Targets

Abl interactor 3

ABI3 is an adaptor protein expressed in microglia that plays roles in actin cytoskeletal dynamics and cell motility. A rare coding variant in ABI3 (S209F) is associated with increased Alzheimer's disease risk. ABI3 participates in the WAVE regulatory complex and may influence microglial migration, morphological plasticity, and phagocytic function. ABI3 expression is enriched in microglia relative to other CNS cell types.

Apolipoprotein E

Apolipoprotein E (APOE) is the single strongest genetic risk factor for late-onset Alzheimer’s disease, and its function is deeply intertwined with microglial states. While APOE is predominantly produced by astrocytes in the healthy brain, reactive microglia dramatically upregulate APOE expression as they transition into Disease-Associated Microglia (DAM) states. In the context of Alzheimer's, APOE acts as a critical binding partner bridging amyloid plaques and microglial receptors—most notably TREM2. When microglia detect tissue damage, the massive upregulation of APOE serves as an immunometabolic bottleneck that shuts down homeostatic genes (like TGFBR1 and P2RY12) and pushes the cell toward active phagocytosis and containment of amyloid. The APOE4 isoform—which structurally differs to APOE3 and APOE2—causes a toxic gain-of-function and loss-of-clearance. Microglia expressing APOE4 exhibit impaired lipid metabolism, stunted phagocytosis, and hyper-inflammatory responses. This disrupted axis causes microglia to fail at forming protective barriers around plaques, ultimately exacerbating tau spread and directly mediating neurodegeneration.

AXL receptor tyrosine kinase

AXL is a TAM family receptor tyrosine kinase (along with TYRO3 and MERTK) that mediates efferocytosis—phagocytosis of apoptotic cells and debris—in microglia. AXL uses Gas6 and Protein S as bridging ligands and signals through phosphatidylserine-exposed on apoptotic cells. AXL is a marker of disease-associated microglia and is upregulated in AD brain. AXL-mediated clearance may be protective or may also facilitate uptake of prion-like protein aggregates.

Bridging integrator 1 (Amphiphysin 2)

BIN1 is the second-most significant genetic risk locus for late-onset Alzheimer's disease after APOE. BIN1 encodes amphiphysin 2, involved in membrane remodeling, endocytosis, and actin regulation. In microglia, BIN1 modulates endocytic trafficking. BIN1 also influences tau pathology; it interacts with tau and may regulate tau propagation. BIN1 expression is altered in AD brain tissue.

Complement C1q subunit A

C1QA encodes a subunit of the C1q complement complex, which is produced by microglia and tags synapses for elimination during development and disease. In Alzheimer's disease and aging, excessive C1q-mediated synaptic tagging followed by microglial phagocytosis contributes to synapse loss. C1q is markedly upregulated in the aging and diseased brain. Blocking C1q has been shown to reduce synapse loss in disease models.

Complement component 3

C3 is the central effector of the complement cascade and a key mediator of synapse elimination by microglia. C3b opsonizes synapses and neurites for phagocytosis by microglia via the complement receptor CR3 (ITGAM/CD11b). Elevated C3 expression in the aging and Alzheimer's disease brain contributes to excessive synaptic pruning and neurodegeneration. C3 is produced by both astrocytes and microglia in the diseased brain.

CD33 molecule (Siglec-3)

CD33 (Siglec-3) operates in direct opposition to TREM2, functioning as a primary inhibitory receptor on the microglial surface. As an ITIM-containing (Immunoreceptor Tyrosine-based Inhibitory Motif) sialic acid-binding receptor, its physiological role is to "brake" microglial activation to prevent runaway inflammation. In Alzheimer's pathology, however, excessive CD33 signaling puts a pathological halt on the microglial ability to clear amyloid-beta. GWAS studies identified that higher CD33 expression correlates with significantly elevated amyloid burden and cognitive decline. The signaling axis recruits the phosphatases SHP-1 and SHP-2, which aggressively shut down the pro-phagocytic SYK signaling cascade—essentially "turning off" the cell's ability to transition into a protective state. Fascinatingly, a protective genetic variant acts as a natural CD33 inhibitor: the rs3865444 minor allele heavily favors the production of a truncated CD33 isoform (D2-CD33) that lacks the sialic acid-binding domain. Individuals with this protective variant have more phagocytically active microglia, confirming CD33 as a prime target for antagonistic antibodies (like AL003) to lift the brake off the microglial immune system.

