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ObjectiveThe neuroanatomical profile of behavioral variant frontotemporal dementia (bvFTD) suggests a common biological etiology of disease despite disparate pathologic causes; we investigated the genetic underpinnings of this selective regional vulnerability to identify new risk factors for bvFTD.MethodsWe used recently developed analytical techniques designed to address the limitations of genome-wide association studies to generate a protein interaction network of 63 bvFTD risk genes. We characterized this network using gene expression data from healthy and diseased human brain tissue, evaluating regional network expression patterns across the lifespan as well as the cell types and biological processes most affected in bvFTD.ResultsWe found that bvFTD network genes show enriched expression across the human lifespan in vulnerable neuronal populations, are implicated in cell signaling, cell cycle, immune function, and development, and are differentially expressed in pathologically confirmed frontotemporal lobar degeneration cases. Five of the genes highlighted by our differential expression analyses, BAIAP2, ERBB3, POU2F2, SMARCA2, and CDC37, appear to be novel bvFTD risk loci.ConclusionsOur findings suggest that the cumulative burden of common genetic variation in an interacting protein network expressed in specific brain regions across the lifespan may influence susceptibility to bvFTD.

Increasing evidence points to a pivotal role of immune processes in the pathogenesis of Alzheimer disease, which is the most prevalent neurodegenerative and dementia-causing disease of our time. Multiple lines of information provided by experimental, epidemiological, neuropathological and genetic studies suggest a pathological role for innate and adaptive immune activation in this disease. Here, we review the cell types and pathological mechanisms involved in disease development as well as the influence of genetics and lifestyle factors. Given the decade-long preclinical stage of Alzheimer disease, these mechanisms and their interactions are driving forces behind the spread and progression of the disease. The identification of treatment opportunities will require a precise understanding of the cells and mechanisms involved as well as a clear definition of their temporal and topographical nature. We will also discuss new therapeutic strategies for targeting neuroinflammation, which are now entering the clinic and showing promise for patients., Competing Interests: Competing interests: A.J.T. serves/served on scientific advisory boards and/or as a consultant with Alnylam, Apellis, and Montis and has a research contract from Visterra. C.Cruchaga has received research support from GSK and EISAI. C.Cruchaga is a member of the scientific advisory board of Circular Genomics and owns stocks. C.Cruchaga is a member of the scientific advisory board of Admit. D.J.B. has a financial interest related to this research. He is a co-inventor on patents held by Mayo Clinic, patent applications licensed to or filed by Unity Biotechnology, and a Unity Biotechnology shareholder. Research in the Baker Laboratory has been reviewed by the Mayo Clinic Conflict of Interest Review Board and is being conducted in compliance with Mayo Clinic Conflict of Interest policies. D.M. serves on the advisory board of Mindimmune, InMed and SynapsDx. He collaborates with Hesperos Inc. C.Cunningham has acted on the advisory board for Exalys Therapeutics and has received a small research grant from IONIS Therapeutics. C.T. has research contracts with Acumen, ADx Neurosciences, AC-Immune, Alamar, Aribio, Axon Neurosciences, Beckman-Coulter, BioConnect, Bioorchestra, Brainstorm Therapeutics, Celgene, Cognition Therapeutics, EIP Pharma, Eisai, Eli Lilly, Fujirebio, Instant Nano Biosensors, Novo Nordisk, Olink, PeopleBio, Quanterix, Roche, Toyama and Vivoryon. She is editor in chief of Alzheimer Research and Therapy, and serves on editorial boards of Molecular Neurodegeneration, Neurology: Neuroimmunology & Neuroinflammation, Medidact Neurologie Springer, and serves on committee to define guidelines for cognitive disturbances and one for acute neurology in the Netherlands. She had consultancy/speaker contracts for Aribio, Biogen, Beckman-Coulter, Cognition Therapeutics, Eli Lilly, Merck, Novo Nordisk, Olink, Roche and Veravas. D.B. has served as a consultant for Biogen. D.R.T. collaborated with Novartis Pharma AG (Switzerland) and GE-Healthcare (UK). G.D. holds two patents on immunomodulatory treatments in Alzheimer disease and tauopathies, has served on the scientific advisory board of Coya Therapeutics, and received lecturer fees from Eisai and research support from Institut Roche. H.Z. has served at scientific advisory boards and/or as a consultant for Abbvie, Acumen, Alector, Alzinova, ALZPath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave, has given lectures sponsored by Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD, and is a co-founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program (outside submitted work). K.A. is co-founder and member of the SAB for Willow Neuroscience, Inc. L.A. has been consultant for Intelgenx. M.C. is a member of the scientific advisory board of Vigil, NGMBio, Cell Signalling Technology, Cartesian, and Halyard; receives research support from Ono Pharmaceutical; and has patents pending on LILRB4 and TREM2. O.B. co-founded and is on the scientific advisory board of Glial Therapeutics and GliaX. O.B. collaborates with GSK and Regulus Therapeutics and received research funding from Sanofi, GSK, honoraria for lectures, and consultancy for UCB, Camp4, Ono Pharma USA, and General Biophysics. R.Mancuso has or had scientific collaborations with Alector, Nodthera, Alchemab and Roche, and has been consultant for Sanofi. R.R. is a full time employee at Third Rock Ventures, a firm that creates new biotech companies, including those addressing neurodegeneration. He is also Co-Founder and holds equity at Abata Therapeutics. S.A.L. maintains a financial interest in AstronauTx Ltd. and Synapticure, and sits on the SAB of the Global BioAccess Fund. S.H. has received speaking fees from Eisai Ltd, Novo Nordisk, and Alnylam, receives research funding from Eisai Ltd., and has a collaborative project with Ionis Ltd. W.M.vdF. receives or has received funding by ZonMW, NWO, EU-JPND, EU-IHI, Alzheimer Nederland, Hersenstichting CardioVascular Onderzoek Nederland, Health Holland, Topsector Life Sciences & Health, stichting Dioraphte, Gieskes-Strijbis fonds, stichting Equilibrio, Edwin Bouw fonds, Pasman stichting, stichting Alzheimer & Neuropsychiatrie Foundation, Philips, Biogen MA Inc., Novartis-NL, Life-MI, AVID, Roche BV, Eli Lilly-NL, Fujifilm, Eisai, Combinostics. W.M.vdF. has been an invited speaker at Biogen MA Inc., Danone, Eisai, WebMD Neurology (Medscape), NovoNordisk, Springer Healthcare, and European Brain Council; consultant to Oxford Health Policy Forum CIC, Roche, Biogen MA Inc., and Eisai; all funding paid to her institution. W.M.vdF. participated in advisory boards of Biogen MA Inc., Roche, and Eli Lilly. W.M.vdF. is a member of the steering committee of EVOKE/EVOKE+ (NovoNordisk); all funding paid to her institution. W.M.vdF. is a member of the steering committee of PAVE and Think Brain Health. W.M.vdF. was an Associate Editor of Alzheimer’s Research & Therapy in 2020/2021 and is an Associate Editor at Brain. P.E. was funded by the Medical Research Council and now by Higher Education Funding Council for England (HEFCE). He has also received grants from Alzheimer’s Research, UK, Alzheimer’s Drug Discovery Foundation, Alzheimer’s Society, UK, Medical Research Council, Alzheimer’s Association US, Van-Geest foundation, and European Union grants. P.E. is a consultant to Roche, Pfizer, and Novo Nordisk. He has received educational and research grants from GE Healthcare, Novo Nordisk, Piramal Life Science/Life Molecular Imaging, Avid Radiopharmaceuticals and Eli Lilly. He was a member of the Scientific Advisory Board at Novo Nordisk. All other authors have no conflicts of interest to declare., (© 2024. Springer Nature Limited.)

