Brain Cell Types Research Articles

Differential Vulnerability and Response to Injury among Brain Cell Types Comprising the Neurovascular Unit.

The neurovascular unit (NVU) includes multiple different cell types, including neurons, astrocytes, endothelial cells, and pericytes, which respond to insults on very different time or dose scales. We defined differential vulnerability among these cell types, using response to two different insults: oxygen-glucose deprivation (OGD) and thrombin-mediated cytotoxicity. We found that neurons are most vulnerable, followed by endothelial cells and astrocytes. After temporary focal cerebral ischemia in male rats, we found significantly more injured neurons, compared with astrocytes in the ischemic area, consistent with differential vulnerability in vivo. We sought to illustrate different and shared mechanisms across all cell types during response to insult. We found that gene expression profiles in response to OGD differed among the cell types, with a paucity of gene responses shared by all types. All cell types activated genes relating to autophagy, apoptosis, and necroptosis, but the specific genes differed. Astrocytes and endothelial cells also activated pathways connected to DNA repair and antiapoptosis. Taken together, the data support the concept of differential vulnerability in the NVU and suggest that different elements of the unit will evolve from salvageable to irretrievable on different time scales while residing in the same brain region and receiving the same (ischemic) blood flow. Future work will focus on the mechanisms of these differences. These data suggest future stroke therapy development should target different elements of the NVU differently.

Single-cell mechanical assay unveils viscoelastic similarities in normal and neoplastic brain cells

Understanding cancer cell mechanics allows for the identification of novel disease mechanisms, diagnostic biomarkers, and targeted therapies. In this study, we utilized our previously established fluid shear stress assay to investigate and compare the viscoelastic properties of normal immortalized human astrocytes and invasive human glioblastoma (GBM) cells when subjected to physiological levels of shear stress that are present in the brain microenvironment. We used a parallel-flow microfluidic shear system and a camera-coupled optical microscope to expose single cells to fluid shear stress and monitor the resulting deformation in real time, respectively. From the video-rate imaging, we fed cell deformation information from digital image correlation into a three-parameter generalized Maxwell model to quantify the nuclear and cytoplasmic viscoelastic properties of single cells. We further quantified actin cytoskeleton density and alignment in immortalized human astrocytes and GBM cells via fluorescence microscopy and image analysis techniques. Results from our study show that contrary to the behavior of many extracranial cells, normal and cancerous brain cells do not exhibit significant differences in their viscoelastic properties. Moreover, we also found that the viscoelastic properties of the nucleus and cytoplasm as well as the actin cytoskeletal densities of both brain cell types are similar. Our work suggests that malignant GBM cells exhibit unique mechanical behaviors not seen in other cancer cell types. These results warrant future studies to elucidate the distinct biophysical characteristics of the brain and reveal novel mechanical attributes of GBM and other primary brain tumors.

Cell subtype-specific effects of genetic variation in the Alzheimer's disease brain.

The relationship between genetic variation and gene expression in brain cell types and subtypes remains understudied. Here, we generated single-nucleus RNA sequencing data from the neocortex of 424 individuals of advanced age; we assessed the effect of genetic variants on RNA expression in cis (cis-expression quantitative trait loci) for seven cell types and 64 cell subtypes using 1.5 million transcriptomes. This effort identified 10,004 eGenes at the cell type level and 8,099 eGenes at the cell subtype level. Many eGenes are only detected within cell subtypes. A new variant influences APOE expression only in microglia and is associated with greater cerebral amyloid angiopathy but not Alzheimer's disease pathology, after adjusting for APOEε4, providing mechanistic insights into both pathologies. Furthermore, only a TMEM106B variant affects the proportion of cell subtypes. Integration of these results with genome-wide association studies highlighted the targeted cell type and probable causal gene within Alzheimer's disease, schizophrenia, educational attainment and Parkinson's disease loci.

Contrasting somatic mutation patterns in aging human neurons and oligodendrocytes

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons.

Anterograde trans-neuronal labeling of striatal interneurons in relation to dopamine neurons in the substantia nigra pars compacta.

