Index
Papers
Curated literature on microglial biology, indexed by target, disease, species, method, and evidence type.
Targeted cellular micropharmacies deliver therapeutic agents to the brain.
Malviya M, Baniya S, Wong E, Jain T, Manoranjan B, Vogt KC, Kehs Z, Silberman PC, Dao T, Li Y, Scheinberg DA
The systemic administration of therapeutic agents, particularly large, charged molecules such as antibodies, has limited efficacy in treating central nervous system (CNS) disorders. In addition, the slow progression of neurodegenerative diseases makes repeated intrathecal injections unfeasible. Alzheimer's disease is characterized by the accumulation of Aβ amyloid plaques. Microglia contribute to the clearance of Aβ, but are inhibited by the expression of CD33. Therefore, antibody blocking of CD33 may enhance the phagocytosis of Aβ by microglial cells, slowing AD progression. Here, we use cells as "targeted cellular micropharmacies" that are retained in the CNS to deliver therapeutic proteins directly into the brain. To achieve this, we genetically engineered CD4 T-cells to express: (1) a chimeric antigen receptor against GD2 to retain the cells in the brain, (2) ectopic FoxP3 to reduce inflammation, (3) secreted IL-2 to promote cell longevity, and (4) secreted anti-CD33 scFv antibody. Our proof-of-concept demonstrates that therapeutic antibodies can be delivered to the brain for at least 8 weeks to treat neurological disorders. Other agents could be similarly delivered into the brain by this platform.
CD33 Isoform Splicing Dysregulation: A Molecular Determinant of Microglial Dysfunction in Alzheimer's Disease Pathology.
Li XY, Zhang Y, Ran Z, Luo JX, Yu XQ, Lu MH
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, and chronic neuroinflammation. Genome-wide association studies (GWAS) have identified microglial dysfunction as central to AD pathogenesis, with CD33 emerging as a critical genetic risk factor. This review explores the dual roles of CD33 isoforms, CD33M (pro-pathogenic) and CD33m (protective), in modulating microglial activity, Aβ clearance, and neuroinflammatory responses. We dissect the molecular mechanisms underlying isoform formation, including genetic polymorphisms (e.g., rs3865444, rs12459419) and splicing regulation by hnRNPA/B, PTBP1, and SRSF1. Additionally, we highlight the antagonistic interplay between CD33 and TREM2, emphasizing their convergence on DAP12 signaling and downstream pathways. Emerging therapeutic strategies targeting CD33, such as isoform-specific immunotherapies, small-molecule splicing modulators, and Siglec-glycan interactions, are critically evaluated for their potential to mitigate AD pathology. By integrating recent preclinical and clinical advancements, this review underscores the necessity of precision approaches to harness CD33's therapeutic potential while addressing challenges like blood-brain barrier penetration and species-specific discrepancies.
Targeting microglia-mediated neuroinflammation in Alzheimer's disease: mechanisms and therapeutic approaches.
