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https://orcid.org/0000-0001-9800-5923All Publications
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C4d, a high-affinity LilrB2 ligand, is elevated in Alzheimer's disease and mediates synapse pruning.
Proceedings of the National Academy of Sciences of the United States of America
2025; 122 (38): e2519253122
Abstract
Synapse pruning sculpts neural circuits throughout life. The human Leukocyte immunoglobulin-like receptor type B2 (LilrB2)/murine Paired immunoglobulin receptor B (PirB) receptors expressed in neurons and complement protein C4 have been separately implicated in pruning. Here, we report that C4d, a C4 cleavage product with unknown function, binds LilrB2/PirB with nanomolar affinity. C4d and LilrB2 colocalize at excitatory synapses in the human cerebral cortex as well as with beta amyloid in Alzheimer's disease (AD). C4d, as well as C4, increase with age and more so in AD. To examine whether C4d-PirB interactions can drive pruning, dendritic spines-the postsynaptic structure of excitatory synapses-were monitored on L5 pyramidal neurons in the mouse cerebral cortex: A significant decrease in dendritic spine density occurred in WT with C4d exposure, but KO of PirB completely prevented this loss. Together, our findings reveal an unexpected physiological role for C4d in pruning and imply that different complement cascade components may collaborate to engage both neuronal and glial-specific effectors of synaptic pruning.
View details for DOI 10.1073/pnas.2519253122
View details for PubMedID 40966293
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Repopulated microglia induce expression of Cxcl13 with differential changes in Tau phosphorylation but do not impact amyloid pathology
JOURNAL OF NEUROINFLAMMATION
2022; 19 (1): 173
Abstract
Adult microglia rely on self-renewal through division to repopulate and sustain their numbers. However, with aging, microglia display morphological and transcriptional changes that reflect a heightened state of neuroinflammation. This state threatens aging neurons and other cells and can influence the progression of Alzheimer's disease (AD). In this study, we sought to determine whether renewing microglia through a forced partial depletion/repopulation method could attenuate AD pathology in the 3xTg and APP/PS1 mouse models.We pharmacologically depleted the microglia of two cohorts of 21- to 22-month-old 3xTg mice and one cohort of 14-month-old APP/PS1 mice using PLX5622 formulated in chow for 2 weeks. Following depletion, we returned the mice to standard chow diet for 1 month to allow microglial repopulation. We assessed the effect of depletion and repopulation on AD pathology, microglial gene expression, and surface levels of homeostatic markers on microglia using immunohistochemistry, single-cell RNAseq and flow cytometry.Although we did not identify a significant impact of microglial repopulation on amyloid pathology in either of the AD models, we observed differential changes in phosphorylated-Tau epitopes after repopulation in the 3xTg mice. We provide evidence that repopulated microglia in the hippocampal formation exhibited changes in the levels of homeostatic microglial markers. Lastly, we identified novel subpopulations of microglia by performing single-cell RNAseq analysis on CD45int/+ cells from hippocampi of control and repopulated 3xTg mice. In particular, one subpopulation induced after repopulation is characterized by heightened expression of Cxcl13.Overall, we found that depleting and repopulating microglia causes overexpression of microglial Cxcl13 with disparate effects on Tau and amyloid pathologies.
View details for DOI 10.1186/s12974-022-02532-9
View details for Web of Science ID 000820635800001
View details for PubMedID 35787714
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Microglia and astrocytes show limited, acute alterations in morphology and protein expression following a single developmental alcohol exposure.