C-type lectin domain family 7 member A (Dectin-1)

CLEC7A encodes Dectin-1, a pattern recognition receptor that recognizes β-glucans and is a prominent marker of plaque-associated, disease-associated microglia (DAM). CLEC7A expression is strongly induced in microglia surrounding amyloid plaques and following neuronal injury. Dectin-1 signaling activates the NLRP3 inflammasome and drives inflammatory cytokine production. Its strong DAM-specific expression positions CLEC7A as both a marker and potential functional mediator of disease microglia.

Colony stimulating factor 1 receptor

CSF1R (Colony Stimulating Factor 1 Receptor) is the absolute, non-redundant survival receptor for the entire microglial lineage. The sheer existence of microglia in the brain relies on continuous trophic signaling through this axis via its ligands, IL-34 and CSF-1. When CSF1R signaling is pharmacologically blocked (e.g., via PLX3397), microglia rapidly and uniformly undergo apoptosis, allowing researchers to essentially "delete" microglia from the brain within a matter of days. Astoundingly, upon drug withdrawal, the brain repopulates the entire microglial compartment from surviving nestin-positive progenitors, entirely resetting the myeloid landscape. Clinically, heterozygous mutations in CSF1R lead to ALSP (Adult-onset Leukoencephalopathy with Axonal Spheroids and Pigmented Glia), an aggressive neurodegenerative condition caused by primary microglial failure. In Alzheimer's and MS, CSF1R is often targeted by pharmaceutical inhibitors to "wipe out" neurotoxic, hyper-inflammatory microglial populations, with the hypothesis that forcing a repopulation might restore a younger, more homeostatic immune environment.

Cystatin F

CST7 encodes cystatin F, a cysteine protease inhibitor that is a prominent marker of disease-associated microglia (DAM). CST7 expression is strongly upregulated in microglia surrounding amyloid plaques and in other microglial activation contexts. As an inhibitor of lysosomal cysteine proteases such as cathepsins, CST7 may regulate lysosomal degradation capacity in disease states. Its strong DAM-specific expression makes it a useful marker for isolating and characterizing disease-state microglia.

CX3C motif chemokine receptor 1 (Fractalkine receptor)

CX3CR1 (the Fractalkine receptor) is the primary "tethering" axis between microglia and neurons. It binds exclusively to CX3CL1 (Fractalkine), which is constitutively expressed on the surface of healthy neurons. This one-to-one interaction exerts a critical, continuous inhibitory signal that prevents microglia from erroneously attacking viable neuronal bodies and synapses. When neurons undergo stress or undergo apoptosis, they downregulate CX3CL1, releasing the microglial "brake." This signals the microglia that the neuron is damaged and vulnerable, initiating phagocytic cleanup. Without CX3CR1 signaling, microglia become hyper-vigilant and pathologically over-prune synapses, leading to severe connectivity deficits and cognitive behavioral abnormalities in animal models. In neurodegenerative contexts like Alzheimer's and ALS, the disruption of the CX3CL1-CX3CR1 axis precipitates rampant microglial toxicity. Strategies seeking to leverage this pathway are heavily focused on mimicking the natural neuro-immune suppression signal to force hyper-reactive microglia back into a subdued, non-destructive surveillance state in the face of ongoing neuroinflammation.

Glycoprotein NMB (Osteoactivin)

GPNMB is a lysosomal glycoprotein expressed on microglia that is upregulated in disease-associated and lipid-laden microglial states. GPNMB is co-regulated with progranulin (GRN) and both are involved in microglial lysosomal function. Elevated GPNMB has been observed in Parkinson's disease brain and in GBA1-related lipid storage contexts. GPNMB may be shed as a soluble form and could serve as a biomarker of microglial lysosomal stress.

