Ubiquitin Ligase COP1 Suppresses Neuroinflammation by Degrading c/EBPß in Microglia.

Dysregulated microglia are intimately involved in neurodegeneration, including Alzheimer's disease (AD) pathogenesis, but the mechanisms controlling pathogenic microglial gene expression remain poorly understood. The transcription factor CCAAT/enhancer binding protein beta (c/EBPß) regulates pro-inflammatory genes in microglia and is upregulated in AD. We show expression of c/EBPß in microglia is regulated post-translationally by the ubiquitin ligase COP1 (also called RFWD2). In the absence of COP1, c/EBPß accumulates rapidly and drives a potent pro-inflammatory and neurodegeneration-related gene program, evidenced by increased neurotoxicity in microglia-neuronal co-cultures. Antibody blocking studies reveal that neurotoxicity is almost entirely attributable to complement. Remarkably, loss of a single allele of Cebpb prevented the pro-inflammatory phenotype. COP1-deficient microglia markedly accelerated tau-mediated neurodegeneration in a mouse model where activated microglia play a deleterious role. Thus, COP1 is an important suppressor of pathogenic c/EBPß-dependent gene expression programs in microglia.

Neutral or detrimental effects of TREM2 agonist antibodies in preclinical models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.

Diffusion Tensor MRI is sensitive to fibrotic injury in a mouse model of oxalate induced chronic kidney disease.

Chronic kidney disease (CKD) is characterized by inflammation and fibrosis in the kidney. Renal biopsies and estimated glomerular filtration rate (eGFR) remain the standard of care, but these endpoints have limitations in detecting the stage, progression, and spatial distribution of fibrotic pathology in the kidney. MRI diffusion tensor imaging (DTI) has emerged as a promising non-invasive technology to evaluate renal fibrosis in vivo both in clinical and preclinical studies. However, these imaging studies have not systematically identified fibrosis particularly deeper in the kidney where biopsy sampling is limited, or completed an extensive analysis of whole organ histology, blood biomarkers, and gene expression to evaluate the relative strengths and weaknesses of MRI for evaluating renal fibrosis. In this study, we performed DTI in the sodium oxalate mouse model of CKD. The DTI parameters fractional anisotropy, apparent diffusion coefficient, and axial diffusivity were compared between the control and oxalate groups with region-of-interest (ROI) analysis to determine changes in the cortex and medulla. Additionally, voxel-based analysis (VBA) was implemented to systematically identify local regions of injury over the whole kidney. DTI parameters were found to be significantly different in the medulla by both ROI analysis and VBA, which also spatially matched with collagen III IHC. The DTI parameters in this medullary region exhibited moderate to strong correlations with histology, blood biomarkers, hydroxyproline and gene expression. Our results thus highlight the sensitivity of DTI to the heterogeneity of renal fibrosis and importance of whole kidney non-invasive imaging.

TREM2-dependent microglial function is essential for remyelination and subsequent neuroprotection.

Disability in multiple sclerosis (MS) is driven in part by the failure of remyelination and progressive neurodegeneration. Microglia, and specifically triggering receptor expressed on myeloid cells 2 (TREM2), a factor highly expressed in microglia, have been shown to play an important role in remyelination. Here, using a focal demyelination model in the brain, we demonstrate that demyelination is persistent in TREM2 knockout mice, lasting more than 6 weeks after lysolecithin injection and resulting in substantial neurodegeneration. We also find that TREM2 knockout mice exhibit an altered glial response following demyelination. TREM2 knockout microglia demonstrate defects in migration and phagocytosis of myelin debris. In addition, human monocyte-derived macrophages from subjects with a TREM2 mutation prevalent in human disease also show a defect in myelin debris phagocytosis. Together, we highlight the central role of TREM2 signaling in remyelination and neuroprotection. These findings provide insights into how chronic demyelination might lead to axonal damage and could help identify novel neuroprotective therapeutic targets for MS.

Micro-CT imaging and structural analysis of glomeruli in a model of Adriamycin-induced nephropathy.

