Automated image segmentation uncovers the role of CD74high human microglia in cognitive decline.

The role of activated microglia in Alzheimer's disease (AD) is well established; the proportion of stage III activated microglia has been associated with AD and cognitive decline, but this morphologically defined subtype is relatively uncommon (1-2% of microglia) and its cellular function is unknown. Single-cell RNA-sequencing revealed CD74 as a marker gene that is enriched in immunologically active microglial subtypes associated with AD. Here, we evaluated the relationship between CD74 expression, AD-related traits, and microglial morphology using dorsolateral prefrontal cortex samples from two brain collections (ROSMAP: n=63, NYBB: n=91).

Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS.

Single-nucleus multiomics in brains from Hispanic individuals reveal -driven disruption of focal adhesion signaling in the presence of cerebrovascular pathology.

The apolipoprotein E ε4 allele ( ) is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), yet its molecular impact on cerebrovascular biology remains inconclusive, particularly in underrepresented populations with elevated vascular burden. Individuals from Hispanic ancestry experience disproportionately high rates of cerebrovascular pathology, offering a unique opportunity to investigate the mechanisms of cerebrovascular pathology in AD. Here, we performed single-nucleus RNA sequencing (snSeq) on 413,175 nuclei from 52 postmortem Hispanic brains to determine -associated cell type specific transcriptomic changes in a population with elevated cerebrovascular risk.

Single-cell elderly blood-CSF atlas implicates peripherally influenced immune dysregulation in normal pressure hydrocephalus.

We have generated a single-cell RNA sequencing atlas of peripheral blood and ventricular CSF in idiopathic normal pressure hydrocephalus (iNPH) patients totaling 140,207 single-cell transcriptomes. We found proinflammatory alterations in peripheral blood and CSF monocytes in iNPH patients with lower baseline cognitive function. We also identified CSF cell populations likely representing periventricular sloughing of degenerating neuroglial cells.

The role of alpha-synuclein in synucleinopathy: Impact on lipid regulation at mitochondria-ER membranes.

The protein alpha-synuclein (αSyn) plays a pivotal role in the pathogenesis of synucleinopathies, including Parkinson's disease and multiple system atrophy, with growing evidence indicating that lipid dyshomeostasis is a key phenotype in these neurodegenerative disorders. Previously, we identified that αSyn localizes, at least in part, to mitochondria-associated endoplasmic reticulum membranes (MAMs), which are transient functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors.

A proteogenomic tool uncovers protein markers for human microglial states.

Human microglial heterogeneity has been largely described using transcriptomic data. Here, we introduce a microglial proteomic data resource and a Cellular Indexing of Transcriptomes and Epitopes by Sequencing panel enhanced with antibodies targeting 17 microglial cell surface proteins (mCITE-Seq). We evaluated mCITE-Seq on HMC3 microglia-like cells, induced-pluripotent stem cell-derived microglia (iMG), and freshly isolated primary human microglia.

A factor-based analysis of individual human microglia uncovers regulators of an Alzheimer-related transcriptional signature.

Human microglial heterogeneity is only beginning to be appreciated at the molecular level. Here, we present a large, single-cell atlas of expression signatures from 441,088 live microglia broadly sampled across a diverse set of brain regions and neurodegenerative and neuroinflammatory diseases obtained from 161 donors sampled at autopsy or during a neurosurgical procedure. Using single-cell hierarchical Poisson factorization (scHPF), we derived a 23-factor model for continuous gene expression signatures across microglia which capture specific biological processes (e.

High throughput identification of genetic regulators of microglial inflammatory processes in Alzheimer's disease.

Genome-wide association studies (GWAS) have identified over a hundred genetic risk factors for Alzheimer's disease (AD), many of which are predominantly expressed in microglia. However, the pathogenic role for most of them remains unclear. To systematically investigate how AD GWAS variants influence human microglial inflammatory responses, we conducted CRISPR inhibition (CRISPRi) screens targeting 119 AD GWAS hits in hiPSC-derived microglia (iMGLs) and used the production of reactive oxygen species (ROS) in response to the viral mimic poly(I:C) as a functional readout.

ε4-induced Fibronectin at the blood-brain barrier is a conserved pathological mediator of disrupted astrocyte-endothelia interaction in Alzheimer's disease.

Unlabelled: Blood-brain barrier (BBB) dysfunction is a key feature of Alzheimer's disease (AD), particularly in individuals carrying the allele. This dysfunction worsens neuroinflammation and hinders the removal of toxic proteins, such as amyloid-beta (Aβ42), from the brain. In post-mortem brain tissues and in animal models, we previously reported that fibronectin accumulates at the BBB predominantly in carriers.