Li BF, Chen XY, Xie R, Mo YF, Wu YZ, Meng Y, Han XL, Chen MH, Peng YJ
While the recent approval of amyloid-beta (Aβ)-clearing monoclonal antibodies (mAbs) marks a milestone in treating Alzheimer's disease (AD), their modest clinical efficacy has catalyzed a paradigm shift, underscoring the necessity of targeting complementary pathological drivers. Neuroinflammation, once considered a secondary phenomenon, is now established as a third core pathological pillar of AD, with microglia at its epicenter. This review provides a comprehensive analysis of the multifaceted role of microglia in AD pathogenesis and evaluates the rapidly evolving landscape of microglia-targeted therapeutic strategies. We first delineate the dynamic and dichotomous function of microglia, which act as a "double-edged sword." Emerging evidence reveals a complex, three-stage functional arc: microglia are implicated in the initial seeding of Aβ plaques, then transition to a neuroprotective role by containing established plaques, and finally devolve into a chronic, pro-inflammatory state that drives neurodegeneration. We then delve into the core molecular mechanisms governing this plasticity, including the pivotal Triggering Receptor Expressed on Myeloid Cells 2 (TREM2)-APOE signaling axis, the inhibitory receptor Cluster of Differentiation 33 (CD33), and key intracellular hubs like the NLRP3 inflammasome, which directly link genetic risk factors to microglial dysregulation. Based on this mechanistic understanding, we critically evaluate diverse therapeutic strategies, ranging from suppressing neurotoxic inflammation (e.g., TNF-α and NLRP3 inhibitors) to enhancing protective functions (e.g., TREM2 agonism and CD33 antagonism), eliminating senescent microglia (senolytics), and utilizing advanced nanoplatforms for brain-targeted delivery. Finally, we highlight the critical role of neuroinflammatory biomarkers within the emerging ATI(N) framework for enabling precision medicine. In conclusion, targeting microglia represents a vital therapeutic avenue that moves beyond amyloid-centric approaches, where a sophisticated understanding of their stage-dependent functions is paramount for developing effective immunomodulatory therapies to alter the devastating course of AD.
INPP5D is an Alzheimer's disease risk gene implicated in microglial phagocytosis
Butler CA, et al.
Characterized INPP5D (SHIP1) expression and function in human and mouse microglia. INPP5D is a phosphoinositide phosphatase that negatively regulates TREM2 signaling and phagocytosis. AD-associated INPP5D variants are associated with increased expression, suggesting that INPP5D limits microglial protective function. INPP5D inhibition enhances microglial amyloid clearance.
Distinct amyloid-β and tau-associated microglia profiles in Alzheimer's disease
Gerrits E, Brouwer N, Kooistra SM, Woodbury ME, Vermeiren Y, et al.
Applied spatial transcriptomics to post-mortem AD brain tissue to map the spatial distribution of microglial states relative to pathological lesions. Identified enrichment of TREM2+ and SPP1+ microglial sub-populations around amyloid plaques and neurofibrillary tangles. Provided spatial context for disease-associated microglial states.
Single-cell multi-region dissection of Alzheimer's disease
Zhou Y, Song WM, Andhey PS, Swain A, et al.
Large single-cell RNA-seq study of AD brain tissue across multiple regions. Identified a human AD microglial state (HAM) distinct from mouse DAM, enriched for APOE, SPP1, and CHI3L1. Showed that TREM2 loss-of-function reduces microglial response to amyloid pathology in humans. Cross-disease comparison with other neurodegenerative conditions.
Single-cell analysis of human microglia reveals neuropathology-associated reactivity during Alzheimer's disease progression
Hammond TR, Dufort C, et al.
Single-cell RNA-seq profiling of mouse microglia across multiple developmental stages and pathological contexts. Revealed significant microglial heterogeneity, including distinct proliferative, homeostatic, and disease-associated subpopulations. Homeostatic markers P2RY12, CX3CR1, and TMEM119 decline in disease-associated states.
Spatial transcriptomics reveals unique molecular fingerprints of human microglia
Masuda T, Sankowski R, Staszewski O, Böttcher C, Amann L, Sagar, et al.
Used spatial transcriptomics and single-cell sequencing to map human microglia subpopulations across different brain regions. Found region-specific microglial transcriptional identities in human tissue. This study resolved the heterogeneity of human microglia beyond what was observable with bulk sequencing approaches.
Single-cell transcriptomic analysis of Alzheimer's disease
Mathys H, Davila-Velderrain J, Peng Z, Gao F, Mohammadi S, Young JZ, et al.
First large-scale single-nucleus RNA-seq study of the AD brain, profiling over 80,000 nuclei from 48 individuals. Identified disease-associated transcriptional changes across neurons, oligodendrocytes, astrocytes, and microglia. Microglial changes preceded and correlated with pathology progression. TREM2 and SPP1 were among the most differentially expressed microglial genes in AD.