Granulin precursor (Progranulin)

Progranulin (GRN) is a massive, multi-functional lysosomal protein critical for maintaining proper microglial degradative capacity. While its exact receptor interactions span sortilin and potentially EphA2, its primary biological duty is regulating the processing and flux of lipids and protein aggregates through the microglial endolysosomal network. Heterozygous loss-of-function mutations in GRN cause profound haploinsufficiency, making it one of the leading genetic drivers of Frontotemporal Dementia (FTD). Without sufficient progranulin, microglial lysosomes fail to acidify properly or process complex lipids, causing pathological catastrophic swelling of the lysosomal compartment. This forces microglia into a hyper-inflammatory, senescent state where they can engulf debris but cannot digest it. Conversely, complete bi-allelic loss of GRN results in Neuronal Ceroid Lipofuscinosis (NCL), a devastating pediatric lysosomal storage disorder. Therapeutically, GRN haploinsufficiency represents one of the most promising precision-medicine targets in neurology; companies like Alector are actively developing monoclonal antibodies (like latozinemab) to block sortilin-mediated degradation of progranulin, artificially elevating GRN levels back to operational thresholds in order to rescue microglial lysosomal function.

Hexosaminidase subunit beta

HEXB encodes the beta subunit of hexosaminidase, a lysosomal enzyme required for ganglioside catabolism. HEXB deficiency causes Sandhoff disease, a lysosomal storage disorder with progressive neurodegeneration. In the CNS, HEXB is highly expressed in microglia, and its deficiency leads to lysosomal dysfunction and microglial pathology. HEXB is also a marker used to distinguish microglia from other brain myeloid cells in single-cell studies.

Inositol polyphosphate-5-phosphatase D (SHIP1)

INPP5D (commonly known as SHIP1) is a powerful lipid phosphatase that serves as the central "off-switch" for the microglial PI3K pathway. It sits exactly downstream of major microglial receptors—including TREM2 and CSF1R—where its physiological job is to convert PIP3 into PIP2, thereby terminating survival and activation signals. GWAS meta-analyses firmly established INPP5D as a late-onset Alzheimer’s disease risk locus. Pathologically, elevated INPP5D activity is frequently found in human AD brains, particularly in microglia clustering around amyloid plaques. Because INPP5D directly depletes the PIP3 pool, it completely neutralizes the PI3K-AKT signaling that microglia desperately need to maintain phagocytosis and cell survival. When INPP5D levels are too high, microglia undergo apoptosis or become trapped in a stalled, dysfunctional state—unable to finish engulfing plaque debris. Inhibition of INPP5D is currently one of the most exciting theoretical routes for restoring microglial competence, as shutting down this enzyme mathematically forces an increase in PIP3, artificially driving the cell into a hyper-phagocytic, hyper-resilient state.

Integrin subunit alpha M (CD11b / CR3)

ITGAM encodes the CD11b subunit of the complement receptor CR3 (Mac-1), which mediates phagocytosis of C3b-opsonized substrates including synapses and amyloid. Variants at the ITGAM locus are associated with Alzheimer's disease risk. CR3 on microglia mediates complement-dependent synaptic pruning; excessive CR3-mediated pruning may contribute to synapse loss in neurodegeneration. ITGAM expression is upregulated in activated microglia.

Leukocyte immunoglobulin-like receptor B2

LILRB2 is an inhibitory receptor expressed on myeloid cells including microglia that binds APOE and other ligands to suppress immune activation. LILRB2 may mediate some of the immunosuppressive effects of APOE on microglial function. Variants near the LILRB2 locus have been identified in Alzheimer's disease GWAS. Its interaction with APOE4 may contribute to impaired microglial responses in high-risk individuals.

Leucine-rich repeat kinase 2

LRRK2 is a multidomain kinase with roles in vesicular trafficking, autophagy, and inflammatory signaling. It is expressed in microglia and macrophages, and gain-of-function mutations (most commonly G2019S) are the most common genetic cause of Parkinson's disease. In microglia, LRRK2 regulates lysosomal function, cytokine secretion, and responses to pathogen-associated molecular patterns. LRRK2 inhibitors are in clinical trials for Parkinson's disease.