Glomeruli number and size are important for determining the pathogenesis of glomerular disease, chronic kidney disease, and hypertension. Moreover, renal injury can occur in specific cortical layers and alter glomerular spatial distribution. In this study, we present a comprehensive structural analysis of glomeruli in a model of Adriamycin (doxorubicin) nephropathy. Glomeruli are imaged (micro-CT at 10 × 10 × 10 µm3) in kidney specimens from C57Bl/6 mouse cohorts: control treated with saline ( n = 9) and Adriamycin treated with 20 mg/kg Adriamycin ( n = 7). Several indices were examined, including glomerular number, glomerular volume, glomerular volume heterogeneity, and spatial density at each glomerulus and in each cortical layer (superficial, midcortical, and juxtamedullary). In the Adriamycin-treated animals, glomerular number decreased significantly in the left kidney [control: 8,298 ± 221, Adriamycin: 6,781 ± 630 (mean ± SE)] and right kidney (control: 7,317 ± 367, Adriamycin: 5,522 ± 508), and glomerular volume heterogeneity increased significantly in the left kidney (control: 0.642 ± 0.015, Adriamycin: 0.786 ± 0.018) and right kidney (control: 0.739 ± 0.016, Adriamycin: 0.937 ± 0.023). Glomerular spatial density was not affected. Glomerular volume heterogeneity increased significantly in the superficial and midcortical layers of the Adriamycin cohort. Adriamycin did not affect glomerular volume or density metrics in the juxtamedullary region, suggesting a compensatory mechanism of juxtamedullary glomeruli to injury in the outer cortical layers. Left/right asymmetry was observed in kidney size and various glomeruli metrics. The methods presented here can be used to evaluate renal disease models with subtle changes in glomerular endowment locally or across the entire kidney, and they provide an imaging tool to investigate diverse interventions and therapeutic drugs.

Muscle specific kinase (MuSK) activation preserves neuromuscular junctions in the diaphragm but is not sufficient to provide a functional benefit in the SOD1G93A mouse model of ALS.

Amyotrophic lateral sclerosis (ALS), a neurodegenerative disease affecting motor neurons, is characterized by rapid decline of motor function and ultimately respiratory failure. As motor neuron death occurs late in the disease, therapeutics that prevent the initial disassembly of the neuromuscular junction may offer optimal functional benefit and delay disease progression. To test this hypothesis, we treated the SOD1G93A mouse model of ALS with an agonist antibody to muscle specific kinase (MuSK), a receptor tyrosine kinase required for the formation and maintenance of the neuromuscular junction. Chronic MuSK antibody treatment fully preserved innervation of the neuromuscular junction when compared with control-treated mice; however, no preservation of diaphragm function, motor neurons, or survival benefit was detected. These data show that anatomical preservation of neuromuscular junctions in the diaphragm via MuSK activation does not correlate with functional benefit in SOD1G93A mice, suggesting caution in employing MuSK activation as a therapeutic strategy for ALS patients.

Magnetic susceptibility anisotropy outside the central nervous system.

Magnetic-susceptibility-based MRI has made important contributions to the characterization of tissue microstructure, chemical composition, and organ function. This has motivated a number of studies to explore the link between microstructure and susceptibility in organs and tissues throughout the body, including the kidney, heart, and connective tissue. These organs and tissues have anisotropic magnetic susceptibility properties and cellular organizations that are distinct from the lipid organization of myelin in the brain. For instance, anisotropy is traced to the epithelial lipid orientation in the kidney, the myofilament proteins in the heart, and the collagen fibrils in the knee cartilage. The magnetic susceptibility properties of these and other tissues are quantified using specific MRI tools: susceptibility tensor imaging (STI), quantitative susceptibility mapping (QSM), and individual QSM measurements with respect to tubular and filament directions determined from diffusion tensor imaging. These techniques provide complementary and supplementary information to that produced by traditional MRI methods. In the kidney, STI can track tubules in all layers including the cortex, outer medulla, and inner medulla. In the heart, STI detected myofibers throughout the myocardium. QSM in the knee revealed three unique layers in articular cartilage by exploiting the anisotropic susceptibility features of collagen. While QSM and STI are promising tools to study tissue susceptibility, certain technical challenges must be overcome in order to realize routine clinical use. This paper reviews essential experimental findings of susceptibility anisotropy in the body, the underlying mechanisms, and the associated MRI methodologies. Copyright © 2016 John Wiley & Sons, Ltd.