Microglia Biology: One Century of Evolving Concepts
Prinz M, Jung S, Priller J
Comprehensive review of microglial function in CNS development, homeostasis, and disease. Covered microglial ontogeny, transcriptional control, spatial heterogeneity, and diverse roles in neurodegenerative and neuroinflammatory conditions. Highlighted key unanswered questions and therapeutic opportunities.
The major risk factors for Alzheimer's disease: age, sex, and genes modulate the microglia response to Abeta plaques
Sala Frigerio C, Wolfs L, Fattorelli N, Thrupp N, Voytyuk I, Schmidt I, et al.
Single-cell RNA-seq of human AD and control brains revealed microglial heterogeneity modulated by age, sex, and TREM2/APOE genotype. Identified human microglial sub-states not present in mouse models, including a population characterized by high MHC-II expression. Demonstrated that genetic risk factors directly shape microglial transcriptional states.
Complement C3 Is Activated in Human AD Brain and Is Required for Neurodegeneration in Mouse Models of Amyloidosis and Tauopathy
Wu T, Dejanovic B, Gandin VD, et al.
Showed elevated complement activity in blood and brain of Alzheimer's disease patients. C1q deposits co-localize with amyloid plaques and synapses. C3 knockout mice show reduced synaptic elimination and attenuated cognitive deficits in AD models. Provides therapeutic rationale for complement inhibition in AD.
The microglia universe
Deczkowska A, Keren-Shaul H, Weiner A, Colonna M, Schwartz M, Amit I
Comprehensive review of microglial states including homeostatic microglia, disease-associated microglia (DAM), and other reactive states across neurological diseases. Synthesized single-cell transcriptomic data to propose a unified framework of microglial reactivity. Highlighted DAM as a neuroprotective response requiring TREM2 signaling.
APOE4 causes widespread molecular and cellular alterations associated with Alzheimer's disease phenotypes in human iPSC-derived brain cell types
Lin YT, Seo J, Gao F, Feldman HM, Wen HL, Penney J, et al.
Used iPSC-derived brain cells to map the transcriptomic and cellular consequences of APOE4. In microglia-like cells, APOE4 disrupts lipid metabolism, impairs phagocytosis, and increases inflammatory gene expression. Targeted correction of APOE4 to APOE3 rescues these phenotypes, establishing APOE4's direct microglial toxicity.
Microglia in health and disease
Colonna M, Butovsky O
Comprehensive review of microglial biology covering origin, homeostasis, transcriptional identity, and disease states. Reviewed evidence for microglial involvement in Alzheimer's disease, ALS, MS, and other CNS disorders. Synthesized genetic and functional evidence for TREM2, DAP12/TYROBP, CX3CR1, and other core microglial genes.
LRRK2 is expressed in microglia and differentially regulates microglial pro- and anti-inflammatory responses
Cook DA, Kanber M, et al.
Demonstrated that LRRK2 is expressed in microglia and regulates cytokine production and microglial inflammatory responses. LRRK2 G2019S mutant microglia show exaggerated pro-inflammatory responses. LRRK2 kinase inhibition attenuates microglial activation. Established microglia as a key cellular context for LRRK2 function in PD.
A common haplotype lowers PU.1 expression in myeloid cells and delays onset of Alzheimer's disease
Huang KL, Marcora E, Pimenova AA, et al.
Showed that non-coding Alzheimer's disease risk variants at the SPI1 (PU.1) locus delay PU.1 expression and reduce microglial function. Lower PU.1 activity is associated with later disease onset. PU.1 is a master transcription factor for myeloid cell identity and regulates expression of many AD risk genes including TREM2, CD33, and MS4A family members.
Disease-associated microglia: a universal response to neurological insults
Keren-Shaul H, Spinrad A, Weiner A, Matcovitch-Natan O, Dvir-Szternfeld R, Ulland TK, et al.