Lysosomal dysfunction is causally linked to neurodegeneration in many lysosomal storage disorders (LSDs) and is associated with various age-related neurodegenerative diseases 1,2 , but there is limited understanding of the mechanisms by which altered lysosomal function leads to changes in gene expression that drive pathogenic cellular phenotypes. To investigate this question, we performed systematic imaging, transcriptomic, and epigenetic studies of major brain cell types in Sgsh null (KO) mice, a preclinical mouse model for Sanfilippo syndrome (Mucopolysaccharidosis Type IIIA, MPS-IIIA) 3,4 . MPS-IIIA is a neurodegenerative LSD caused by homozygous loss-of-function (LoF) mutations in SGSH which results in severe early-onset developmental, behavioral, and neurocognitive impairment 5-15 . Electron microscopy, immunohistochemistry, and single-nucleus RNA-sequencing analysis revealed microglia as the cell type exhibiting the most dramatic phenotypic alterations in Sgsh KO mice. Further temporal analysis of microglia gene expression showed dysregulation of genes associated with lysosomal function and immune signaling pathways beginning early in the course of the disease. Sgsh deficiency similarly resulted in increases in open chromatin and histone acetylation at thousands of putative microglia-specific enhancers associated with upregulated genes but had much less impact on the epigenetic landscapes of neurons or oligodendrocytes. We provide evidence for dominant and context-dependent roles of members of the MITF/TFE family as major drivers of microglia-specific epigenetic and transcriptional changes resulting from lysosomal stress that are dependent on collaborative interactions with PU.1/ETS and C/EBP transcription factors. Lastly, we show that features of the transcriptomic and epigenetic alterations observed in murine Sgsh deficiency are also observed in microglia derived from mouse models of age-related neurodegeneration and in human Alzheimer's disease patients, revealing common and disease-specific transcriptional mechanisms associated with disease-associated microglia phenotypes.

Triggering receptor expressed on myeloid cells 2 (TREM2) is involved in neuroinflammation and HIV-associated neurocognitive impairment (NCI). People with HIV (PWH) using cannabis exhibit lower inflammation and neurological disorders. We hypothesized that TREM2 dysfunction mediates HIV neuropathogenesis and can be reversed by cannabinoids. EcoHIV-infected wildtype (WT) and TREM2 R47H mutant mice were used to study HIV's impact on TREM2 and behavior. TREM2 and related gene expressions were examined in monocyte-derived macrophages (MDMs) from PWH ( n = 42) and people without HIV (PWoH; n = 19) with varying cannabis use via RNA sequencing and qPCR. Differences in membrane-bound and soluble TREM2 (sTREM2) were evaluated using immunocytochemistry (ICC) and ELISA. EcoHIV increased immature and C-terminal fragment forms of TREM2 in WT mice but not in TREM2 R47H mice, with increased IBA1 protein in TREM2 R47H hippocampi, correlating with worse memory test performance. TREM2 mRNA levels increased with age in PWoH but not in PWH. Cannabidiol (CBD) treatment increased TREM2 mRNA alone and with IL1β. RNA-seq showed the upregulation of TREM2-related transcripts in cannabis-using PWH compared to naïve controls. IL1β increased sTREM2 and reduced membrane-bound TREM2, effects partially reversed by CBD. These findings suggest HIV affects TREM2 expression modulated by cannabis and CBD, offering insights for therapeutic strategies.