MER proto-oncogene tyrosine kinase

MERTK is a TAM family receptor tyrosine kinase that mediates efferocytosis and anti-inflammatory signaling in microglia. It uses Gas6 and Protein S as bridging ligands for phosphatidylserine recognition on apoptotic cells. MERTK promotes phagocytic clearance of cell debris, lipid droplets, and myelin. MERTK signaling also suppresses proinflammatory cytokine production following phagocytosis, linking clearance to resolution of inflammation.

Membrane spanning 4-domains A4A

MS4A4A is a member of the membrane-spanning 4-domains family expressed on microglia. Variants in the MS4A gene cluster are significantly associated with Alzheimer's disease risk and with soluble TREM2 (sTREM2) levels in CSF. MS4A4A co-localizes with TREM2 at the cell surface and modulates TREM2 shedding, thereby influencing sTREM2 levels that may serve as biomarkers of microglial engagement.

Membrane spanning 4-domains A6A

MS4A6A is co-expressed with MS4A4A in microglia and is part of the MS4A gene cluster associated with Alzheimer's disease risk. MS4A6A expression changes in disease-associated microglial states. The MS4A cluster variants collectively influence sTREM2 CSF levels, suggesting coordinated roles in TREM2 processing on the microglial surface.

NLR family pyrin domain-containing 3

NLRP3 is an innate immune sensor that forms the NLRP3 inflammasome complex, leading to caspase-1 activation and processing of pro-IL-1β and pro-IL-18. In microglia, NLRP3 is activated by diverse damage signals including amyloid-beta fibrils, tau aggregates, and alpha-synuclein. NLRP3 inflammasome activation in microglia is implicated in neuroinflammation driving neurodegeneration. NLRP3 inhibitors are in clinical development for multiple inflammatory diseases.

Purinergic receptor P2Y12

P2RY12 is a purinergic G-protein coupled receptor that defines the core signature of homeostatic, surveillance-state microglia. It is exquisitely sensitive to extracellular ADP and ATP, which are instantly released by injured neurons or disrupted vasculature following a local micro-lesion. Under physiological conditions, P2RY12 acts as the primary "steering wheel" for microglia. Within minutes of detecting an ATP gradient, P2RY12 signaling reorganizes the microglial actin cytoskeleton, directing their motile processes to rapidly extend toward and continuously survey the site of damage, sealing small vascular ruptures in the process. Crucially, P2RY12 is sharply downregulated the moment microglia encounter chronic, severe pathology—such as amyloid plaques, tau tangles, or demyelinated lesions. Its expression serves as an inverse biomarker for disease severity: intact P2RY12 indicates healthy tissue, while its absence demarcates fully transitioned Disease-Associated Microglia (DAM). Consequently, recovering P2RY12 expression is often used as a benchmark for therapeutic interventions attempting to restore healthy microglial homeostasis.

Phospholipase C gamma 2

Phospholipase C Gamma 2 (PLCG2) is a critical signaling enzyme uniquely enriched in microglia within the central nervous system. It functions as the direct downstream effector for TREM2 and other ITAM-containing receptors, acting as the key transducer that converts membrane receptor activation into intracellular calcium mobilization. Upon TREM2-TYROBP activation, SYK phosphorylates PLCG2, which then cleaves PIP2 into IP3 and DAG. This immediately triggers the release of calcium from the endoplasmic reticulum, an event strictly required for driving microglial phagocytosis, chemotaxis, and the transcriptional shift into the Disease-Associated Microglia (DAM) state. A rare coding variant in PLCG2 (P522R) was discovered to uniquely protect against Alzheimer's disease. This hypermorphic (gain-of-function) mutation slightly enhances the enzyme's baseline activity, allowing microglia to respond more robustly to pathological insults without becoming hyper-inflammatory. Conversely, loss-of-function variants lock microglia in a homeostatic or stalled state, entirely preventing their ability to corral amyloid plaques, cementing PLCG2 as a high-value target for pharmacological agonism to enhance neuroprotective clearance.