Identified and characterized the disease-associated microglia (DAM) transcriptional state using single-cell RNA-seq in mouse AD models. DAM signature includes upregulation of TREM2, SPP1, CST7, CLEC7A, and GPNMB while downregulating homeostatic markers P2RY12 and CX3CR1. TREM2 was shown to be required for the full DAM transition.
APOE and TREM2 regulate the disease-associated microglial response in Alzheimer's disease
Krasemann S, Madore C, Cialic R, Baufeld C, Calcagno N, El Fatimy R, et al.
Identified a microglial state regulatory axis in which TREM2 signaling via APOE drives the transition from homeostatic to disease-associated microglia (DAM). Blocking APOE or TREM2 impairs the DAM response. This work established TREM2-APOE as the central signaling axis for disease-associated microglial activation.
MS4A4A: a novel cell surface marker for M2 macrophages and plasma cells
Sanyal R, Polyak MJ, Zuccolo J, et al.
Characterized MS4A4A expression in macrophages and microglia. Showed that MS4A4A is induced in alternatively activated (M2) macrophages and is regulated by IL-4 signaling. MS4A4A is a Siglec-3 (CD33) binding partner and modulates microglial surface receptor dynamics. Relevant to the MS4A gene cluster implicated in Alzheimer's disease GWAS.
Microglia sculpt postnatal neural circuits in an activity and complement-dependent manner
Salter MW, Stevens B
Review of the evidence that microglia actively remodel synaptic circuits throughout life. Covered complement-dependent synapse elimination, microglial phagocytosis of synaptic material, and the dysregulation of this process in neurodevelopmental and neurodegenerative disorders. Highlighted microglia as key effectors of synaptic homeostasis.
ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy
Shi Y, Yamada K, Liddelow SA, et al., Holtzman DM
Demonstrated that APOE4 impairs microglial amyloid clearance and exacerbates tau-mediated neurodegeneration. Anti-APOE antibodies reduced amyloid plaque burden in mouse models. APOE4 microglia show impaired phagocytic capacity relative to APOE3 microglia, directly linking APOE genotype to microglial function.
Rare coding variants in PLCG2, ABI3, and TREM2 implicate microglial-mediated innate immunity in Alzheimer's disease
Sims R, van der Lee SJ, Naj AC, Bellenguez C, Badarinarayan N, Jakobsdottir J, et al.
Large-scale whole-genome sequencing and exome sequencing study identified rare protective variants in PLCG2 and ABI3 and confirmed TREM2 coding variants as Alzheimer's disease risk factors. Established PLCG2 P522R as a hypermorphic protective variant enhancing microglial immune function. Highlighted the convergent microglial immune pathway in AD genetics.
Lysosomal processing of progranulin
Zhou X, Paushter DH, Feng T, Sun L, et al.
Showed that progranulin localizes to lysosomes in microglia and regulates lysosomal cathepsin activity and pH. GRN-deficient microglia have enlarged lysosomes with aberrant cathepsin levels. This lysosomal dysfunction phenotype can be rescued by progranulin supplementation, the basis for recombinant GRN therapy approaches.
TMEM119 marks a subset of microglia for deep brain stimulation circuit mapping
Bennett ML, Bennett FC, Liddelow SA, Ajami B, Zamanian JL, Fernhoff NB, et al.
Identified TMEM119 as a specific marker of homeostatic microglia in both mice and humans. Created TMEM119-GFP reporter mice and showed that TMEM119 expression is lost in reactive microglia. Demonstrated TMEM119's utility as a pan-microglial homeostatic marker for isolation and study.
Complement and microglia mediate early synapse loss in Alzheimer mouse models
Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, Li S, Ramakrishnan S, et al.
Demonstrated that C1q and C3 tag synapses for microglial elimination in early Alzheimer's disease mouse models, prior to plaque formation. Blocking C3 with CR3 antagonism reduced synapse loss. Established the complement-microglial pruning axis as a driver of early synaptic loss in AD.