Recent advances in neural tracing have unveiled numerous neural circuits characterized by brain region and cell type specificity, illuminating the underpinnings of specific functions and behaviors. Dopaminergic (DA) neurons in the midbrain are highly heterogeneous in terms of gene and protein expression and axonal projections. Different cell types within the substantia nigra pars compacta (SNc) tend to project to the striatum in a cell-type-dependent manner characterized by specific topography. Given the wide and dense distribution of DA axons, coupled with a combination of synaptic and volume transmission, it remains unclear how DA release is spatially and temporally regulated, to appropriately achieve specific behaviors and functions. Our hypothesis posits that hidden rules governing synapse formation between pre-synaptic DA neuron types and striatal neuron types may modulate the effect of DA at a single-cell level. To address this conjecture, we employed adeno-associated virus serotype 1 (AAV1) to visualize the neural circuitry of DA neurons. AAV1 has emerged as a potent anatomical instrument capable of labeling and visualizing pre- and post-synaptic neurons simultaneously through anterograde trans-synaptic labeling. First, AAV1-Cre was injected into the SNc, resulting in Cre expression in both medium spiny neurons and interneurons in the striatum. Due to the potential occurrence of the retrograde transfer of AAV1, only striatal interneurons were considered for trans-synaptic or trans-neuronal labeling. Interneuron types expressing parvalbumin, choline acetyltransferase, somatostatin, or nitrogen oxide synthase exhibited Cre expression. Using a combination of AAV1-Cre and Cre-driven fluorophore expressing AAVs, striatal interneurons and the axons originating from the SNc were visualized in distinct colors. Using immunofluorescence against neurotransmitter transporters, almost all axons in the striatum visualized using this approach were confirmed to be dopaminergic. Moreover, individual DA axons established multiple appositions on the somata and proximal dendrites of interneurons. This finding suggests that irrespective of the extensive and widespread axonal arborization of DA neurons, a particular DA neuron may exert a significant influence on specific interneurons. Thus, AAV1-based labeling of the DA system can be a valuable tool to uncover the concealed rules governing these intricate relationships.

Single-Nucleus Sequencing of Silkworm Larval Brain Reveals the Key Role of Lysozyme in the Antiviral Immune Response in Brain Hemocytes

Introduction: The brain is considered as an immune-privileged organ, yet innate immune reactions can occur in the central nervous system of vertebrates and invertebrates. Silkworm (Bombyx mori) is an economically important insect and a lepidopteran model species. The diversity of cell types in the silkworm brain, and how these cell subsets produce an immune response to virus infection, remains largely unknown. Methods: Single-nucleus RNA sequencing (snRNA-seq), bioinformatics analysis, RNAi, and other methods were mainly used to analyze the cell types and gene functions of the silkworm brain. Results: We used snRNA-seq to identify 19 distinct clusters representing Kenyon cell, glial cell, olfactory projection neuron, optic lobes neuron, hemocyte-like cell, and muscle cell types in the B. mori nucleopolyhedrovirus (BmNPV)-infected and BmNPV-uninfected silkworm larvae brain at the late stage of infection. Further, we found that the cell subset that exerts an antiviral function in the silkworm larvae brain corresponds to hemocytes. Specifically, antimicrobial peptides were significantly induced by BmNPV infection in the hemocytes, especially lysozyme, exerting antiviral effects. Conclusion: Our single-cell dataset reveals the diversity of silkworm larvae brain cells, and the transcriptome analysis provides insights into the immune response following virus infection at the single-cell level.

Coexpression network analysis of the adult brain sheds light on the pathogenic mechanism of DDR1 in schizophrenia and bipolar disorder

DDR1 has been linked to schizophrenia (SCZ) and bipolar disorder (BD) in association studies. DDR1 encodes 58 distinct transcripts, which can be translated into five isoforms (DDR1a-e) and are expressed in the brain. However, the transcripts expressed in each brain cell type, their functions and their involvement in SCZ and BD remain unknown. Here, to infer the processes in which DDR1 transcripts are involved, we used transcriptomic data from the human brain dorsolateral prefrontal cortex of healthy controls (N = 936) and performed weighted gene coexpression network analysis followed by enrichment analyses. Then, to explore the involvement of DDR1 transcripts in SCZ (N = 563) and BD (N = 222), we studied the association of coexpression modules with disease and performed differential expression and transcript significance analyses. Some DDR1 transcripts were distributed across five coexpression modules identified in healthy controls (MHC). MHC1 and MHC2 were enriched in the cell cycle and proliferation of astrocytes and OPCs; MHC3 and MHC4 were enriched in oligodendrocyte differentiation and myelination; and MHC5 was enriched in neurons and synaptic transmission. Most of the DDR1 transcripts associated with SCZ and BD pertained to MHC1 and MHC2. Altogether, our results suggest that DDR1 expression might be altered in SCZ and BD via the proliferation of astrocytes and OPCs, suggesting that these processes are relevant in psychiatric disorders.