Imaging whole-brain cytoarchitecture of mouse with MRI-based quantitative susceptibility mapping.

The proper microstructural arrangement of complex neural structures is essential for establishing the functional circuitry of the brain. We present an MRI method to resolve tissue microstructure and infer brain cytoarchitecture by mapping the magnetic susceptibility in the brain at high resolution. This is possible because of the heterogeneous magnetic susceptibility created by varying concentrations of lipids, proteins and irons from the cell membrane to cytoplasm. We demonstrate magnetic susceptibility maps at a nominal resolution of 10-µm isotropic, approaching the average cell size of a mouse brain. The maps reveal many detailed structures including the retina cell layers, olfactory sensory neurons, barrel cortex, cortical layers, axonal fibers in white and gray matter. Olfactory glomerulus density is calculated and structural connectivity is traced in the optic nerve, striatal neurons, and brainstem nerves. The method is robust and can be readily applied on MRI scanners at or above 7T.

Rapid multi-orientation quantitative susceptibility mapping.

Three-dimensional gradient echo (GRE) is the main workhorse sequence used for susceptibility weighted imaging (SWI), quantitative susceptibility mapping (QSM), and susceptibility tensor imaging (STI). Achieving optimal phase signal-to-noise ratio requires late echo times, thus necessitating a long repetition time (TR). Combined with the large encoding burden of whole-brain coverage with high resolution, this leads to increased scan time. Further, the dipole kernel relating the tissue phase to the underlying susceptibility distribution undersamples the frequency content of the susceptibility map. Scans at multiple head orientations along with calculation of susceptibility through multi-orientation sampling (COSMOS) are one way to effectively mitigate this issue. Additionally, STI requires a minimum of 6 head orientations to solve for the independent tensor elements in each voxel. The requirements of high-resolution imaging with long TR at multiple orientations substantially lengthen the acquisition of COSMOS and STI. The goal of this work is to dramatically speed up susceptibility mapping at multiple head orientations. We demonstrate highly efficient acquisition using 3D-GRE with Wave-CAIPI and dramatically reduce the acquisition time of these protocols. Using R=15-fold acceleration with Wave-CAIPI permits acquisition per head orientation in 90s at 1.1mm isotropic resolution, and 5:35min at 0.5mm isotropic resolution. Since Wave-CAIPI fully harnesses the 3D spatial encoding capability of receive arrays, the maximum g-factor noise amplification remains below 1.30 at 3T and 1.12 at 7T. This allows a 30-min exam for STI with 12 orientations, thus paving the way to its clinical application.

MRI tools for assessment of microstructure and nephron function of the kidney.

MRI can provide excellent detail of renal structure and function. Recently, novel MR contrast mechanisms and imaging tools have been developed to evaluate microscopic kidney structures including the tubules and glomeruli. Quantitative MRI can assess local tubular function and is able to determine the concentrating mechanism of the kidney noninvasively in real time. Measuring single nephron function is now a near possibility. In parallel to advancing imaging techniques for kidney microstructure is a need to carefully understand the relationship between the local source of MRI contrast and the underlying physiological change. The development of these imaging markers can impact the accurate diagnosis and treatment of kidney disease. This study reviews the novel tools to examine kidney microstructure and local function and demonstrates the application of these methods in renal pathophysiology.

Dynamic contrast-enhanced quantitative susceptibility mapping with ultrashort echo time MRI for evaluating renal function.