Gene expression is influenced by chromatin architecture via controlled access of regulatory factors to DNA. To better understand gene regulation in the human dorsal root ganglion (hDRG) we used bulk and spatial transposase-accessible chromatin technology followed by sequencing (ATAC-seq). Using bulk ATAC-seq, we detected that in females diverse differentially accessible chromatin regions (DARs) mapped to the X chromosome and in males to autosomal genes. EGR1/3 and SP1/4 transcription factor binding motifs were abundant within DARs in females, and JUN, FOS and other AP-1 factors in males. To dissect the open chromatin profile in hDRG neurons, we used spatial ATAC-seq. The neuron cluster showed higher chromatin accessibility in GABAergic, glutamatergic, and interferon-related genes in females, and in Ca 2+ - signaling-related genes in males. Sex differences in transcription factor binding sites in neuron-proximal barcodes were consistent with the trends observed in bulk ATAC-seq data. We validated that EGR1 expression is biased to female hDRG compared to male. Strikingly, XIST , the long-noncoding RNA responsible for X inactivation, hybridization signal was found to be highly dispersed in the female neuronal but not non-neuronal nuclei suggesting weak X inactivation in female hDRG neurons. Our findings point to baseline epigenomic sex differences in the hDRG that likely underlie divergent transcriptional responses that determine mechanistic sex differences in pain., Competing Interests: Conflict of Interest Statement The authors declare no financial conflicts of interest related to this work.

The catecholamine neurotransmitter dopamine is classically known for regulation of central nervous system (CNS) functions such as reward, movement, and cognition. Increasing evidence also indicates that dopamine regulates critical functions in peripheral organs and is an important immunoregulatory factor. We have previously shown that dopamine increases NF-κB activity, inflammasome activation, and the production of inflammatory cytokines such as IL-1β in human macrophages. As myeloid lineage cells are central to the initiation and resolution of acute inflammatory responses, dopamine-mediated dysregulation of these functions could both impair the innate immune response and exacerbate chronic inflammation. However, the exact pathways by which dopamine drives myeloid inflammation are not well defined, and studies in both rodent and human systems indicate that dopamine can impact the production of inflammatory mediators through both D1-like dopamine receptors (DRD1, DRD5) and D2-like dopamine receptors (DRD2, DRD3, and DRD4). Therefore, we hypothesized that dopamine-mediated production of IL-1β in myeloid cells is regulated by the ratio of different dopamine receptors that are activated. Our data in primary human monocyte-derived macrophages (hMDM) indicate that DRD1 expression is necessary for dopamine-mediated increases in IL-1β, and that changes in the expression of DRD2 and other dopamine receptors can alter the magnitude of the dopamine-mediated increase in IL-1β. Mature hMDM have a high D1-like to D2-like receptor ratio, which is different relative to monocytes and peripheral blood mononuclear cells (PBMCs). We further confirm in human microglia cell lines that a high ratio of D1-like to D2-like receptors promotes dopamine-induced increases in IL-1β gene and protein expression using pharmacological inhibition or overexpression of dopamine receptors. RNA-sequencing of dopamine-treated microglia shows that genes encoding functions in IL-1β signaling pathways, microglia activation, and neurotransmission increased with dopamine treatment. Finally, using HIV as an example of a chronic inflammatory disease that is substantively worsened by comorbid substance use disorders (SUDs) that impact dopaminergic signaling, we show increased effects of dopamine on inflammasome activation and IL-1β in the presence of HIV in both human macrophages and microglia. These data suggest that use of addictive substances and dopamine-modulating therapeutics could dysregulate the innate inflammatory response and exacerbate chronic neuroimmunological conditions like HIV. Thus, a detailed understanding of dopamine-mediated changes in inflammation, in particular pathways regulating IL-1β, will be critical to effectively tailor medication regimens.

Genomic mosaicism describes the phenomenon where some but not all cells within a tissue harbor unique genetic mutations. Traditionally, research focused on the impact of genomic mosaicism on clinical phenotype-motivated by its involvement in cancers and overgrowth syndromes. More recently, we increasingly shifted towards the plethora of neutral mosaic variants that can act as recorders of cellular lineage and environmental exposures. Here, we summarize the current state of the field of genomic mosaicism research with a special emphasis on our current understanding of this phenomenon in brain development and homeostasis. Although the field of genomic mosaicism has a rich history, technological advances in the last decade have changed our approaches and greatly improved our knowledge. We will provide current definitions and an overview of contemporary detection approaches for genomic mosaicism. Finally, we will discuss the impact and utility of genomic mosaicism., (© 2023. The Author(s).)

Debate remains around the anatomical origins of specific brain cell subtypes and lineage relationships within the human forebrain 1-7 . Thus, direct observation in the mature human brain is critical for a complete understanding of its structural organization and cellular origins. Here we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific mosaic variant barcode analysis. From four hemispheres and two different human neurotypical donors, we identified 287 and 780 mosaic variants, respectively, that were used to deconvolve clonal dynamics. Clonal spread and allele fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted than resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome transcriptome analysis at both a cell-type-specific and a single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1 + inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of mosaic variants across 17 locations within one parietal lobe reveals that restriction of clonal spread in the anterior-posterior axis precedes restriction in the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus, cell-type-resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells 1 . However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aβ induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease., (© 2024. The Author(s).)