Journal of neuroscience research
2021; 99 (8): 2008-2025
Abstract
Fetal alcohol spectrum disorders (FASD) are the most common cause of nonheritable, preventable mental disability and are characterized by cognitive, behavioral, and physical impairments. FASD occurs in almost 5% of births in the United States, but despite this prevalence there is no known cure, largely because the biological mechanisms that translate alcohol exposure to neuropathology are not well understood. While the effects of early ethanol exposure on neuronal survival and circuitry have received more attention, glia, the cells most closely tied to initiating and propagating inflammatory events, could be an important target for alcohol in the developing brain. Inflammation is known to alter developmental trajectories, but it has recently been shown that even small changes in both astrocytes and microglia in the absence of full-blown inflammatory signaling can alter brain function long-term. Here, we studied the acute response of astrocytes and microglia to a single exposure to ethanol in development across sexes in a mouse model of human third trimester exposure, in order to understand how these cells may transition from their normal developmental path to a different program that leads to FASD neuropathology. We found that although a single ethanol exposure delivered subcutaneously on postnatal day 4 did not cause large changes in microglial morphology or the expression of AldH1L1 and GFAP in the cortex and hippocampus, subtle effects were observed. These findings suggest that even a single, early ethanol exposure can induce mild acute alterations in glia that could contribute to developmental deficits.
View details for DOI 10.1002/jnr.24808
View details for PubMedID 33606320
View details for PubMedCentralID PMC8349862
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The role of P2Y12 in the kinetics of microglial self-renewal and maturation in the adult visual cortex in vivo.
eLife
2021; 10
Abstract
Microglia are the brain's resident immune cells with a tremendous capacity to autonomously self-renew. Because microglial self-renewal has largely been studied using static tools, its mechanisms and kinetics are not well understood. Using chronic in vivo two-photon imaging in awake mice, we confirm that cortical microglia show limited turnover and migration under basal conditions. Following depletion, however, microglial repopulation is remarkably rapid and is sustained by the dynamic division of remaining microglia, in a manner that is largely independent of signaling through the P2Y12 receptor. Mathematical modeling of microglial division demonstrates that the observed division rates can account for the rapid repopulation observed in vivo. Additionally, newly born microglia resemble mature microglia within days of repopulation, although morphological maturation is different in newly born microglia in P2Y12 knock out mice. Our work suggests that microglia rapidly locally and that newly born microglia do not recapitulate the slow maturation seen in development but instead take on mature roles in the CNS.
View details for DOI 10.7554/eLife.61173
View details for PubMedID 34250902
View details for PubMedCentralID PMC8341987
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An overview of microglia ontogeny and maturation in the homeostatic and pathological brain.
The European journal of neuroscience
2021; 53 (11): 3525-3547
Abstract
Microglia are the resident immune cells of the central nervous system (CNS) and are increasingly recognized as critical players in development, brain homeostasis, and disease pathogenesis. The lifespan, maintenance, proliferation, and turnover of microglia are important factors that regulate microglial behavior and affect their roles in the CNS. However, emerging evidence suggests that microglia are morphologically and phenotypically distinct in different brain areas, at different ages, and during disease. Ongoing research focuses on understanding how microglia acquire specific phenotypes in response to extrinsic cues in the environment and how phenotypes are specified by intrinsic properties of different populations of microglia. With the development of pharmacological and genetic tools that allow the investigation of microglia in vivo, there have been considerable advances in understanding molecular signatures of both homeostatic microglia and those reacting to injury and disease. Here, we review the master gene regulators that define microglia as well as discuss the evidence that microglia are heterogeneous and fall into distinct clusters that display specific intrinsic properties and perform unique tasks in different settings. Taken together, the information presented supports the idea that microglia morphology and transcriptional heterogeneity should be considered when studying the complex nature of microglia and their roles in brain health and disease.
View details for DOI 10.1111/ejn.15225
View details for PubMedID 33835613
View details for PubMedCentralID PMC8225243
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Loss of P2Y12 Has Behavioral Effects in the Adult Mouse.