Dynamic contrast-enhanced (DCE) MRI can provide key insight into renal function. DCE MRI is typically achieved through an injection of a gadolinium (Gd)-based contrast agent, which has desirable T1 quenching and tracer kinetics. However, significant T2* blooming effects and signal voids can arise when Gd becomes very concentrated, especially in the renal medulla and pelvis. One MRI sequence designed to alleviate T2* effects is the ultrashort echo time (UTE) sequence. In the present study, we observed T2* blooming in the inner medulla of the mouse kidney, despite using UTE at an echo time of 20 microseconds and a low dose of 0.03 mmol/kg Gd. We applied quantitative susceptibility mapping (QSM) and resolved the signal void into a positive susceptibility signal. The susceptibility values [in parts per million (ppm)] were converted into molar concentrations of Gd using a calibration curve. We determined the concentrating mechanism (referred to as the concentrating index) as a ratio of maximum Gd concentration in the inner medulla to the renal artery. The concentrating index was assessed longitudinally over a 17-wk course (3, 5, 7, 9, 13, 17 wk of age). We conclude that the UTE-based DCE method is limited in resolving extreme T2* content caused by the kidney's strong concentrating mechanism. QSM was able to resolve and confirm the source of the blooming effect to be the large positive susceptibility of concentrated Gd. UTE with QSM can complement traditional magnitude UTE and offer a powerful tool to study renal pathophysiology.

Optimization of saturation-recovery dynamic contrast-enhanced MRI acquisition protocol: monte carlo simulation approach demonstrated with gadolinium MR renography.

Dynamic contrast-enhanced (DCE) MRI is widely used for the measurement of tissue perfusion and to assess organ function. MR renography, which is acquired using a DCE sequence, can measure renal perfusion, filtration and concentrating ability. Optimization of the DCE acquisition protocol is important for the minimization of the error propagation from the acquired signals to the estimated parameters, thus improving the precision of the parameters. Critical to the optimization of contrast-enhanced T1 -weighted protocols is the balance of the T1 -shortening effect across the range of gadolinium (Gd) contrast concentration in the tissue of interest. In this study, we demonstrate a Monte Carlo simulation approach for the optimization of DCE MRI, in which a saturation-recovery T1 -weighted gradient echo sequence is simulated and the impact of injected dose (D) and time delay (TD, for saturation recovery) is tested. The results show that high D and/or high TD cause saturation of the peak arterial signals and lead to an overestimation of renal plasma flow (RPF) and glomerular filtration rate (GFR). However, the use of low TD (e.g. 100 ms) and low D leads to similar errors in RPF and GFR, because of the Rician bias in the pre-contrast arterial signals. Our patient study including 22 human subjects compared TD values of 100 and 300 ms after the injection of 4 mL of Gd contrast for MR renography. At TD = 100 ms, we computed an RPF value of 157.2 ± 51.7 mL/min and a GFR of 33.3 ± 11.6 mL/min. These results were all significantly higher than the parameter estimates at TD = 300 ms: RPF = 143.4 ± 48.8 mL/min (p = 0.0006) and GFR = 30.2 ± 11.5 mL/min (p = 0.0015). In conclusion, appropriate optimization of the DCE MRI protocol using simulation can effectively improve the precision and, potentially, the accuracy of the measured parameters. Copyright © 2016 John Wiley & Sons, Ltd.

Susceptibility tensor imaging of the kidney and its microstructural underpinnings.

PURPOSE: The purpose of this study was to determine whether susceptibility tensor imaging (STI) could overcome limitations of current techniques to detect tubules throughout the kidney. METHODS: Normal mouse kidneys (n = 4) were imaged at 9.4T using a three-dimensional gradient multi-echo sequence (55-micron isotropic resolution). Phase images from 12 orientations were obtained to compute the susceptibility tensor. Diffusion tensor imaging (DTI) with 12 encoding directions was compared with STI. Tractography was performed to visualize and track the course of tubules with DTI and STI. Confocal microscopy was used to identify which tubular segments of the nephron were detected by DTI and STI. RESULTS: Diffusion anisotropy was limited to the inner medulla of the kidney. DTI did not find a significant number of coherent tubular tracks in the outer medulla or cortex. With STI, we found strong susceptibility anisotropy and many tracks in the inner and outer medulla and in limited areas of the cortex. CONCLUSION: STI was able to track tubules throughout the kidney, whereas DTI was limited to the inner medulla. STI provides a novel contrast mechanism related to local tubule microstructure and may offer a powerful method to study the nephron.

4D MRI of polycystic kidneys from rapamycin-treated Glis3-deficient mice.