How neuroinflammation contributes to neurodegeneration
Ransohoff RM
Critical review challenging prevalent oversimplifications of microglial biology. Argued against the binary M1/M2 polarization framework and emphasized the complexity of microglial states. Emphasized that homeostatic microglia are highly specialized and cannot be reduced to peripheral macrophage analogies.
Schizophrenia risk from complex variation of complement component 4
Sekar A, Bialas AR, de Rivera H, Davis A, Hammond TR, Kamitaki N, et al.
Demonstrated that elevated C4A expression from specific structural genomic variants drives excess synaptic pruning through C3 deposition and microglial complement receptor-mediated elimination. Identified a mechanism linking complement-mediated synaptic pruning to schizophrenia risk. Microglia are the effector cells mediating complement-dependent synapse elimination.
TREM2 sustains microglial expansion and plaque containment in Alzheimer's disease
Wang Y, Ulland TK, Ulrich JD, Song W, et al.
Demonstrated that TREM2 deficiency impairs microglial proliferation and metabolic fitness in response to amyloid plaques. TREM2-deficient microglia fail to surround and compact plaques, leading to increased plaque-associated neuritic dystrophy. TREM2 was shown to drive the transition from homeostatic to disease-associated microglial states.
TREM2 is a receptor that senses amyloid-beta plaques and lipid bilayers
Yeh FL, Wang Y, Tom I, et al.
Showed that TREM2 binds to ApoE and other lipoproteins as well as amyloid-beta plaques. TREM2 engagement with lipid-associated ligands promotes microglial migration toward and clustering around amyloid plaques. This ligand promiscuity places TREM2 at the interface of lipid sensing and amyloid clearance.
TREM2 macrophage survival signals are required for normal brain homeostasis
Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, et al.
Showed that TREM2 signaling promotes microglial survival and proliferation through PI3K/AKT pathway activation. TREM2-deficient mice show reduced microglial numbers in some brain regions. The paper placed TREM2 as a central survival factor for brain-resident macrophages.
Defining microglial identity in the mouse brain using a combined transcriptomic and proteomics approach
Butovsky O, Jedrychowski MP, Moore CS, et al.
Established a comprehensive transcriptomic and proteomic signature distinguishing microglia from other brain cells and peripheral macrophages. Identified TMEM119, P2RY12, and SALL1 as specific microglial homeostatic markers. Showed that these markers are lost in disease states, establishing a molecular definition of microglial identity.
Elimination of microglia improves cognitive function following cranial irradiation
Elmore MR, Najafi AR, Koike MA, Green KN, et al.
Showed that pharmacological inhibition of CSF1R (using PLX5622) efficiently depletes microglia from the adult mouse brain. Upon drug withdrawal, the brain is rapidly repopulated by new microglia from residual progenitors. Established CSF1R inhibition as the standard method for microglial depletion, enabling numerous subsequent mechanistic studies.
Soluble TREM2 inhibits Tau seeding and progression of Alzheimer's disease
Kleinberger G, Yamanishi Y, Suárez-Calvet M, Czirr E, Lohmann E, Cuyvers E, et al.
Identified TREM2 proteolytic shedding producing soluble TREM2 (sTREM2) in cerebrospinal fluid. Disease-causing mutations impair TREM2 shedding. Elevated sTREM2 in CSF is associated with Alzheimer's disease and FTD. This work established sTREM2 as a potential biomarker of microglial activity.
Colony stimulating factor 1 receptor (CSF1R) signaling mediates macrophage and microglia differentiation
Stanley ER, Chitu V
Comprehensive review of CSF1R biology, covering its role as the receptor for both CSF1 (M-CSF) and IL-34. Reviewed CSF1R signaling in macrophage development, survival, and proliferation, with specific focus on microglia. Highlighted CSF1R as the non-redundant survival receptor for the microglial lineage from development through adulthood.