International journal of molecular sciences
2021; 22 (4)
Abstract
While microglia have been established as critical mediators of synaptic plasticity, the molecular signals underlying this process are still being uncovered. Increasing evidence suggests that microglia utilize these signals in a temporally and regionally heterogeneous manner. Subsequently, it is necessary to understand the conditions under which different molecular signals are employed by microglia to mediate the physiological process of synaptic remodeling in development and adulthood. While the microglial purinergic receptor P2Y12 is required for ocular dominance plasticity, an adolescent form of experience-dependent plasticity, it remains unknown whether P2Y12 functions in other forms of plasticity at different developmental time points or in different brain regions. Using a combination of ex vivo characterization and behavioral testing, we examined how the loss of P2Y12 affects developmental processes and behavioral performance in adulthood in mice. We found P2Y12 was not required for an early form of plasticity in the developing visual thalamus and did not affect microglial migration into barrels in the developing somatosensory cortex. In adult mice, however, the loss of P2Y12 resulted in alterations in recognition and social memory, as well as anxiety-like behaviors, suggesting that while P2Y12 is not a universal regulator of synaptic plasticity, the loss of P2Y12 is sufficient to cause functional defects.
View details for DOI 10.3390/ijms22041868
View details for PubMedID 33668516
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Cerebellar microglia are dynamically unique and survey Purkinje neurons in vivo.
Developmental neurobiology
2018; 78 (6): 627-644
Abstract
Microglia are the innate immune cells of the central nervous system and are also important participants in normal development and synaptic plasticity. Here, we demonstrate that the microglia of the mouse cerebellum represent a unique population compared to cortical microglia. Microglia are more sparsely distributed within the cerebellum and have a markedly less ramified morphology compared to their cortical counterparts. Using time-lapse in vivo imaging, we found that these differences in distribution and morphology ultimately lead to decreased parenchymal surveillance by cerebellar microglia. We also observed a novel form of somal motility in cerebellar microglia in vivo, which has not been described in cortical populations. We captured microglial interactions with Purkinje neurons in vivo. Cerebellar microglia interact dynamically with both the dendritic arbors and somas of Purkinje neurons. These findings suggest that cerebellar microglia are physiologically distinct from cortical populations and that these differences may ultimately alter how they could contribute to plasticity and disease processes in the cerebellum. © 2017 Wiley Periodicals, Inc. Develop Neurobiol 78: 627-644, 2018.
View details for DOI 10.1002/dneu.22572
View details for PubMedID 29285893
View details for PubMedCentralID PMC6544048
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A Pilot Study of Inhaled CO Therapy in Neonatal Hypoxia-Ischemia: Carboxyhemoglobin Concentrations and Brain Volumes.
Frontiers in pediatrics
2018; 6: 120
Abstract
Objective: The objective of this pilot study was to start evaluating the efficacy and the safety (i.e., carboxyhemoglobin concentration of carbon monoxide (CO)) as a putative neuroprotective therapy in neonates. Study Design: Neonatal C57BL/6 mice were exposed to CO at a concentration of either 200 or 250 ppm for a period of 1 h. The pups were then sacrificed at 0, 10, 20, 60, 120, 180, and 240 min after exposure to either concentration of CO, and blood was collected for analysis of carboxyhemoglobin. Following the safety study, 7-day-old pups underwent a unilateral carotid ligation. After recovery, the pups were exposed to a humidified gas mixture of 8% oxygen and 92% nitrogen for 20 min in a hypoxia chamber. One hour after the hypoxia exposure, the pups were randomized to one of two groups: air (HI+A) or carbon monoxide (HI+CO). An inhaled dose of 250 ppm of CO was administered to the pups for 1 h per day for a period of 3 days. At 7 days post-injury, the pups were sacrificed and the brains analyzed for cortical and hippocampal volumes. Results: CO exposure at 200 and 250 ppm produced a peak carboxyhemoglobin concentration of 21.52 ± 1.18% and 27.55 ± 3.58%, respectively. The carboxyhemoglobin concentrations decreased rapidly, reaching control concentrations by 60 min post exposure. At 14 days of age (7 days post injury), the HI+CO (treated with 1 h per day of 250 ppm of CO for 3 days post injury) had significant preservation of the ratio of ipsilateral to contralateral cortex (median 1.07, 25% 0.97, 75% 1.23, n = 10) compared the HI+A group (p < 0.05). Conclusion: CO exposure of 250 ppm did not reach carboxyhemoglobin concentrations which would induce acute neurologic abnormalities and was effective in preserving cortical volumes following hypoxic-ischemic injury.