The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response-potentially beneficial in the cortex and harmful in the striatum-in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes., (© 2023. The Author(s).)

Depression is a common and disabling comorbidity in rheumatoid arthritis that not only decreases the likelihood of remission and treatment adherence but also increases the risk of disability and mortality in patients with rheumatoid arthritis. Compelling data that link immune mechanisms to major depressive disorder indicate possible common mechanisms that drive the pathology of the two conditions. Preclinical evidence suggests that pro-inflammatory cytokines, which are prevalent in rheumatoid arthritis, have various effects on monoaminergic neurotransmission, neurotrophic factors and measures of synaptic plasticity. Neuroimaging studies provide insight into the consequences of inflammation on the brain (for example, on neural connectivity), and clinical trial data highlight the beneficial effects of immune modulation on comorbid depression. Major depressive disorder occurs more frequently in patients with rheumatoid arthritis than in the general population, and major depressive disorder also increases the risk of a future diagnosis of rheumatoid arthritis, further highlighting the link between rheumatoid arthritis and major depressive disorder. This Review focuses on interactions between peripheral and central immunobiological mechanisms in the context of both rheumatoid arthritis and major depressive disorder. Understanding these mechanisms will provide a basis for future therapeutic development, not least in depression., (© 2023. Springer Nature Limited.)

People living with HIV are affected by the chronic consequences of neurocognitive impairment (NCI) despite antiretroviral therapies that suppress viral replication, improve health and extend life. Furthermore, viral suppression does not eliminate the virus, and remaining infected cells may continue to produce viral proteins that trigger neurodegeneration. Comorbidities such as diabetes mellitus are likely to contribute substantially to CNS injury in people living with HIV, and some components of antiretroviral therapy exert undesirable side effects on the nervous system. No treatment for HIV-associated NCI has been approved by the European Medicines Agency or the US Food and Drug Administration. Historically, roadblocks to developing effective treatments have included a limited understanding of the pathophysiology of HIV-associated NCI and heterogeneity in its clinical manifestations. This heterogeneity might reflect multiple underlying causes that differ among individuals, rather than a single unifying neuropathogenesis. Despite these complexities, accelerating discoveries in HIV neuropathogenesis are yielding potentially druggable targets, including excessive immune activation, metabolic alterations culminating in mitochondrial dysfunction, dysregulation of metal ion homeostasis and lysosomal function, and microbiome alterations. In addition to drug treatments, we also highlight the importance of non-pharmacological interventions. By revisiting mechanisms implicated in NCI and potential interventions addressing these mechanisms, we hope to supply reasons for optimism in people living with HIV affected by NCI and their care providers., (© 2023. Springer Nature Limited.)

Debate remains around anatomic origins of specific brain cell subtypes and lineage relationships within the human forebrain. Thus, direct observation in the mature human brain is critical for a complete understanding of the structural organization and cellular origins. Here, we utilize brain mosaic variation within specific cell types as distinct indicators for clonal dynamics, denoted as cell-type-specific Mosaic Variant Barcode Analysis. From four hemispheres from two different human neurotypical donors, we identified 287 and 780 mosaic variants (MVs), respectively that were used to deconvolve clonal dynamics. Clonal spread and allelic fractions within the brain reveal that local hippocampal excitatory neurons are more lineage-restricted compared with resident neocortical excitatory neurons or resident basal ganglia GABAergic inhibitory neurons. Furthermore, simultaneous genome-transcriptome analysis at both a cell-type-specific and single-cell level suggests a dorsal neocortical origin for a subgroup of DLX1 + inhibitory neurons that disperse radially from an origin shared with excitatory neurons. Finally, the distribution of MVs across 17 locations within one parietal lobe reveals restrictions of clonal spread in the anterior-posterior axis precedes that of the dorsal-ventral axis for both excitatory and inhibitory neurons. Thus cell-type resolved somatic mosaicism can uncover lineage relationships governing the development of the human forebrain., Competing Interests: Competing interests K.K. is a senior scientist at Bioskryb Genomics Inc. All other authors declare no competing interests.

