43 research outputs found
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Differential effects of partial and complete loss of TREM2 on microglial injury response and tauopathy.
Alzheimer's disease (AD), the most common form of dementia, is characterized by the abnormal accumulation of amyloid plaques and hyperphosphorylated tau aggregates, as well as microgliosis. Hemizygous missense variants in Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) are associated with elevated risk for developing late-onset AD. These variants are hypothesized to result in loss of function, mimicking TREM2 haploinsufficiency. However, the consequences of TREM2 haploinsufficiency on tau pathology and microglial function remain unknown. We report the effects of partial and complete loss of TREM2 on microglial function and tau-associated deficits. In vivo imaging revealed that microglia from aged TREM2-haploinsufficient mice show a greater impairment in their injury response compared with microglia from aged TREM2-KO mice. In transgenic mice expressing mutant human tau, TREM2 haploinsufficiency, but not complete loss of TREM2, increased tau pathology. In addition, whereas complete TREM2 deficiency protected against tau-mediated microglial activation and atrophy, TREM2 haploinsufficiency elevated expression of proinflammatory markers and exacerbated atrophy at a late stage of disease. The differential effects of partial and complete loss of TREM2 on microglial function and tau pathology provide important insights into the critical role of TREM2 in AD pathogenesis
Brst Cohomology and Invariants of 4D Gravity in Ashtekar Variables
We discuss the BRST cohomologies of the invariants associated with the
description of classical and quantum gravity in four dimensions, using the
Ashtekar variables. These invariants are constructed from several BRST
cohomology sequences. They provide a systematic and clear characterization of
non-local observables in general relativity with unbroken diffeomorphism
invariance, and could yield further differential invariants for four-manifolds.
The theory includes fluctuations of the vierbein fields, but there exits a
non-trivial phase which can be expressed in terms of Witten's topological
quantum field theory. In this phase, the descent sequences are degenerate, and
the corresponding classical solutions can be identified with the conformally
self-dual sector of Einstein manifolds. The full theory includes fluctuations
which bring the system out of this sector while preserving diffeomorphism
invariance.Comment: 15 page
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Axon-Axon Interactions Regulate Topographic Optic Tract Sorting via CYFIP2-Dependent WAVE Complex Function
The axons of retinal ganglion cells (RGCs) are topographically sorted before they arrive at the optic tectum. This pre-target sorting, typical of axon tracts throughout the brain, is poorly understood. Here, we show that Cytoplasmic FMR1-Interacting Proteins (CYFIPs) fulfil non-redundant functions in RGCs, with CYFIP1 mediating axon growth and CYFIP2 specifically involved in axon sorting. We find that CYFIP2 mediates homotypic and heterotypic contact-triggered fasciculation and repulsion responses between dorsal and ventral axons. CYFIP2 associates with transporting ribonucleoprotein particles in axons and regulates translation. Axon-axon contact stimulates CYFIP2 to move into growth cones where it joins the actin nucleating WAVE regulatory complex (WRC) in the periphery and regulates actin remodeling and filopodial dynamics. CYFIP2’s function in axon sorting is mediated by its binding to the WRC but not its translational regulation. Together, these findings uncover CYFIP2 as a key regulatory link between axon-axon interactions, filopodial dynamics and optic tract sorting.This work was supported by Wellcome Trust Programme Grants ( 085314 , C.E.H.), Wellcome Trust Investigator Award (SIA 100329/Z/12/Z , W.A.H.), European Research Council Advanced Grant ( 322817 , C.E.H.), EMBO Long Term Fellowship ( ALTF849-2013 , J.-M.C.), Cambridge Trust, Croucher Foundation, and Sir Edward Youde Memorial Fund (H.H.W.)
