2025

• Celebrating neuropathology's contributions to Alzheimer's Disease Research Centers.

  Fischer, D. L., Grinberg, L. T., Ahrendsen, J. T., Beach, T. G., Bieniek, K. F., Castellani, R. J., Chkheidze, R., Cobos, I., Cohen, M., Crary, J. F., Dickson, D. W., Dugger, B. N., Dunlop, S. R., Farrell, K., Ghetti, B., Haeri, M., Harrison, W., Head, E., Hiniker, A., Huang, E. J., Huttner, A., Jamshidi, P., Kapasi, A., Keene, C. D., Kofler, J., Latimer, C. S., McKee, A. C., Mente, K., Miller, M. B., Montine, T. J., Morris, M., Murray, M. E., Nelson, P. T., Newell, K. L., Perrin, R. J., Ramani, B., Reichard, R. R., Roy, S., Schlachetzki, J. C., Seeley, W. W., Serrano, G. E., Spina, S., Teich, A. F., Wang, S. J., Wisniewski, T., Lee, E. B.

  Alzheimer's & dementia : the journal of the Alzheimer's Association

  ABSTRACT
  Alzheimer's disease (AD) is the most common form of dementia. Neuropathologically, AD stands out as a mixed proteinopathy. Beta-amyloid and tau biomarkers can now add in-vivo support to the AD diagnosis. Rarely, a patient with AD confirmed at autopsy may have a negative amyloid PET. Here we describe a pedigree in whom the index case was amyloid PET-negative. We performed genetic sequencing of two affected siblings to identify a set of candidate single nucleotide variants (SNVs) and structural variants (SVs) associated with disease and rare in healthy older controls from several large genetic databases.We performed long-read sequencing (LRS) to comprehensively evaluate both SNVs and SVs. The index case, an APOE3/E4 male, developed memory trouble at 68 that progressed to probable AD at 72. Notably (Figure 1) his amyloid-PET scan, which was confirmed to be of high technical quality, was negative. His tau PET scan was positive and his plasma Abeta42/40 was in the expected range for Stanford AD patients. His family history is extensive and suggestive of an autosomal dominant pattern of late-onset AD (Figure 2). The patient's sister was diagnosed with AD at 62. We filtered their shared heterozygous SNVs keeping those with a minor allele frequency < 0.01 in gnomAD and that were not present in any ADSP healthy controls (HC) over 70y.o. (N=19771;62.1%females;81±6.4y.o). Shared SVs were kept as candidates if they were not seen in any Stanford LRS HC (N=95;59%females;72±1.5y.o.) RESULT: Neuropathological analysis revealed that both siblings met the A3B3C3 criteria for AD and had cerebral amyloid angiopathy. Among rare mutations on genes expressed in the brain (Table 1), a novel missense in ADNP (Activity-Dependent-Neuroprotector-Homeobox), and a 267bp deletion on TET1 (Tet-Methylcytosine-Dioxygenase) were identified. The 3426bp insertion on ATP8A2 (ATPase-Phospholipid-Transporting-8A2) was the longest, rare insertion found. Additionally, a large duplication (∼20Kbp) and inversion (∼160Kbp) were observed.This study highlights an unusual AD pedigree and emphasizes the potential utility of LRS in identifying causal SNVs and SVs. In future work we plan to perform additional amyloid stains to understand why the index case PET was amyloid-negative. We are also assessing additional family members to improve our ability to identify a causal mutation.

  https://www.ncbi.nlm.nih.gov/pubmed/41085158 https://doi.org/10.1002/alz.70734

  More

• Precise MRI-histology coregistration of paraffin-embedded tissue with blockface imaging.

  Wang, Y., Ho, W., Huszar, I. N., DiGiacomo, P., Taghavi, H. M., Tao, L., Choi, M., Nguyen, N., Leventis, S., Camarillo, D. B., Schlömer, P., Axer, M., Shao, W., Rusu, M., Cobos, I., Nirschl, J., Georgiadis, M., Zeineh, M.

  Imaging neuroscience (Cambridge, Mass.)