Signal regulatory protein alpha (CD172a)

SIRPA encodes SIRPα (CD172a), an inhibitory receptor that interacts with CD47 on healthy cells to generate a 'don't eat me' signal, preventing microglial phagocytosis of live neurons. The SIRPα-CD47 axis calibrates microglial phagocytic activity and protects viable neurons. Disruption of this checkpoint may contribute to excessive synaptic or neuronal elimination in neurodegeneration. Targeting this axis is also being explored in oncology.

Transcription factor PU.1 (SPI1)

SPI1 encodes PU.1, a master transcription factor that is essential for microglial identity and is among the most highly expressed transcription factors in microglia. Variants at the SPI1 locus are associated with Alzheimer's disease risk. PU.1 activity regulates the expression of many microglial genes including TREM2, TYROBP, CD33, and CX3CR1. Lower PU.1 expression has been proposed to reduce microglial gene expression and thereby alter AD risk.

Secreted phosphoprotein 1 (Osteopontin)

SPP1 encodes osteopontin, a secreted glycoprotein and marker of disease-associated microglial states. SPP1-positive microglia represent a subset of activated cells found in close proximity to amyloid plaques and sites of neurodegeneration. SPP1 expression is strongly upregulated in the disease-associated microglia (DAM) signature and in proliferating microglia. Its levels are elevated in CSF of neurodegeneration patients.

Transmembrane protein 119

TMEM119 (Transmembrane Protein 119) is renowned as the gold-standard marker for distinguishing brain-resident microglia from infiltrating peripheral macrophages. While macrophages share nearly all the same myeloid machinery (like IBA1, CD68, and ITGAM), TMEM119 is uniquely restricted to the brain-derived microglial lineage under homeostatic conditions. Despite its ubiquity in microglial research, the precise biological function of TMEM119 remains elusive. Current evidence suggests it is structurally related to cell-surface rigidity or tethering to the extracellular matrix, playing a structural role in maintaining the vast, deeply ramified morphology characteristic of resting microglia. Similar to P2RY12, TMEM119 expression collapses entirely when microglia enter the pro-inflammatory or Disease-Associated Microglia (DAM) state. Its primary utility in the field remains as a sophisticated molecular beacon: researchers rely on TMEM119 to prove that a therapeutic intervention or transcriptomic signature specifically applies to the endogenous brain-resident immune system rather than peripheral monocytes leaking across a degraded blood-brain barrier.

Triggering receptor expressed on myeloid cells 2

TREM2 (Triggering Receptor Expressed on Myeloid Cells 2) is arguably the most heavily investigated microglial target in neurodegenerative disease. It operates as a critical lipid and damage-sensing receptor that orchestrates the microglial response to neurodegenerative pathologies, particularly amyloid-beta plaques and apoptotic neurons. Upon ligand binding—frequently to APOE, lipids, or polyanionic molecules—TREM2 associates with the ITAM-containing adaptor protein TYROBP (Dap12). This initiates a potent intracellular signaling cascade through SYK and PI3K pathways. This cascade is absolutely essential for driving microglia out of their homeostatic state and into the Disease-Associated Microglia (DAM) phenotype. In Alzheimer's disease, functional TREM2 signaling is required for microglia to physically barrier amyloid plaques, compacting them and preventing neurotoxic halo formation. Heterozygous loss-of-function variants (most notably R47H) severely impair this lipid-sensing and compaction ability, leading to diffuse, highly toxic plaques and an inflamed microenvironment, conferring a 2-4x increased risk for late-onset AD. Conversely, complete bi-allelic loss of TREM2 or TYROBP results in Nasu-Hakola disease, driving extreme early-onset dementia and bone cysts due to complete failure of myeloid cell clearance functionality. Therapeutics currently aim to use agonistic antibodies to artificially force-start the protective DAM state early in disease progression.

Tyrosine kinase-binding protein (DAP12)

TYROBP (DAP12) is a transmembrane signaling adaptor that pairs with multiple activating receptors on microglia, including TREM2. It contains an immunoreceptor tyrosine-based activation motif (ITAM) that recruits and activates downstream kinases including Syk. TYROBP is a hub of the microglial gene network and its expression is co-regulated with TREM2 and other innate immune receptor genes.