The nuclear receptor co-repressor (NCoR) complex mediates transcriptional repression dependent on histone deacetylation by histone deacetylase 3 (HDAC3) as a component of the complex. Unexpectedly, we found that signaling by the receptor activator of nuclear factor κB (RANK) converts the NCoR/HDAC3 co-repressor complex to a co-activator of AP-1 and NF-κB target genes that are required for mouse osteoclast differentiation. Accordingly, the dominant function of NCoR/HDAC3 complexes in response to RANK signaling is to activate, rather than repress, gene expression. Mechanistically, RANK signaling promotes RNA-dependent interaction of the transcriptional co-activator PGC1β with the NCoR/HDAC3 complex, resulting in the activation of PGC1β and inhibition of HDAC3 activity for acetylated histone H3. Non-coding RNAs Dancr and Rnu12, which are associated with altered human bone homeostasis, promote NCoR/HDAC3 complex assembly and are necessary for RANKL-induced osteoclast differentiation in vitro. These findings may be prototypic for signal-dependent functions of NCoR in other biological contexts., Competing Interests: Declaration of interests C.K.G. is a co-founder, equity holder, and member of the Scientific Advisory Board of Asteroid Therapeutics. J.T.K. is on the Molecular Cell advisory board., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Microglia phenotypes are highly regulated by the brain environment, but the transcriptional networks that specify the maturation of human microglia are poorly understood. Here, we characterized stage-specific transcriptomes and epigenetic landscapes of fetal and postnatal human microglia and acquired corresponding data in induced pluripotent stem cell (iPSC)-derived microglia, in cerebral organoids, and following engraftment into humanized mice. Parallel development of computational approaches that considered transcription factor (TF) co-occurrence and enhancer activity allowed prediction of shared and state-specific gene regulatory networks associated with fetal and postnatal microglia. Additionally, many features of the human fetal-to-postnatal transition were recapitulated in a time-dependent manner following the engraftment of iPSC cells into humanized mice. These data and accompanying computational approaches will facilitate further efforts to elucidate mechanisms by which human microglia acquire stage- and disease-specific phenotypes., Competing Interests: Declaration of interests M.B.-J. is a co-inventor of patent application WO/2018/160496, related to the differentiation of pluripotent stem cells into microglia and co-founder of NovoGlia, Inc., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Microglia are specialized brain-resident macrophages that play crucial roles in brain development, homeostasis, and disease. However, until now, the ability to model interactions between the human brain environment and microglia has been severely limited. To overcome these limitations, we developed an in vivo xenotransplantation approach that allows us to study functionally mature human microglia (hMGs) that operate within a physiologically relevant, vascularized immunocompetent human brain organoid (iHBO) model. Our data show that organoid-resident hMGs gain human-specific transcriptomic signatures that closely resemble their in vivo counterparts. In vivo two-photon imaging reveals that hMGs actively engage in surveilling the human brain environment, react to local injuries, and respond to systemic inflammatory cues. Finally, we demonstrate that the transplanted iHBOs developed here offer the unprecedented opportunity to study functional human microglia phenotypes in health and disease and provide experimental evidence for a brain-environment-induced immune response in a patient-specific model of autism with macrocephaly., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microglia are critical regulators of brain development that engulf synaptic proteins during postnatal synapse remodeling. However, the mechanisms through which microglia sense the brain environment are not well defined. Here, we characterized the regulatory program downstream of interleukin-33 (IL-33), a cytokine that promotes microglial synapse remodeling. Exposing the developing brain to a supraphysiological dose of IL-33 altered the microglial enhancer landscape and increased binding of stimulus-dependent transcription factors including AP-1/FOS. This induced a gene expression program enriched for the expression of pattern recognition receptors, including the scavenger receptor MARCO. CNS-specific deletion of IL-33 led to increased excitatory/inhibitory synaptic balance, spontaneous absence-like epileptiform activity in juvenile mice, and increased seizure susceptibility in response to chemoconvulsants. We found that MARCO promoted synapse engulfment, and Marco-deficient animals had excess thalamic excitatory synapses and increased seizure susceptibility. Taken together, these data define coordinated epigenetic and functional changes in microglia and uncover pattern recognition receptors as potential regulators of postnatal synaptic refinement., (© 2022 Han et al.)

In addition to tau and Aβ pathologies, inflammation plays an important role in Alzheimer's disease (AD). Variants in APOE and TREM2 increase AD risk. ApoE4 exacerbates tau-linked neurodegeneration and inflammation in P301S tau mice and removal of microglia blocks tau-dependent neurodegeneration. Microglia adopt a heterogeneous population of transcriptomic states in response to pathology, at least some of which are dependent on TREM2. Previously, we reported that knockout (KO) of TREM2 attenuated neurodegeneration in P301S mice that express mouse Apoe. Because of the possible common pathway of ApoE and TREM2 in AD, we tested whether TREM2 KO (T2KO) would block neurodegeneration in P301S Tau mice expressing ApoE4 (TE4), similar to that observed with microglial depletion. Surprisingly, we observed exacerbated neurodegeneration and tau pathology in TE4-T2KO versus TE4 mice, despite decreased TREM2-dependent microgliosis. Our results suggest that tau pathology-dependent microgliosis, that is, TREM2-independent microgliosis, facilitates tau-mediated neurodegeneration in the presence of ApoE4., Competing Interests: Declaration of interests D.M.H. is as an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies. D.M.H. and J.D.U. are inventors on a submitted patent on TREM2 antibodies. D.M.H. co-founded and is on the scientific advisory board of C2N Diagnostics. D.M.H. is on the scientific advisory board of Denali, Genentech (South San Francisco, CA), and Cajal Neuroscience and consults for Alector. D.M.H. is on the advisory board for Neuron., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Cognitive impairment in individuals infected with HIV is highly prevalent despite life-long antiretroviral therapy. A growing line of evidence suggests that the human brain serves as a sanctuary for HIV persistence. Microglia, the innate immune cells of the brain parenchyma, may serve as a reservoir for HIV and drive the pathogenesis of HIV-associated neurocognitive disorders. Here, we highlight recent advances in understanding microglia diversity in HIV regarding their epigenome, transcriptome, and function., Competing Interests: Conflict of interest statement Noe declared., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD., Competing Interests: Declaration of interests F.H.G. is an advisory board member of Cell Stem Cell., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a movement disorder characterized by neuroinflammation, α-synuclein pathology, and neurodegeneration. Most cases of PD are non-hereditary, suggesting a strong role for environmental factors, and it has been speculated that disease may originate in peripheral tissues such as the gastrointestinal (GI) tract before affecting the brain. The gut microbiome is altered in PD and may impact motor and GI symptoms as indicated by animal studies, although mechanisms of gut-brain interactions remain incompletely defined. Intestinal bacteria ferment dietary fibers into short-chain fatty acids, with fecal levels of these molecules differing between PD and healthy controls and in mouse models. Among other effects, dietary microbial metabolites can modulate activation of microglia, brain-resident immune cells implicated in PD. We therefore investigated whether a fiber-rich diet influences microglial function in α-synuclein overexpressing (ASO) mice, a preclinical model with PD-like symptoms and pathology. Feeding a prebiotic high-fiber diet attenuates motor deficits and reduces α-synuclein aggregation in the substantia nigra of mice. Concomitantly, the gut microbiome of ASO mice adopts a profile correlated with health upon prebiotic treatment, which also reduces microglial activation. Single-cell RNA-seq analysis of microglia from the substantia nigra and striatum uncovers increased pro-inflammatory signaling and reduced homeostatic responses in ASO mice compared to wild-type counterparts on standard diets. However, prebiotic feeding reverses pathogenic microglial states in ASO mice and promotes expansion of protective disease-associated macrophage (DAM) subsets of microglia. Notably, depletion of microglia using a CSF1R inhibitor eliminates the beneficial effects of prebiotics by restoring motor deficits to ASO mice despite feeding a prebiotic diet. These studies uncover a novel microglia-dependent interaction between diet and motor symptoms in mice, findings that may have implications for neuroinflammation and PD., Competing Interests: RA, JS, JB, TT, MZ, JB, TK, SC, LM, GH, JK, MT, RK, VG, CG No competing interests declared, TC, AK, BH has equity in RiteCarbs, a company developing prebiotic diets for Parkinson's disease, SM has equity in Axial Therapeutics, a company developing gut-restricted drugs for Parkinson's disease, (© 2022, Abdel-Haq et al.)