  ABSTRACT
  Single-cell omics is advancing our understanding of selective neuronal vulnerability in Alzheimer's disease (AD), revealing specific subtypes that are either susceptible or resilient to neurodegeneration. Using single-nucleus and spatial transcriptomics to compare neocortical regions affected early (prefrontal cortex and precuneus) or late (primary visual cortex) in AD, we identified a resilient excitatory population in layer 4 of the primary visual cortex expressing RORB, CUX2, and EYA4. Layer 4 neurons in association neocortex also remained relatively preserved as AD progressed and shared overlapping molecular signatures of resilience. Early in the disease, resilient neurons upregulated genes associated with synapse maintenance, synaptic plasticity, calcium homeostasis, and neuroprotective factors, including GRIN2A, RORA, NRXN1, NLGN1, NCAM2, FGF14, NRG3, NEGR1, and CSMD1. We also identified KCNIP4, which encodes a voltage-gated potassium (Kv) channel-interacting protein that interacts with Kv4.2 channels and presenilins, as a key factor linked to resilience. KCNIP4 was consistently upregulated in the early stages of pathology. Furthermore, AAV-mediated overexpression of Kcnip4 in a humanized AD mouse model reduced the expression of the activity-dependent genes Arc and c-Fos, suggesting compensatory mechanisms against neuronal hyperexcitability. Our dataset provides a valuable resource for investigating mechanisms underlying resilience to neurodegeneration.

  https://www.ncbi.nlm.nih.gov/pubmed/40800888 https://doi.org/10.1162/IMAG.a.106

  More

• Precise MRI-Histology Coregistration of Paraffin-Embedded Tissue with Blockface Imaging.

  Wang, Y., Ho, W., Huszar, I. N., DiGiacomo, P., Taghavi, H. M., Tao, L., Choi, M., Nguyen, N., Leventis, S., Camarillo, D. B., Schlomer, P., Axer, M., Wei, S., Rusu, M., Cobos, I., Nirschl, J., Georgiadis, M., Zeineh, M.

  bioRxiv : the preprint server for biology

  ABSTRACT
  Thyroid-stimulating hormone-secreting adenomas (TSH-oma) are exceptionally rare.1 The primary treatment is surgical resection with radiation and pharmacotherapy postoperatively if subtotal resection, especially with cavernous sinus invasion.2 We present the case of a 29-year-old man with TSH-oma with cavernous sinus medial wall invasion. This is the first documented case with selective resection of the cavernous sinus medial wall to achieve a complete resection and biochemical remission in TSH-oma through endoscopic endonasal approach. The patient had elevated TSH and thyroid hormones with symptoms of weight loss, palpitations, excess sweating, and decreased endurance. MRI revealed a 1.3 × 2.1 × 1.2 cm contrast-enhancing sellar mass with rightward pituitary gland displacement without evidence of cavernous sinus invasion (Knosp 2). The patient consented to procedure/publication. No institutional review board approval needed per institution. We performed standard resection of the firm sellar tumor portion and noted that there was tumor invasion into the left cavernous sinus medial wall dura. The bony opening was expanded to expose the anterior wall of the cavernous sinus, which was opened to identify the cavernous internal carotid artery and the medial wall attachments. The thickened medial wall was completely resected. We achieved a complete tumor resection, and the patient's TSH and thyroid hormone dropped to a desired threshold.3 Tumor stained for GATA3 and PIT1, characterizing the TSH-oma.4,5 Understanding cavernous sinus vascular and ligamentous anatomy allows for safe separation of invaded medial wall dura from the cavernous internal carotid artery,6 allowing for a more complete tumor resection, improving surgical cure rates, and sparing the patient from future radiation and pharmacotherapy.

  https://www.ncbi.nlm.nih.gov/pubmed/40501733 https://doi.org/10.1101/2025.06.02.657335

  More

2024

• Basic Science and Pathogenesis.

  Talozzi, L., Peña-Tauber, A., Jensen, T. D., Wilson, E. N., Young, C. B., Stewart, I., Cobos, I., Vallejo, K., Hefti, M. M., Guen, Y. L., Williams, K., Vossler, H., Gorzynski, J., Andreasson, K. I., Mormino, E., Ashley, E., Greicius, M. D.