Alzheimer's disease-associated CD33 is expressed by inflammatory monocytes and is not significantly expressed in the brain
Griciuc A, Serrano-Pozo A, Parrado AR, Lesinski AN, Asselin CN, Mullin K, et al.
Showed that CD33 (Siglec-3) expression in human microglia impairs amyloid-beta uptake and clearance. The Alzheimer's risk-associated CD33 variant rs3865444 reduces CD33 expression and increases microglial amyloid clearance. CD33 knockout mice show enhanced microglial amyloid phagocytosis and reduced plaque burden.
TREM2 variants in Alzheimer's disease
Guerreiro R, Wojtas A, Bras J, Carrasquillo M, Rogaeva E, Majounie E, et al.
Companion study to Jonsson et al. (2013) identifying the R47H variant in TREM2 as conferring a three-fold increased risk of late-onset Alzheimer's disease. Whole-exome sequencing across multiple AD cohorts confirmed TREM2 as a significant microglial genetic risk factor.
NLRP3 inflammasome activation mediates tau pathology
Heneka MT, Kummer MP, Stutz A, Delekate A, et al.
Showed that amyloid-beta activates the NLRP3 inflammasome in microglia, leading to caspase-1 activation and IL-1beta secretion. NLRP3-deficient mice have reduced amyloid burden and improved memory in AD mouse models. Identified NLRP3 as a critical microglial sensor of amyloid pathology.
TREM2 variants associated with Alzheimer's disease
Jonsson T, Stefansson H, Steinberg S, Jonsdottir I, Jonsson PV, Gudjonsson SA, et al.
Identified the R47H variant in TREM2 as conferring approximately 3-fold increased risk for Alzheimer's disease, similar in magnitude to the APOE ε4 effect in some populations. This seminal paper established microglial TREM2 as a major AD risk gene.
Complement-dependent synaptic elimination during development and disease
Stephan AH, et al.
Reviewed evidence that the complement cascade, including C1q and C3, tags synapses for elimination by microglia throughout development and in disease. Highlighted how this mechanism becomes aberrantly reactivated in aging and neurodegeneration. Microglia express complement receptors (including CR3/ITGAM) to mediate synaptic pruning.
BIN1 regulates BACE1 intracellular trafficking and amyloid-beta production
Tan MS, Yu JT, et al.
Showed that BIN1 (Bridging Integrator 1) interacts with tau and regulates tau spread between neurons. BIN1 expression is highest in microglia and oligodendrocytes. BIN1 knockdown reduces tau propagation in neuronal cultures. BIN1 GWAS variants modulate BIN1 expression levels and are associated with Alzheimer's disease risk.
Progranulin deficiency promotes neuroinflammation and neuron loss following toxin-induced injury
Martens LH, Zhang J, Barmada SJ, et al.
Showed that progranulin-deficient microglia display exaggerated inflammatory responses and impaired phagocytosis. In the context of toxin-induced neuronal injury, GRN knockout mice show greater neuroinflammation and neurodegeneration. Progranulin regulates lysosomal function and cytokine production in microglia.
Synapse elimination by complement deposition and microglial engulfment in early Alzheimer's disease
Schafer DP, Lehrman EK, Kautzman AG, Koyama R, Mardinly AR, Yamasaki R, et al.
Demonstrated that microglia engulf synaptic material through a CR3/C3-dependent mechanism during normal postnatal development. Using two-photon microscopy and immunoEM, showed microglia internalize presynaptic terminals tagged with C3 and C1q. In retinogeniculate refinement, C3 knockout mice have impaired synapse elimination, establishing complement-CR3 as the core synaptic pruning mechanism.
Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease
Hollingworth P, Harold D, Sims R, Gerrish A, Lambert JC, Carrasquillo MM, et al.