Neuronal exosomal miRNAs modulate mitochondrial functions and cell death in bystander neuronal cells under Parkinson’s disease stress conditions

Parkinson’s Disease (PD) is a chronic neurodegenerative disorder characterized by progressive loss of midbrain dopaminergic neurons in the substantia nigra part of the brain. Pathology spread to numerous brain regions and cell types suggests that intercellular communication is essential to PD progression. Exosomes mediate intercellular communication between neurons, glia, and other cell types throughout PD-relevant brain regions. However, the mechanism remains unclear, and its implication in PD pathology, is not well understood. In the current study, we explored the role of exosomes in modulating the response to PD-relevant toxicants. In cellular models of PD, neuronal cell-derived exosomes are readily internalized by recipient neuronal cells as intact vesicles. Internalized exosomes in bystander neuronal cells localize to mitochondria and dysregulate mitochondrial functions, leading to cell death under PD stress conditions. NGS analysis of exosomes released by neuronal cells subjected to PD stress conditions showed that levels of specific miRNAs were altered in exosomes under PD stress conditions. Bioinformatic analysis of the miRNA targets revealed enriched pathways related to neuronal processes and morphogenesis, apoptosis and ageing. Levels of two miRNAs, hsa-miR-30a-5p and hsa-miR-181c-5p, were downregulated in exosomes under PD stress conditions. Expression of the identified miRNAs in neuronal cells led to their enrichment in exosomes, and exosome uptake in neuronal cells ameliorated mitochondrial dysfunction induced by PD stress conditions and rescued cell death. In conclusion, loss of enrichment of specific miRNAs, including miR-30a-5p and miR-181c-5p, under PD stress conditions causes mitochondrial dysfunction and neuronal death, and hence may lead to progression of PD.

Human stem cell transplantation models of Alzheimer's disease.

Alzheimer's disease (AD) is the most frequent form of dementia. It is characterized by pronounced neuronal degeneration with formation of neurofibrillary tangles and deposition of amyloid β throughout the central nervous system. Animal models have provided important insights into the pathogenesis of AD and they have shown that different brain cell types including neurons, astrocytes and microglia have important functions in the pathogenesis of AD. However, there are difficulties in translating promising therapeutic observations in mice into clinical application in patients. Alternative models using human cells such as human induced pluripotent stem cells (iPSCs) may provide significant advantages, since they have successfully been used to model disease mechanisms in neurons and in glial cells in neurodegenerative diseases in vitro and in vivo. In this review, we summarize recent studies that describe the transplantation of human iPSC-derived neurons, astrocytes and microglial cells into the forebrain of mice to generate chimeric transplantation models of AD. We also discuss opportunities, challenges and limitations in using differentiated human iPSCs for in vivo disease modeling and their application for biomedical research.

Spatially resolved transcriptome of the aging mouse brain.

Brain aging is associated with cognitive decline, memory loss and many neurodegenerative disorders. The mammalian brain has distinct structural regions that perform specific functions. However, our understanding in gene expression and cell types within the context of the spatial organization of the mammalian aging brain is limited. Here we generated spatial transcriptomic maps of young and old mouse brains. We identified 27 distinguished brain spatial domains, including layer-specific subregions that are difficult to dissect individually. We comprehensively characterized spatial-specific changes in gene expression in the aging brain, particularly for isocortex, the hippocampal formation, brainstem and fiber tracts, and validated some gene expression differences by qPCR and immunohistochemistry. We identified aging-related genes and pathways that vary in a coordinated manner across spatial regions and parsed the spatial features of aging-related signals, providing important clues to understand genes with specific functions in different brain regions during aging. Combined with single-cell transcriptomics data, we characterized the spatial distribution of brain cell types. The proportion of immature neurons decreased in the DG region with aging, indicating that the formation of new neurons is blocked. Finally, we detected changes in information interactions between regions and found specific pathways were deregulated with aging, including classic signaling WNT and layer-specific signaling COLLAGEN. In summary, we established a spatial molecular atlas of the aging mouse brain (http://sysbio.gzzoc.com/Mouse-Brain-Aging/), which provides important resources and novel insights into the molecular mechanism of brain aging.

Comprehensive analysis of genetic associations and single-cell expression profiles reveals potential links between migraine and multiple diseases: a phenome-wide association study.