  Alzheimer's & dementia : the journal of the Alzheimer's Association

  ABSTRACT
  CSF1R-related disorder (CSF1R-RD) is a neurodegenerative condition that predominantly affects white matter due to genetic alterations in the CSF1R gene, which is expressed by microglia. We studied an elderly man with a hereditary, progressive dementing disorder of unclear etiology. Standard genetic testing for leukodystrophy and other neurodegenerative conditions was negative. Brain autopsy revealed classic features of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP), including confluent white matter degeneration with axonal spheroids and pigmented glial cells in the affected white matter, consistent with CSF1R-RD. Subsequent long-read sequencing identified a novel deletion in CSF1R that was not detectable with short-read exome sequencing. To gain insight into potential mechanisms underlying white matter degeneration in CSF1R-RD, we studied multiple brain regions exhibiting varying degrees of white matter pathology. We found decreased CSF1R transcript and protein across brain regions, including intact white matter. Single nuclear RNA sequencing (snRNAseq) identified two disease-associated microglial cell states: lipid-laden microglia (expressing GPNMB, ATG7, LGALS1, LGALS3) and inflammatory microglia (expressing IL2RA, ATP2C1, FCGBP, VSIR, SESN3), along with a small population of CD44+ peripheral monocyte-derived macrophages exhibiting migratory and phagocytic signatures. GPNMB+ lipid-laden microglia with ameboid morphology represented the end-stage disease microglia state. Disease-associated oligodendrocytes exhibited cell stress signatures and dysregulated apoptosis-related genes. Disease-associated oligodendrocyte precursor cells (OPCs) displayed a failure in their differentiation into mature myelin-forming oligodendrocytes, as evidenced by upregulated LRP1, PDGFRA, SOX5, NFIA, and downregulated NKX2-2, NKX6.2, SOX4, SOX8, TCF7L2, YY1, ZNF488. Overall, our findings highlight microglia-oligodendroglia crosstalk in demyelination, with CSF1R dysfunction promoting phagocytic and inflammatory microglia states, an arrest in OPC differentiation, and oligodendrocyte depletion.

  https://www.ncbi.nlm.nih.gov/pubmed/39750840 https://doi.org/10.1002/alz.090996

  More

• Deciphering glial contributions to CSF1R-related disorder via single-nuclear transcriptomic profiling: a case study.

  Pan, J., Fores-Martos, J., Delpirou Nouh, C., Jensen, T. D., Vallejo, K., Cayrol, R., Ahmadian, S., Ashley, E. A., Greicius, M. D., Cobos, I.

  Acta neuropathologica communications

  ABSTRACT
  The cerebellum contains most of the neurons in the human brain and exhibits distinctive modes of development and aging. In this work, by developing our single-cell three-dimensional (3D) genome assay-diploid chromosome conformation capture, or Dip-C-into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we resolved the first 3D genome structures of single cerebellar cells, created life-spanning 3D genome atlases for both humans and mice, and jointly measured transcriptome and chromatin accessibility during development. We found that although the transcriptome and chromatin accessibility of cerebellar granule neurons mature in early postnatal life, 3D genome architecture gradually remodels throughout life, establishing ultra-long-range intrachromosomal contacts and specific interchromosomal contacts that are rarely seen in neurons. These results reveal unexpected evolutionarily conserved molecular processes that underlie distinctive features of neural development and aging across the mammalian life span.

  https://www.ncbi.nlm.nih.gov/pubmed/39217398 https://doi.org/10.1186/s40478-024-01853-5

  More

• Endoscopic Endonasal Resection of a Thyroid-Stimulating Hormone-Secreting Pituitary Adenoma With Invasion of the Medial Wall of the Cavernous Sinus.

  Ljubimov, V. A., Rychen, J., Lee, C. K., Cobos Sillero, M. I., Xu, Y., Fernandez-Miranda, J. C.

  Operative neurosurgery (Hagerstown, Md.)