As the CNS-resident macrophages and member of the myeloid lineage, microglia fulfill manifold functions important for brain development and homeostasis. In the context of neurodegenerative diseases, they have been implicated in degenerative and regenerative processes. The discovery of distinct activation patterns, including increased phagocytosis, indicated a damaging role of myeloid cells in multiple system atrophy (MSA), a devastating, rapidly progressing atypical parkinsonian disorder. Here, we analyzed the gene expression profile of microglia in a mouse model of MSA ( MBP29-h α -syn ) and identified a disease-associated expression profile and upregulation of the colony-stimulating factor 1 ( Csf1 ). Thus, we hypothesized that CSF1 receptor-mediated depletion of myeloid cells using PLX5622 modifies the disease progression and neuropathological phenotype in this mouse model. Intriguingly, sex-balanced analysis of myeloid cell depletion in MBP29-h α -syn mice revealed a two-faced outcome comprising an improved survival rate accompanied by a delayed onset of neurological symptoms in contrast to severely impaired motor functions. Furthermore, PLX5622 reversed gene expression profiles related to myeloid cell activation but reduced gene expression associated with transsynaptic signaling and signal release. While transcriptional changes were accompanied by a reduction of dopaminergic neurons in the SNpc, striatal neuritic density was increased upon myeloid cell depletion in MBP29-h α -syn mice. Together, our findings provide insight into the complex, two-faced role of myeloid cells in the context of MSA emphasizing the importance to carefully balance the beneficial and adverse effects of CSF1R inhibition in different models of neurodegenerative disorders before its clinical translation. SIGNIFICANCE STATEMENT Myeloid cells have been implicated as detrimental in the disease pathogenesis of multiple system atrophy. However, long-term CSF1R-dependent depletion of these cells in a mouse model of multiple system atrophy demonstrates a two-faced effect involving an improved survival associated with a delayed onset of disease and reduced inflammation which was contrasted by severely impaired motor functions, synaptic signaling, and neuronal circuitries. Thus, this study unraveled a complex role of myeloid cells in multiple system atrophy, which indicates important functions beyond the previously described disease-associated, destructive phenotype and emphasized the need of further investigation to carefully and individually fine-tune immunologic processes in different neurodegenerative diseases., (Copyright © 2022 the authors.)