Migraine is a common neurological disorder that affects more than one billion people worldwide. Recent genome-wide association studies have identified 123 genetic loci associated with migraine risk. However, the biological mechanisms underlying migraine and its relationships with other complex diseases remain unclear. We performed a phenome-wide association study (PheWAS) using UK Biobank data to investigate associations between migraine and 416 phenotypes. Mendelian randomization was employed using the IVW method. For loci associated with multiple diseases, pleiotropy was tested using MR-Egger. Single-cell RNA sequencing data was analyzed to profile the expression of 73 migraine susceptibility genes across brain cell types. qPCR was used to validate the expression of selected genes in microglia. PheWAS identified 15 disorders significantly associated with migraine, with one association detecting potential pleiotropy. Single-cell analysis revealed elevated expression of seven susceptibility genes (including ZEB2, RUNX1, SLC24A3, ANKDD1B, etc.) in brain glial cells. And qPCR confirmed the upregulation of these genes in LPS-treated microglia. This multimodal analysis provides novel insights into the link between migraine and other diseases. The single-cell profiling suggests the involvement of specific brain cells and molecular pathways. Validation of gene expression in microglia supports their potential role in migraine pathology. Overall, this study uncovers pleiotropic relationships and the biological underpinnings of migraine susceptibility.

Integrating spatial and single-cell transcriptomics to characterize the molecular and cellular architecture of the ischemic mouse brain.

Neuroinflammation is acknowledged as a pivotal pathological event after cerebral ischemia. However, there is limited knowledge of the molecular and spatial characteristics of nonneuronal cells, as well as of the interactions between cell types in the ischemic brain. Here, we used spatial transcriptomics to study the ischemic hemisphere in mice after stroke and sequenced the transcriptomes of 19,777 spots, allowing us to both visualize the transcriptional landscape within the tissue and identify gene expression profiles linked to specific histologic entities. Cell types identified by single-cell RNA sequencing confirmed and enriched the spatial annotation of ischemia-associated gene expression in the peri-infarct area of the ischemic hemisphere. Analysis of ligand-receptor interactions in cell communication revealed galectin-9 to cell-surface glycoprotein CD44 (LGALS9-CD44) as a critical signaling pathway after ischemic injury and identified microglia and macrophages as the main source of galectins after stroke. Extracellular vesicle-mediated Lgals9 delivery improved the long-term functional recovery in photothrombotic stroke mice. Knockdown of Cd44 partially reversed these therapeutic effects, inhibiting oligodendrocyte differentiation and remyelination. In summary, our study provides a detailed molecular and cellular characterization of the peri-infact area in a murine stroke model and revealed Lgals9 as potential treatment target that warrants further investigation.

Abstract 56: Temporal Blood Exposure in Neural Organoids Stimulates Dynamic Astrocyte Reactivity

Introduction: The impact of intracerebral hemorrhage (ICH) and timing of surgical evacuation on brain cell types is poorly understood. Here, we identify cell type specific responses to blood exposure in an organoid model of ICH using single cell transcriptomics. Methods: Human organoids consisting of excitatory/inhibitory neurons, neural progenitor cells (NPC), astrocytes, pericytes, and microglia were generated from induced pluripotent stem cells and treated with 5% blood for 6 or 24 hours. Organoids were dissociated and sequenced (scRNAseq). scRNAseq alignment, filtering, and analysis was performed using cellranger, SoupX, Scrublet, and Seurat in R to cluster and identify the cell type composition of organoids. Associations of expression to blood exposure were conducted with mixed-effect linear models. Significance was determined using Benjamini-Hochberg multiple testing correction (FDR <5%). Pathway enrichment was performed with FUMA at FDR<5%. Results: We resolved excitatory and inhibitory neurons, NPCs, astrocytes, pericytes, epithelial cells, fibroblasts, and microglia with cell type-specific responses to blood. Long exposure to blood induced significant transcriptomic responses, whereas short exposure did not. Astrocytes were the most reactive cell type to blood exposure, and upregulated pathways included proliferative and catabolic processes. Fibroblasts and epithelial cells showed the most downregulated pathways, including impairment of interferon signaling pathways and metabolism. Conclusion: Blood exposure induces transcriptomic changes in a temporal and cell type specific manner. Longer exposure to blood induces higher reactivity, and such reactivity is especially mediated by astrocyte upregulation of catabolic and proliferative processes. These results suggest that astrocytes may mediate cerebral response to blood in the setting of ICH, and reinforce early evacuation of ICH as a means to mitigate cellular reactivity.