Invariant Regularization of Anomaly-Free Chiral Theories
We present a generalization of the Frolov-Slavnov invariant regularization
scheme for chiral fermion theories in curved spacetimes. local gauge symmetries
of the theory, including local Lorentz invariance. The perturbative scheme
works for arbitrary representations which satisfy the chiral gauge anomaly and
the mixed Lorentz-gauge anomaly cancellation conditions. Anomalous theories on
the other hand manifest themselves by having divergent fermion loops which
remain unregularized by the scheme. Since the invariant scheme is promoted to
also include local Lorentz invariance, spectator fields which do not couple to
gravity cannot be, and are not, introduced. Furthermore, the scheme is truly
chiral (Weyl) in that all fields, including the regulators, are left-handed;
and only the left-handed spin connection is needed. The scheme is, therefore,
well suited for the study of the interaction of matter with all four known
forces in a completely chiral fashion. In contrast with the vectorlike
formulation, the degeneracy between the Adler-Bell-Jackiw current and the
fermion number current in the bare action is preserved by the chiral
regularization scheme.Comment: 28pgs, LaTeX. Typos corrected. Further remarks on singlet current
The Standard Model with gravity couplings
In this paper, we examine the coupling of matter fields to gravity within the
framework of the Standard Model of particle physics. The coupling is described
in terms of Weyl fermions of a definite chirality, and employs only
(anti)self-dual or left-handed spin connection fields. It is known from the
work of Ashtekar and others that such fields can furnish a complete description
of gravity without matter. We show that conditions ensuring the cancellation of
perturbative chiral gauge anomalies are not disturbed. We also explore a global
anomaly associated with the theory, and argue that its removal requires that
the number of fundamental fermions in the theory must be multiples of 16. In
addition, we investigate the behavior of the theory under discrete
transformations P, C and T; and discuss possible violations of these discrete
symmetries, including CPT, in the presence of instantons and the
Adler-Bell-Jackiw anomaly.Comment: Extended, and replaced with LaTex file. 25 Page
AD-linked R47H-TREM2 mutation induces disease-enhancing microglial states via AKT hyperactivation
The hemizygous R47H variant of triggering receptor expressed on myeloid cells 2 (TREM2), a microglia-specific gene in the brain, increases risk for late-onset Alzheimer’s disease (AD). Using transcriptomic analysis of single nuclei from brain tissues of patients with AD carrying the R47H mutation or the common variant (CV)–TREM2, we found that R47H-associated microglial subpopulations had enhanced inflammatory signatures reminiscent of previously identified disease-associated microglia (DAM) and hyperactivation of AKT, one of the signaling pathways downstream of TREM2. We established a tauopathy mouse model with heterozygous knock-in of the human TREM2 with the R47H mutation or CV and found that R47H induced and exacerbated TAU-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had substantial overlaps with R47H microglia in human AD brains, including robust increases in proinflammatory cytokines, activation of AKT signaling, and elevation of a subset of DAM signatures. Pharmacological AKT inhibition with MK-2206 largely reversed the enhanced inflammatory signatures in primary R47H microglia treated with TAU fibrils. In R47H heterozygous tauopathy mice, MK-2206 treatment abolished a tauopathy-dependent microglial subcluster and rescued tauopathy-induced synapse loss. By uncovering disease-enhancing mechanisms of the R47H mutation conserved in human and mouse, our study supports inhibitors of AKT signaling as a microglial modulating strategy to treat AD
Impact of primary kidney disease on the effects of empagliflozin in patients with chronic kidney disease: secondary analyses of the EMPA-KIDNEY trial
Background: The EMPA KIDNEY trial showed that empagliflozin reduced the risk of the primary composite outcome of kidney disease progression or cardiovascular death in patients with chronic kidney disease mainly through slowing progression. We aimed to assess how effects of empagliflozin might differ by primary kidney disease across its broad population. Methods: EMPA-KIDNEY, a randomised, controlled, phase 3 trial, was conducted at 241 centres in eight countries (Canada, China, Germany, Italy, Japan, Malaysia, the UK, and the USA). Patients were eligible if their estimated glomerular filtration rate (eGFR) was 20 to less than 45 mL/min per 1·73 m2, or 45 to less than 90 mL/min per 1·73 m2 with a urinary albumin-to-creatinine ratio (uACR) of 200 mg/g or higher at screening. They were randomly assigned (1:1) to 10 mg oral empagliflozin once daily or matching placebo. Effects on kidney disease progression (defined as a sustained ≥40% eGFR decline from randomisation, end-stage kidney disease, a sustained eGFR below 10 mL/min per 1·73 m2, or death from kidney failure) were assessed using prespecified Cox models, and eGFR slope analyses used shared parameter models. Subgroup comparisons were performed by including relevant interaction terms in models. EMPA-KIDNEY is registered with ClinicalTrials.gov, NCT03594110. Findings: Between May 15, 2019, and April 16, 2021, 6609 participants were randomly assigned and followed up for a median of 2·0 years (IQR 1·5–2·4). Prespecified subgroupings by primary kidney disease included 2057 (31·1%) participants with diabetic kidney disease, 1669 (25·3%) with glomerular disease, 1445 (21·9%) with hypertensive or renovascular disease, and 1438 (21·8%) with other or unknown causes. Kidney disease progression occurred in 384 (11·6%) of 3304 patients in the empagliflozin group and 504 (15·2%) of 3305 patients in the placebo group (hazard ratio 0·71 [95% CI 0·62–0·81]), with no evidence that the relative effect size varied significantly by primary kidney disease (pheterogeneity=0·62). The between-group difference in chronic eGFR slopes (ie, from 2 months to final follow-up) was 1·37 mL/min per 1·73 m2 per year (95% CI 1·16–1·59), representing a 50% (42–58) reduction in the rate of chronic eGFR decline. This relative effect of empagliflozin on chronic eGFR slope was similar in analyses by different primary kidney diseases, including in explorations by type of glomerular disease and diabetes (p values for heterogeneity all >0·1). Interpretation: In a broad range of patients with chronic kidney disease at risk of progression, including a wide range of non-diabetic causes of chronic kidney disease, empagliflozin reduced risk of kidney disease progression. Relative effect sizes were broadly similar irrespective of the cause of primary kidney disease, suggesting that SGLT2 inhibitors should be part of a standard of care to minimise risk of kidney failure in chronic kidney disease. Funding: Boehringer Ingelheim, Eli Lilly, and UK Medical Research Council