The drivers of sporadic Alzheimer's disease (AD) remain incompletely understood. Utilizing directly converted induced neurons (iNs) from AD-patient-derived fibroblasts, we identified a metabolic switch to aerobic glycolysis in AD iNs. Pathological isoform switching of the glycolytic enzyme pyruvate kinase M (PKM) toward the cancer-associated PKM2 isoform conferred metabolic and transcriptional changes in AD iNs. These alterations occurred via PKM2's lack of metabolic activity and via nuclear translocation and association with STAT3 and HIF1α to promote neuronal fate loss and vulnerability. Chemical modulation of PKM2 prevented nuclear translocation, restored a mature neuronal metabolism, reversed AD-specific gene expression changes, and re-activated neuronal resilience against cell death., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The structure of the human neocortex underlies species-specific traits and reflects intricate developmental programs. Here we sought to reconstruct processes that occur during early development by sampling adult human tissues. We analysed neocortical clones in a post-mortem human brain through a comprehensive assessment of brain somatic mosaicism, acting as neutral lineage recorders 1,2 . We combined the sampling of 25 distinct anatomic locations with deep whole-genome sequencing in a neurotypical deceased individual and confirmed results with 5 samples collected from each of three additional donors. We identified 259 bona fide mosaic variants from the index case, then deconvolved distinct geographical, cell-type and clade organizations across the brain and other organs. We found that clones derived after the accumulation of 90-200 progenitors in the cerebral cortex tended to respect the midline axis, well before the anterior-posterior or ventral-dorsal axes, representing a secondary hierarchy following the overall patterning of forebrain and hindbrain domains. Clones across neocortically derived cells were consistent with a dual origin from both dorsal and ventral cellular populations, similar to rodents, whereas the microglia lineage appeared distinct from other resident brain cells. Our data provide a comprehensive analysis of brain somatic mosaicism across the neocortex and demonstrate cellular origins and progenitor distribution patterns within the human brain., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Sporadic Alzheimer's disease (AD) exclusively affects elderly people. Using direct conversion of AD patient fibroblasts into induced neurons (iNs), we generated an age-equivalent neuronal model. AD patient-derived iNs exhibit strong neuronal transcriptome signatures characterized by downregulation of mature neuronal properties and upregulation of immature and progenitor-like signaling pathways. Mapping iNs to longitudinal neuronal differentiation trajectory data demonstrated that AD iNs reflect a hypo-mature neuronal identity characterized by markers of stress, cell cycle, and de-differentiation. Epigenetic landscape profiling revealed an underlying aberrant neuronal state that shares similarities with malignant transformation and age-dependent epigenetic erosion. To probe for the involvement of aging, we generated rejuvenated iPSC-derived neurons that showed no significant disease-related transcriptome signatures, a feature that is consistent with epigenetic clock and brain ontogenesis mapping, which indicate that fibroblast-derived iNs more closely reflect old adult brain stages. Our findings identify AD-related neuronal changes as age-dependent cellular programs that impair neuronal identity., Competing Interests: Declaration of interests F.H.G. is an advisory board member of Cell Stem Cell., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The contribution of chronic peripheral inflammation to the pathogenesis of neurodegenerative diseases is an outstanding question. Sustained activation of the peripheral innate and adaptive immune systems occurs in the context of a broad array of disorders ranging from chronic infectious diseases to autoimmune and metabolic diseases. In addition, progressive systemic inflammation is increasingly recognized during aging. Peripheral immune cells could potentially modulate the cellular brain environment via the secretion of soluble molecules. There is an ongoing debate whether peripheral immune cells have the potential to migrate into the brain under certain permissive circumstances. In this perspective, we discuss the possible contribution of chronic peripheral inflammation to the pathogenesis of age-related neurodegenerative diseases with a focus on microglia, the resident immune cells of the brain parenchyma., Competing Interests: None

Neurons are the longest-lived cells in our bodies and lack DNA replication, which makes them reliant on a limited repertoire of DNA repair mechanisms to maintain genome fidelity. These repair mechanisms decline with age, but we have limited knowledge of how genome instability emerges and what strategies neurons and other long-lived cells may have evolved to protect their genomes over the human life span. A targeted sequencing approach in human embryonic stem cell-induced neurons shows that, in neurons, DNA repair is enriched at well-defined hotspots that protect essential genes. These hotspots are enriched with histone H2A isoforms and RNA binding proteins and are associated with evolutionarily conserved elements of the human genome. These findings provide a basis for understanding genome integrity as it relates to aging and disease in the nervous system., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

We present a nuclei isolation protocol for genomic and epigenomic interrogation of multiple cell type populations in the human and rodent brain. The nuclei isolation protocol allows cell type-specific profiling of neurons, microglia, oligodendrocytes, and astrocytes, being compatible with fresh and frozen samples obtained from either resected or postmortem brain tissue. This 2-day procedure consists of tissue homogenization with fixation, nuclei extraction, and antibody staining followed by fluorescence-activated nuclei sorting (FANS) and does not require specialized skillsets. Cell type-specific nuclei populations can be used for downstream omic-scale sequencing applications with an emphasis on epigenomic interrogation such as histone modifications, transcription factor binding, chromatin accessibility, and chromosome architecture. The nuclei isolation protocol enables translational examination of archived healthy and diseased brain specimens through utilization of existing medical biorepositories.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by erosive polyarthritis. Beyond joint pathology, RA is associated with neuropsychiatric comorbidity including depression, anxiety, and an increased risk to develop neurodegenerative diseases in later life. Studies investigating the central nervous system (CNS) in preclinical models of RA have leveraged the understanding of the intimate crosstalk between peripheral and central immune responses. This mini review summarizes the current knowledge of CNS comorbidity in RA patients and known underlying cellular mechanisms. We focus on the differential regulation of CNS myeloid and glial cells in different mouse models of RA reflecting different patterns of peripheral immune activation. Moreover, we address CNS responses to anti-inflammatory treatment in human RA patients and mice. Finally, to illustrate the bidirectional communication between the CNS and chronic peripheral inflammation, we present the current knowledge about the impact of the CNS on arthritis. A comprehensive understanding of the crosstalk between the CNS and chronic peripheral inflammation will help to identify RA patients at risk of developing CNS comorbidity, setting the path for future therapeutic approaches in both RA and neuropsychiatric diseases., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors, PS., (Copyright © 2020 Süß, Rothe, Hoffmann, Schlachetzki and Winkler.)