Abstract WP309: UDP-Glucose Exacerbates Neuronal Apoptosis via Its Receptor P2y14 After Subarachnoid Hemorrhage in Rats

Introduction: Subarachnoid hemorrhage (SAH) is a severe subtype of stroke that can lead to poor outcomes. Recent studies reported that uridine diphosphate glucose (UDP-G), one of the intermediates in glucose/glycogen metabolism, can be released from damaged cells and proceed with pathologic conditions by activating the purinergic P2Y14 receptor. This study aimed to elucidate the role of brain UDP-G/P2Y14 signaling after SAH. Hypothesis: The inhibition of the brain UDP-G/P2Y14 signaling pathway would attenuate neuronal apoptosis and neurological deficits after SAH in rats. Methods: A total of 200 adult male Sprague Dawley rats were used. Endovascular perforation method was used to induce SAH. The time course changes of CSF UDP-G, brain protein levels of UDP-G converting enzyme UDP-G pyrophosphorylase-2 (UGP2) and P2Y14 receptors, as well as the brain cell types expressing P2Y14 were examined. A selective P2Y14 receptor inhibitor PPTN hydrochloride or exogenous UDP-G was administered intranasally 1 hour after SAH. SAH grading, neurological evaluation, immunofluorescence, TUNEL staining, Nissl staining, western blot, and liquid chromatography-mass spectrometry were performed. Results: Endogenous CSF UDP-G and brain UGP2 were increased at 3 hours and 6 hours after SAH. The protein level of the brain P2Y14 receptor was not changed temporally and was mainly expressed in neurons 24 hours after SAH. PPTN hydrochloride decreased but exogenous UDP-G aggravated the number of TUNEL-positive neurons, brain protein levels of proapoptotic molecules such as cleaved caspase 3, and modified Garcia neurological score at 24 hours after SAH. Early inhibition of P2Y14 receptor signaling by PPTN hydrochloride preserved the numbers of Nissl staining identified surviving neurons in the hippocampus, amygdala, and cortex with improved water maze learning performance and depressive-like behavior at 1-month post-SAH. Conclusion: Brain UDP-G/P2Y14 receptor signaling activation plays a detrimental role after SAH, as a part of glucose metabolic pathology at the tissue level. P2Y14 receptor inhibitor reduced neuronal apoptosis and improved neurological deficits after SAH, which may serve as potential therapeutics in treating patients with SAH.

Role of transcription factors, noncoding RNAs, epitranscriptomics, and epigenetics in post-ischemic neuroinflammation.

Post-stroke neuroinflammation is pivotal in brain repair, yet persistent inflammation can aggravate ischemic brain damage and hamper recovery. Following stroke, specific molecules released from brain cells attract and activate central and peripheral immune cells. These immune cells subsequently release diverse inflammatory molecules within the ischemic brain, initiating a sequence of events, including activation of transcription factors in different brain cell types that modulate gene expression and influence outcomes; the interactive action of various noncoding RNAs (ncRNAs) to regulate multiple biological processes including inflammation, epitranscriptomic RNA modification that controls RNA processing, stability, and translation; and epigenetic changes including DNA methylation, hydroxymethylation, and histone modifications crucial in managing the genic response to stroke. Interactions among these events further affect post-stroke inflammation and shape the depth of ischemic brain damage and functional outcomes. We highlighted these aspects of neuroinflammation in this review and postulate that deciphering these mechanisms is pivotal for identifying therapeutic targets to alleviate post-stroke dysfunction and enhance recovery.

Single-cell transcriptomics reveals that glial cells integrate homeostatic and circadian processes to drive sleep–wake cycles

The sleep–wake cycle is determined by circadian and sleep homeostatic processes. However, the molecular impact of these processes and their interaction in different brain cell populations are unknown. To fill this gap, we profiled the single-cell transcriptome of adult Drosophila brains across the sleep–wake cycle and four circadian times. We show cell type-specific transcriptomic changes, with glia displaying the largest variation. Glia are also among the few cell types whose gene expression correlates with both sleep homeostat and circadian clock. The sleep–wake cycle and sleep drive level affect the expression of clock gene regulators in glia, and disrupting clock genes specifically in glia impairs homeostatic sleep rebound after sleep deprivation. These findings provide a comprehensive view of the effects of sleep homeostatic and circadian processes on distinct cell types in an entire animal brain and reveal glia as an interaction site of these two processes to determine sleep–wake dynamics.