GWAS meta-analysis identifying MS4A6A/MS4A4E, CD33, EPHA1, and ABCA7 as new Alzheimer's disease susceptibility loci. Companion to Naj et al. 2011. MS4A6A and MS4A4A are expressed in microglia and regulate TREM2 surface expression. CD33 is an inhibitory receptor limiting microglial amyloid clearance.
Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease
Naj AC, Jun G, Beecham GW, Wang LS, Vardarajan BN, Buros J, et al.
Parallel GWAS study to Hollingworth et al. 2011 identifying the same AD loci including the MS4A gene cluster. Confirmed that the MS4A locus on chromosome 11q12 contains multiple AD-associated variants. Established CD33 and BIN1 among the strongest non-APOE genetic risk factors for late-onset AD.
Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, et al.
Demonstrated definitively that adult brain microglia originate from yolk sac erythromyeloid precursors, not from bone marrow monocyte precursors. Used fate-mapping approaches to track microglial origin. Established the unique ontogenetic identity of microglia distinct from other tissue macrophages.
Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
Harold D, Abraham R, Hollingworth P, Sims R, Gerrish A, Hamshere ML, et al.
One of the first large-scale GWAS studies to discover new Alzheimer's disease susceptibility loci beyond APOE. Identified CLU (clusterin) and CR1 (complement receptor 1) as genome-wide significant AD risk genes, implicating lipid metabolism and complement pathways in AD pathogenesis. Companion study to Lambert et al. 2009.
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17
Baker M, Mackenzie IR, Pickering-Brown SM, Gass J, Rademakers R, Lindholm C, et al.
Co-discovered with Cruts et al. that heterozygous loss-of-function mutations in GRN (progranulin) cause frontotemporal lobar degeneration with ubiquitin inclusions (FTLD-U). Progranulin is a pleiotropic growth factor expressed highly in microglia, and haploinsufficiency causes neuroinflammation and lysosomal dysfunction.
Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21
Cruts M, Gijselinck I, van der Zee J, Engelborghs S, Wils H, Pirici D, et al.
Co-discovered with Baker et al. that heterozygous loss-of-function mutations in GRN cause FTLD-U (frontotemporal lobar degeneration with ubiquitin inclusions). Demonstrated that progranulin haploinsufficiency is sufficient to cause disease. Established GRN as the second major FTD gene after MAPT.
ATP mediates rapid microglial response to local brain injury in vivo
Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, et al.
Demonstrated that microglia rapidly extend processes toward sites of local tissue damage using ATP as a damage signal through purinergic P2Y receptors. Companion to Nimmerjahn et al. Two-photon imaging in live mice showed directed microglial process extension within minutes of injury.
Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo
Nimmerjahn A, Kirchhoff F, Helmchen F
Seminal two-photon imaging study demonstrating that 'resting' microglia are in fact highly active, continuously extending and retracting their processes to survey the brain parenchyma. Established that microglia scan their local environment approximately every few hours. This work redefined the concept of microglial quiescence.
Cloning of the gene containing mutations that cause PARK8-linked Parkinson's disease
Paisán-Ruíz C, Jain S, Evans EW, Gilks WP, Simón J, van der Brug M, et al.
Co-identified LRRK2 (leucine-rich repeat kinase 2) as the causal gene for the PARK8 locus linked to familial Parkinson's disease. Demonstrated that LRRK2 is a large GTPase/kinase expressed in neurons and microglia. This discovery opened LRRK2 kinase inhibition as a therapeutic strategy.
Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology
Zimprich A, Biskup S, Leitner P, Lichtner P, Farrer M, Lincoln S, et al.
Co-identified LRRK2 mutations as the cause of autosomal-dominant Parkinson's disease in multiple European families. Identified the G2019S mutation (the most common familial PD mutation worldwide) and other LRRK2 variants. Together with Paisán-Ruíz et al. 2004 established LRRK2 as the leading PD drug target.