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Microglial Sex-Differences in the Context of Alzheimer's Disease
Sex differences have been clinically documented in numerous neurodegenerative diseases, including in Alzheimer’s disease (AD), and yet the reasons for these sex differences are not well understood. Recent studies have found that microglia, the innate immune cells of the central nervous system, are a key cell type involved in AD. Interestingly, this cell type displays sex differences in their expression profiles and function. Could these sex differences in microglia explain the sex differences seen in AD? How can we further probe these differences to better understand disease mechanisms? In Chapter 1 of this dissertation, we broadly set the landscape of sex-differences in AD and focus specifically on the emerging evidence of microglial sex differences in both the healthy and diseased brain. We also support these previous findings through our own preliminary single-nuclei transcriptomic analysis of human AD brain tissues and characterize microglial subpopulations differentially enriched in female versus male samples. Cellular sex differences are largely mediated through sex chromosomes and sex hormones. In Chapter 2, we focus on the sex chromosomes by studying microglial microRNAs (miRNAs) since immune-related miRNAs are highly-enriched on the X chromosome compared to the autosomal chromosomes. In Chapter 2.2, we show that microglial miRNA expression differs in male and female mice and that loss of microglial miRNAs leads to sex-specific changes in the microglial transcriptome and tau pathology. These findings suggest microglial miRNAs influence tau pathogenesis in a sex-specific manner. In Chapter 2.3, we further focus on individual microglial miRNAs by establishing a primary microglia screen to study the effects of highly-expressed microglial miRNAs on phagocytosis of E. coli particles. We found that removal of mature miRNAs in primary microglia reduced their uptake capacity, which was largely reversed by expressing individual miRNAs of the miR-17~92 cluster and its paralog, miR-106a~363 cluster encoded on the X chromosome. Chapter 3 focuses on the sex-specific transcriptomic changes associated with microglia in AD patients with and without the R47H-TREM2 mutation, one of the strongest immune-specific risk factors for late-onset AD. We also utilized a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or the common variant and found R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust transcriptomic sex-differences, increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and enrichment of disease-associated microglia. Finally, in Chapter 4, we conclude on the ways these studies uncovered novel molecular pathways involved in AD pathogenesis through the lens of sex differences, and comment on future lines of investigation with the hope that such studies will lead to potential therapies that can benefit patients of both sexes
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Microglial Sex-Differences in the Context of Alzheimer's Disease
Sex differences have been clinically documented in numerous neurodegenerative diseases, including in Alzheimer’s disease (AD), and yet the reasons for these sex differences are not well understood. Recent studies have found that microglia, the innate immune cells of the central nervous system, are a key cell type involved in AD. Interestingly, this cell type displays sex differences in their expression profiles and function. Could these sex differences in microglia explain the sex differences seen in AD? How can we further probe these differences to better understand disease mechanisms? In Chapter 1 of this dissertation, we broadly set the landscape of sex-differences in AD and focus specifically on the emerging evidence of microglial sex differences in both the healthy and diseased brain. We also support these previous findings through our own preliminary single-nuclei transcriptomic analysis of human AD brain tissues and characterize microglial subpopulations differentially enriched in female versus male samples. Cellular sex differences are largely mediated through sex chromosomes and sex hormones. In Chapter 2, we focus on the sex chromosomes by studying microglial microRNAs (miRNAs) since immune-related miRNAs are highly-enriched on the X chromosome compared to the autosomal chromosomes. In Chapter 2.2, we show that microglial miRNA expression differs in male and female mice and that loss of microglial miRNAs leads to sex-specific changes in the microglial transcriptome and tau pathology. These findings suggest microglial miRNAs influence tau pathogenesis in a sex-specific manner. In Chapter 2.3, we further focus on individual microglial miRNAs by establishing a primary microglia screen to study the effects of highly-expressed microglial miRNAs on phagocytosis of E. coli particles. We found that removal of mature miRNAs in primary microglia reduced their uptake capacity, which was largely reversed by expressing individual miRNAs of the miR-17~92 cluster and its paralog, miR-106a~363 cluster encoded on the X chromosome. Chapter 3 focuses on the sex-specific transcriptomic changes associated with microglia in AD patients with and without the R47H-TREM2 mutation, one of the strongest immune-specific risk factors for late-onset AD. We also utilized a newly-generated tauopathy knock-in mouse model expressing one allele of human TREM2 (hTREM2) with either the R47H mutation or the common variant and found R47H induced and exacerbated tau-mediated spatial memory deficits in female mice. Single-cell transcriptomic analysis of microglia from these mice also revealed transcriptomic changes induced by R47H that had significant overlaps with R47H microglia in human AD brains, including robust transcriptomic sex-differences, increases in proinflammatory cytokines, activation of Syk-Akt-signaling, and enrichment of disease-associated microglia. Finally, in Chapter 4, we conclude on the ways these studies uncovered novel molecular pathways involved in AD pathogenesis through the lens of sex differences, and comment on future lines of investigation with the hope that such studies will lead to potential therapies that can benefit patients of both sexes