Polycystic kidney disease (PKD) is a life-threatening disease that leads to a grotesque enlargement of the kidney and significant loss of function. Several imaging studies with MRI have demonstrated that cyst size in polycystic kidneys can determine disease severity and progression. In the present study, we found that, although kidney volume and cyst volume decreased with drug treatment, renal function did not improve with treatment. Here, we applied dynamic contrast-enhanced MRI to study PKD in a Glis3 (GLI-similar 3)-deficient mouse model. Cysts from this model have a wide range of sizes and develop at an early age. To capture this crucial stage and assess cysts in detail, we imaged during early development (3-17 weeks) and applied high spatiotemporal resolution MRI (125 × 125 × 125 cubic microns every 7.7 s). A drug treatment with rapamycin (also known as sirolimus) was applied to determine whether disease progression could be halted. The effect and synergy (interaction) of aging and treatment were evaluated using an analysis of variance (ANOVA). Structural measurements, including kidney volume, cyst volume and cyst-to-kidney volume ratio, changed significantly with age. Drug treatment significantly decreased these metrics. Functional measurements of time-to-peak (TTP) mean and TTP variance were determined. TTP mean did not change with age, whereas TTP variance increased with age. Treatment with rapamycin generally did not affect these functional metrics. Synergistic effects of treatment and age were not found for any measurements. Together, the size and volume ratio of cysts decreased with drug treatment, whereas renal function remained the same. The quantification of renal structure and function with MRI can comprehensively assess the pathophysiology of PKD and response to treatment.

Four-dimensional MRI of renal function in the developing mouse.

The major roles of filtration, metabolism and high blood flow make the kidney highly vulnerable to drug-induced toxicity and other renal injuries. A method to follow kidney function is essential for the early screening of toxicity and malformations. In this study, we acquired high spatiotemporal resolution (four dimensional) datasets of normal mice to follow changes in kidney structure and function during development. The data were acquired with dynamic contrast-enhanced MRI (via keyhole imaging) and a cryogenic surface coil, allowing us to obtain a full three-dimensional image (isotropic resolution, 125 microns) every 7.7 s over a 50-min scan. This time course permitted the demonstration of both contrast enhancement and clearance. Functional changes were measured over a 17-week course (at 3, 5, 7, 9, 13 and 17 weeks). The time dimension of the MRI dataset was processed to produce unique image contrasts to segment the four regions of the kidney: cortex (CO), outer stripe (OS) of the outer medulla (OM), inner stripe (IS) of the OM and inner medulla (IM). Local volumes, time-to-peak (TTP) values and decay constants (DC) were measured in each renal region. These metrics increased significantly with age, with the exception of DC values in the IS and OS. These data will serve as a foundation for studies of normal renal physiology and future studies of renal diseases that require early detection and intervention.

Quantitative susceptibility mapping of kidney inflammation and fibrosis in type 1 angiotensin receptor-deficient mice.

Disruption of the regulatory role of the kidneys leads to diverse renal pathologies; one major hallmark is inflammation and fibrosis. Conventional magnitude MRI has been used to study renal pathologies; however, the quantification or even detection of focal lesions caused by inflammation and fibrosis is challenging. We propose that quantitative susceptibility mapping (QSM) may be particularly sensitive for the identification of inflammation and fibrosis. In this study, we applied QSM in a mouse model deficient for angiotensin receptor type 1 (AT1). This model is known for graded pathologies, including focal interstitial fibrosis, cortical inflammation, glomerulocysts and inner medullary hypoplasia. We acquired high-resolution MRI on kidneys from AT1-deficient mice that were perfusion fixed with contrast agent. Two MR sequences were used (three-dimensional spin echo and gradient echo) to produce three image contrasts: T1, T2* (magnitude) and QSM. T1 and T2* (magnitude) images were acquired to segment major renal structures and to provide landmarks for the focal lesions of inflammation and fibrosis in the three-dimensional space. The volumes of major renal structures were measured to determine the relationship of the volumes to the degree of renal abnormalities and magnetic susceptibility values. Focal lesions were segmented from QSM images and were found to be closely associated with the major vessels. Susceptibilities were relatively more paramagnetic in wild-type mice: 1.46 ± 0.36 in the cortex, 2.14 ± 0.94 in the outer medulla and 2.10 ± 2.80 in the inner medulla (10(-2) ppm). Susceptibilities were more diamagnetic in knockout mice: -7.68 ± 4.22 in the cortex, -11.46 ± 2.13 in the outer medulla and -7.57 ± 5.58 in the inner medulla (10(-2) ppm). This result was consistent with the increase in diamagnetic content, e.g. proteins and lipids, associated with inflammation and fibrosis. Focal lesions were validated with conventional histology. QSM was very sensitive in detecting pathology caused by small focal inflammation and fibrosis. QSM offers a new MR contrast mechanism to study this common disease marker in the kidney.