An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have used a range of metrics to assess RNA quality but there are few large-scale cross-comparisons of presequencing quality metrics with RNA-seq quality. We analyzed how postmortem interval (PMI) and RNA integrity number (RIN) before RNA-seq relate to RNA quality after sequencing (percent of counts in top 10 genes [PTT], 5' bias, and 3' bias), and with individual gene counts across the transcriptome. We analyzed 4 human cerebrocortical tissue sets (1 surgical, 3 autopsy), sequenced with varying protocols.

Single-cell transcriptomic landscape of the neuroimmune compartment in amyotrophic lateral sclerosis brain and spinal cord.

Development of therapeutic approaches that target specific microglia responses in amyotrophic lateral sclerosis (ALS) is crucial due to the involvement of microglia in ALS progression. Our study identifies the predominant microglia subset in human ALS primary motor cortex and spinal cord as an undifferentiated phenotype with dysregulated respiratory electron transport. Moreover, we find that the interferon response microglia subset is enriched in donors with aggressive disease progression, while a previously described potentially protective microglia phenotype is depleted in ALS.

Pathologic subtyping of Alzheimer's disease brain tissue reveals disease heterogeneity.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes.

An analysis of RNA quality metrics in human brain tissue.

Human brain tissue studies have historically used a range of metrics to assess RNA quality. However, few large-scale cross-comparisons of pre-sequencing quality metrics with RNA-seq quality have been published. Here, we analyze how well metrics gathered before RNA sequencing (post-mortem interval (PMI) and RNA integrity number RIN) relate to analyses of RNA quality after sequencing (Percent of counts in Top Ten genes (PTT), 5' bias, and 3' bias) as well as with individual gene counts across the transcriptome.

A cross-disease resource of living human microglia identifies disease-enriched subsets and tool compounds recapitulating microglial states.

Human microglia play a pivotal role in neurological diseases, but we still have an incomplete understanding of microglial heterogeneity, which limits the development of targeted therapies directly modulating their state or function. Here, we use single-cell RNA sequencing to profile 215,680 live human microglia from 74 donors across diverse neurological diseases and CNS regions. We observe a central divide between oxidative and heterocyclic metabolism and identify microglial subsets associated with antigen presentation, motility and proliferation.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD.

Methods: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.

Reduced may protect against Alzheimer's disease by lowering microglial pro-inflammatory responses via modulation of JNK and NFkB signaling.

Understanding how high-risk individuals are protected from Alzheimer's disease (AD) may illuminate potential therapeutic targets. We identified protective genetic variants in that delayed the onset of AD among individuals carrying the mutation. acts as a JNK pathway scaffold and activates NFκB signaling.

The Role of Alpha-Synuclein in Synucleinopathy: Impact on Lipid Regulation at Mitochondria-ER Membranes.

The protein alpha-synuclein (αSyn) plays a critical role in the pathogenesis of synucleinopathy, which includes Parkinson's disease and multiple system atrophy, and mounting evidence suggests that lipid dyshomeostasis is a critical phenotype in these neurodegenerative conditions. Previously, we identified that αSyn localizes to mitochondria-associated endoplasmic reticulum membranes (MAMs), temporary functional domains containing proteins that regulate lipid metabolism, including the de novo synthesis of phosphatidylserine. In the present study, we have analyzed the lipid composition of postmortem human samples, focusing on the substantia nigra pars compacta of Parkinson's disease and controls, as well as three less affected brain regions of Parkinson's donors.

Alzheimer's disease CSF biomarkers correlate with early pathology and alterations in neuronal and glial gene expression.

Introduction: Normal pressure hydrocephalus (NPH) patients undergoing cortical shunting frequently show early AD pathology on cortical biopsy, which is predictive of progression to clinical AD. The objective of this study was to use samples from this cohort to identify CSF biomarkers for AD-related CNS pathophysiologic changes using tissue and fluids with early pathology, free of post-mortem artifact.

Methods: We analyzed Simoa, proteomic, and metabolomic CSF data from 81 patients with previously documented pathologic and transcriptomic changes.

The neuropathological landscape of small vessel disease and Lewy pathology in a cohort of Hispanic and non-Hispanic White decedents with Alzheimer disease.

Cerebrovascular and α-synuclein pathologies are frequently observed alongside Alzheimer disease (AD). The heterogeneity of AD necessitates comprehensive approaches to postmortem studies, including the representation of historically underrepresented ethnic groups. In this cohort study, we evaluated small vessel disease pathologies and α-synuclein deposits among Hispanic decedents (HD, n = 92) and non-Hispanic White decedents (NHWD, n = 184) from three Alzheimer's Disease Research Centers: Columbia University, University of California San Diego, and University of California Davis.

Bridging the Gap: Multi-Omics Profiling of Brain Tissue in Alzheimer's Disease and Older Controls in Multi-Ethnic Populations.

Introduction: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked African Americans (AA) and Latin Americans (LA), who are disproportionately affected by AD.

Methods: To bridge this gap, Accelerating Medicines Partnership in AD (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors.