREM2; Soluble TREM2,TSPO; Translocator protein, YKL-40; Chitinase 3-like 1