TPL2 kinase activity regulates microglial inflammatory responses and promotes neurodegeneration in tauopathy mice.

Tumor progression locus 2 (TPL2) (MAP3K8) is a central signaling node in the inflammatory response of peripheral immune cells. We find that TPL2 kinase activity modulates microglial cytokine release and is required for microglia-mediated neuron death in vitro. In acute in vivo neuroinflammation settings, TPL2 kinase activity regulates microglia activation states and brain cytokine levels. In a tauopathy model of chronic neurodegeneration, loss of TPL2 kinase activity reduces neuroinflammation and rescues synapse loss, brain volume loss, and behavioral deficits. Single-cell RNA sequencing analysis indicates that protection in the tauopathy model was associated with reductions in activated microglia subpopulations as well as infiltrating peripheral immune cells. Overall, using various models, we find that TPL2 kinase activity can promote multiple harmful consequences of microglial activation in the brain including cytokine release, iNOS (inducible nitric oxide synthase) induction, astrocyte activation, and immune cell infiltration. Consequently, inhibiting TPL2 kinase activity could represent a potential therapeutic strategy in neurodegenerative conditions.

Magnetic resonance histology of age-related nephropathy in the Sprague Dawley rat.

Magnetic resonance histology (MRH) has become a valuable tool in evaluating drug-induced toxicity in preclinical models. However, its application in renal injury has been limited. This study tested the hypothesis that MRH could detect image-based biomarkers of chronic disease, inflammation, or age-related degeneration in the kidney, laying the foundation for more extensive use in evaluating drug toxicity. We examined the entire intact kidney in a spontaneous model of chronic progressive nephropathy. Kidneys from male Sprague Dawley rats were imaged at 8 weeks (n = 4) and 52 weeks (n =4) on a 9.4 T system dedicated to MR microscopy. Several potential contrast mechanisms were explored to optimize the scanning protocols. Full coverage of the entire kidney was achieved with isotropic spatial resolution at 31 microns (voxel volume = 30 pL) using a gradient recalled echo sequence. Isotropic spatial resolution of 15 microns (voxel volume < 4 pL) was achieved in a biopsy core specimen. Qualitative age-related structural changes, such as renal cortical microvasculature, tubular dilation, interstitial fibrosis, and glomerular architecture, were apparent. The nondestructive 3D images allowed measurement of quantitative differences of kidney volume, pelvis volume, main vessel volume, glomerular size, as well as thickness of the cortex, outer medulla, and inner medulla.

Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer's disease mouse models.

Microglia and complement can mediate neurodegeneration in Alzheimer's disease (AD). By integrative multi-omics analysis, here we show that astrocytic and microglial proteins are increased in TauP301S synapse fractions with age and in a C1q-dependent manner. In addition to microglia, we identified that astrocytes contribute substantially to synapse elimination in TauP301S hippocampi. Notably, we found relatively more excitatory synapse marker proteins in astrocytic lysosomes, whereas microglial lysosomes contained more inhibitory synapse material. C1q deletion reduced astrocyte-synapse association and decreased astrocytic and microglial synapses engulfment in TauP301S mice and rescued synapse density. Finally, in an AD mouse model that combines ß-amyloid and Tau pathologies, deletion of the AD risk gene Trem2 impaired microglial phagocytosis of synapses, whereas astrocytes engulfed more inhibitory synapses around plaques. Together, our data reveal that astrocytes contact and eliminate synapses in a C1q-dependent manner and thereby contribute to pathological synapse loss and that astrocytic phagocytosis can compensate for microglial dysfunction.