Background: Anterior spinal cord herniation (aSCH) is a rare cause of myelopathy which may present as pure motor syndrome and mimic other degenerative diseases of the spinal cord. In slowly progressive cases, diagnosis may be impeded by equivocal imaging results and mistaken for evolving upper motor neuron disease. As early imaging studies are lacking, we aimed to provide a detailed description of imaging and neurophysiology findings in a patient with aSCH, focusing on the early symptomatic stages., Case Presentation: We here present the case of a 51-year old male patient with an episode of pain in the right trunk and a normal spinal MRI. After a symptom-free interval of 8 years, spasticity and paresis evolved in the right leg. There was subtle ventral displacement and posterior indentation of the thoracic spinal cord on MRI which, in retrospect, was missed as an early sign of aSCH. After another 3 years, symptoms spread to the left leg and a sensory deficit of the trunk became evident. Follow-up MRI now clearly showed an aSCH. Neurosurgical intervention consisted of remobilization of the herniated spinal cord and patch closure of the dura defect. Over the following years, motor and sensory symptoms partially improved., Conclusions: The history of this patient with aSCH illustrates the importance of careful longitudinal clinical follow-up with repeated imaging studies in progressive upper motor neuron syndromes. Specific attention should be paid to a history of truncal pain and to MRI findings of a ventrally displaced spinal cord. Neurosurgical intervention may halt the progression of herniation.

The human brain is affected by cellular aging. Neurons are primarily generated during embryogenesis and early life with a limited capacity for renewal and replacement, making them some of the oldest cells in the human body. Our present understanding of neurodegenerative diseases points towards advanced neuronal age as a prerequisite for the development of these disorders. While significant progress has been made in understanding the relationship between aging and neurological disease, it will be essential to delve further into the molecular mechanisms of neuronal aging in order to develop therapeutic interventions targeting age-related brain dysfunction. In this mini review, we highlight recent findings on the relationship between the aging of nuclear structures and changes in the epigenetic landscape during neuronal aging and disease., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Systemic immune dysregulation contributes to the development of neuropsychiatric and neurodegenerative diseases. The precise effect of chronic peripheral immune stimulation on myeloid cells across anatomical brain regions is unclear. Here, we demonstrate brain-region-specific differences in myeloid responses induced by chronic peripheral inflammation. This shift in the myeloid compartment is associated with the appearance of an inflammatory myeloid subpopulation in the cortex, striatum, and thalamus accompanied by regional transcriptomic fingerprints that include induction of chemokines, complement factors, and endothelial adhesion molecules. In contrast, myeloid immune responses within the hippocampus and cerebellum are subtle or absent. Treatment with the anti-tumor necrosis factor α (anti-TNF-α) antibody infliximab ablates the region-specific inflammatory response. A region-specific myeloid cell response to chronic peripheral inflammation is observed in postmortem brains from individuals with rheumatoid arthritis. Our data suggest that chronic peripheral inflammation has heterogeneous effects on the brain, as evidenced by the spectrum of myeloid cell responses observed across brain regions., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Alzheimer's Disease (AD) is the most frequent neurodegenerative disorder. Although proteinaceous aggregates of extracellular Amyloid-β (Aβ) and intracellular hyperphosphorylated microtubule- associated tau have long been identified as characteristic neuropathological hallmarks of AD, a disease- modifying therapy against these targets has not been successful. An emerging concept is that microglia, the innate immune cells of the brain, are major players in AD pathogenesis. Microglia are longlived tissue-resident professional phagocytes that survey and rapidly respond to changes in their microenvironment. Subpopulations of microglia cluster around Aβ plaques and adopt a transcriptomic signature specifically linked to neurodegeneration. A plethora of molecules and pathways associated with microglia function and dysfunction has been identified as important players in mediating neurodegeneration. However, whether microglia exert either beneficial or detrimental effects in AD pathology may depend on the disease stage. In this review, we summarize the current knowledge about the stage-dependent role of microglia in AD, including recent insights from genetic and gene expression profiling studies as well as novel imaging techniques focusing on microglia in human AD pathology and AD mouse models., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

We describe a patient with acute herpes simplex encephalitis with left-hemispheric hippocampal, parahippocampal and insular lesions. Although prototypic language areas were unaffected, the patient suffered from an inability to name objects or animals displayed on pictures. This deficit was transient and gradually disappeared 8 weeks after the initial diagnosis. Our findings are in line with a previous report showing similar deficits in a patient with a comparable lesion pattern and support the hypothesis that left insular lesions can produce severe naming deficits. Using FDG-PET we ruled out that functional deactivation in classical language areas account for the observed naming deficits.

Noncoding genetic variation is a major driver of phenotypic diversity, but functional interpretation is challenging. To better understand common genetic variation associated with brain diseases, we defined noncoding regulatory regions for major cell types of the human brain. Whereas psychiatric disorders were primarily associated with variants in transcriptional enhancers and promoters in neurons, sporadic Alzheimer's disease (AD) variants were largely confined to microglia enhancers. Interactome maps connecting disease-risk variants in cell-type-specific enhancers to promoters revealed an extended microglia gene network in AD. Deletion of a microglia-specific enhancer harboring AD-risk variants ablated BIN1 expression in microglia, but not in neurons or astrocytes. These findings revise and expand the list of genes likely to be influenced by noncoding variants in AD and suggest the probable cell types in which they function., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)