Leveraging single-cell ATAC-seq and RNA-seq to identify disease-critical fetal and adult brain cell types

Prioritizing disease-critical cell types by integrating genome-wide association studies (GWAS) with functional data is a fundamental goal. Single-cell chromatin accessibility (scATAC-seq) and gene expression (scRNA-seq) have characterized cell types at high resolution, and studies integrating GWAS with scRNA-seq have shown promise, but studies integrating GWAS with scATAC-seq have been limited. Here, we identify disease-critical fetal and adult brain cell types by integrating GWAS summary statistics from 28 brain-related diseases/traits (average N = 298 K) with 3.2 million scATAC-seq and scRNA-seq profiles from 83 cell types. We identified disease-critical fetal (respectively adult) brain cell types for 22 (respectively 23) of 28 traits using scATAC-seq, and for 8 (respectively 17) of 28 traits using scRNA-seq. Significant scATAC-seq enrichments included fetal photoreceptor cells for major depressive disorder, fetal ganglion cells for BMI, fetal astrocytes for ADHD, and adult VGLUT2 excitatory neurons for schizophrenia. Our findings improve our understanding of brain-related diseases/traits and inform future analyses.

FXTAS Neuropathology Includes Widespread Reactive Astrogliosis and White Matter Specific Astrocyte Degeneration.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset progressive genetic neurodegenerative disorder that occurs in FMR1 premutation carriers. The temporal, spatial, and cell-type specific patterns of neurodegeneration in the FXTAS brain remain incompletely characterized. Intranuclear inclusion bodies are the neuropathological hallmark of FXTAS, which are largest and occur most frequently in astrocytes, glial cells that maintain brain homeostasis. Here, we characterized neuropathological alterations in astrocytes in multiple regions of the FXTAS brain. Striatal and cerebellar sections from FXTAS cases (n = 12) and controls (n = 12) were stained for the astrocyte markers glial fibrillary acidic protein (GFAP) and aldehyde dehydrogenase 1L1 (ALDH1L1) using immunohistochemistry. Reactive astrogliosis severity, the prevalence of GFAP+ fragments, and astrocyte density were scored. Double label immunofluorescence was utilized to detect co-localization of GFAP and cleaved caspase-3. FXTAS cases showed widespread reactive gliosis in both grey and white matter. GFAP staining also revealed remarkably severe astrocyte pathology in FXTAS white matter - characterized by a significant and visible reduction in astrocyte density (-38.7% in striatum and - 32.2% in cerebellum) and the widespread presence of GFAP+ fragments reminiscent of apoptotic bodies. White matter specific reductions in astrocyte density were confirmed with ALDH1L1 staining. GFAP+ astrocytes and fragments in white matter were positive for cleaved caspase-3, suggesting that apoptosis-mediated degeneration is responsible for reduced astrocyte counts. We have established that FXTAS neuropathology includes robust degeneration of astrocytes, which is specific to white matter. Because astrocytes are essential for maintaining homeostasis within the central nervous system, a loss of astrocytes likely further exacerbates neuropathological progression of other cell types in the FXTAS brain. ANN NEUROL 2024;95:558-575.

Regional- and cell type-specific changes of the human brain during aging

As individuals age, cognitive decline becomes more prominent, concomitant with an elevated susceptibility to neurodegenerative diseases and dementia. Additionally, symptoms of chronic neuropsychiatric diseases tend to worsen with age. It is crucial to highlight that the aging process does not affect individuals uniformly, and its effects can vary, even within the same person. This review aims to summary the impact of healthy aging on the human brain, focusing on the variations from different brain regions and cell types. Depending on specific brain regions, the brain exhibits thinning, volume reduction, regional shrinkage, disrupted tissue integrity, decreased cell complexity, or iron accumulation during aging. Moreover, the brain cells exhibit morphology and function changes during aging. Neurons undergo changes characterized by reduced dendrites, dendritic spines, and axons with less compact myelin sheaths, leading to a significant loss of synapses. Comparatively, glia often transform into a reactive phenotype.

Mechanism of Cu entry into the brain: many unanswered questions.

Brain tissue requires high amounts of copper (Cu) for its key physiological processes, such as energy production, neurotransmitter synthesis, maturation of neuropeptides, myelination, synaptic plasticity, and radical scavenging. The requirements for Cu in the brain vary depending on specific brain regions, cell types, organism age, and nutritional status. Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease, Wilson disease, Alzheimer's disease, Parkinson's disease, and others. Despite the well-established role of Cu homeostasis in brain development and function, the mechanisms that govern Cu delivery to the brain are not well defined. This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.