View details for DOI 10.3389/fped.2018.00120
View details for PubMedID 29765933
View details for PubMedCentralID PMC5939051
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Efficacy of Laropiprant in Minimizing Brain Injury Following Experimental Intracerebral Hemorrhage.
Scientific reports
2017; 7 (1): 9489
Abstract
Intracerebral hemorrhage (ICH) is one of the most devastating and disabling forms of stroke, yet effective treatments are still lacking. Prostaglandins and their receptors have been implicated in playing vital roles in ICH outcomes. Recently, laropiprant, a DP1 receptor antagonist, has been used in combination with niacin to abolish the prostaglandin D2-(PGD2)-induced flushing. Here, we test the hypothesis that laropiprant limits bleeding and rescues the brain from ICH. Wildtype (WT) and DP1-/- mice were subjected ICH and neurologic deficits and hemorrhagic lesion outcomes were evaluated at 72 hours after the ICH. To test the therapeutic potential of laropiprant, WT mice subjected to ICH were treated with laropiprant at 1 hour after the ICH. The putative effect of laropiprant on limiting hematoma expansion was tested by an in vivo tail bleeding cessation method and an ex vivo coagulation method. Finally, the roles of laropiprant on gliosis and iron accumulation were also investigated. A significant decrease in the injury volume was observed in DP1-/- as well as laropiprant-treated WT mice. The tail bleeding time was significantly lower in laropiprant group as compared with the vehicle group. Significantly lower Iba-1 and Perls' iron staining in DP1-/- and laropiprant-treated WT groups were observed. Altogether, the data suggest that laropiprant treatment post-ICH attenuates brain damage by targeting primary as well as secondary injuries.
View details for DOI 10.1038/s41598-017-09994-5
View details for PubMedID 28842638
View details for PubMedCentralID PMC5573370
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Efficacy of prophylactic flavan-3-ol in permanent focal ischemia in 12-mo-old mice.
American journal of physiology. Heart and circulatory physiology
2015; 308 (6): H583-91
Abstract
The consumption of flavan-3-ol-containing foods, including (-)-epicatechin (EC), has been linked to lower incidence of cardiovascular disease and stroke. We previously demonstrated nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) -dependent EC efficacy in reducing stroke-induced deficits in 2-mo-old mice; yet stroke is primarily a disease of the elderly. Because neuroinflammation, oxidative stress, and vascular dysfunction are hallmarks of aging, we tested whether Nrf2 mediates EC efficacy in aging mice through modulation of glial responses and blood brain barrier permeability. First, we compared anastomosis in naïve wild-type and C57BL/6 Nrf2(-/-) mice to identify potential differences in cerebrovascular architecture. Data showed no significant differences in the number of anastomoses or mean intersection points, indicating similar gross vascular physiology. To assess efficacy and mechanisms of protection, wild-type or Nrf2(-/-) mice were administered the minimum effective EC dose established in our previous studies before the permanent distal middle cerebral artery occlusion. Similar to previous results with young mice, 12-mo-old wild types also showed significant reductions in infarct volume (41.01 ± 29.57%) and improved performance in removing adhesive tape relative to vehicle-treated controls, whereas a trend toward protection was observed in Nrf2(-/-). However, EC did not reduce immunoreactivity for the microglia/macrophage marker anti-ionized calcium-binding adapter molecule 1, suggesting that dampened activation/recruitment did not account for EC protection. Furthermore, there were no differences in mouse IgG extravasation or spontaneous hemorrhage between EC-treated groups. These data demonstrate that EC protection occurs independent of microglia/macrophage modulation or blood brain barrier preservation, suggesting that the glial cell responses in young mice are compensatory to another, and potentially novel, protective mechanism.
View details for DOI 10.1152/ajpheart.00239.2014
View details for PubMedID 25576625
View details for PubMedCentralID PMC4360057