  ABSTRACT
  Loss of fragile X messenger ribonucleoprotein (FMRP) causes fragile X syndrome (FXS), the most prevalent form of inherited intellectual disability. Here, we show that FMRP interacts with the voltage-dependent anion channel (VDAC) to regulate the formation and function of endoplasmic reticulum (ER)-mitochondria contact sites (ERMCSs), structures that are critical for mitochondrial calcium (mito-Ca2+) homeostasis. FMRP-deficient cells feature excessive ERMCS formation and ER-to-mitochondria Ca2+ transfer. Genetic and pharmacological inhibition of VDAC or other ERMCS components restored synaptic structure, function, and plasticity and rescued locomotion and cognitive deficits of the Drosophila dFmr1 mutant. Expressing FMRP C-terminal domain (FMRP-C), which confers FMRP-VDAC interaction, rescued the ERMCS formation and mito-Ca2+ homeostasis defects in FXS patient iPSC-derived neurons and locomotion and cognitive deficits in Fmr1 knockout mice. These results identify altered ERMCS formation and mito-Ca2+ homeostasis as contributors to FXS and offer potential therapeutic targets.

  https://www.ncbi.nlm.nih.gov/pubmed/38888332 https://doi.org/10.1227/ons.0000000000001240

  More

• Alzheimer's Imaging Consortium.

  Talozzi, L., Peña-Tauber, A., Jensen, T. D., Wilson, E. N., Young, C. B., Stewart, I., Cobos, I., Vallejo, K., Hefti, M. M., Guen, Y. L., Williams, K., Vossler, H., Gorzynski, J., Andreasson, K. I., Mormino, E., Ashley, E., Greicius, M. D.

  Alzheimer's & dementia : the journal of the Alzheimer's Association

  ABSTRACT
  Thyroid-stimulating hormone-secreting adenomas (TSH-oma) are exceptionally rare.1 The primary treatment is surgical resection with radiation and pharmacotherapy postoperatively if subtotal resection, especially with cavernous sinus invasion.2 We present the case of a 29-year-old man with TSH-oma with cavernous sinus medial wall invasion. This is the first documented case with selective resection of the cavernous sinus medial wall to achieve a complete resection and biochemical remission in TSH-oma through endoscopic endonasal approach. The patient had elevated TSH and thyroid hormones with symptoms of weight loss, palpitations, excess sweating, and decreased endurance. MRI revealed a 1.3 × 2.1 × 1.2 cm contrast-enhancing sellar mass with rightward pituitary gland displacement without evidence of cavernous sinus invasion (Knosp 2). The patient consented to procedure/publication. No institutional review board approval needed per institution. We performed standard resection of the firm sellar tumor portion and noted that there was tumor invasion into the left cavernous sinus medial wall dura. The bony opening was expanded to expose the anterior wall of the cavernous sinus, which was opened to identify the cavernous internal carotid artery and the medial wall attachments. The thickened medial wall was completely resected. We achieved a complete tumor resection, and the patient's TSH and thyroid hormone dropped to a desired threshold.3 Tumor stained for GATA3 and PIT1, characterizing the TSH-oma.4,5 Understanding cavernous sinus vascular and ligamentous anatomy allows for safe separation of invaded medial wall dura from the cavernous internal carotid artery,6 allowing for a more complete tumor resection, improving surgical cure rates, and sparing the patient from future radiation and pharmacotherapy.

  https://www.ncbi.nlm.nih.gov/pubmed/39782943 https://doi.org/10.1002/alz.093931

  More

• Enhancing mitosis quantification and detection in meningiomas with computational digital pathology.

  Gu, H., Yang, C., Al-Kharouf, I., Magaki, S., Lakis, N., Williams, C. K., Alrosan, S. M., Onstott, E. K., Yan, W., Khanlou, N., Cobos, I., Zhang, X. R., Zarrin-Khameh, N., Vinters, H. V., Chen, X. A., Haeri, M.

  Acta neuropathologica communications

  ABSTRACT
  The generation and differentiation of B lymphocytes (B cells) is a flexible process with many critical regulatory factors. Previous studies indicated that non-coding RNAs play multiple roles in the development of lymphocytes. However, little has been known about the circular RNA (circRNA) profiles and their competing endogenous RNA (ceRNA) networks in B-cell development and differentiation. Here, four B-cell subsets were purified from single-cell suspensions of mouse bone marrow. Then RNA sequencing (RNA-Seq) was used to display expression profiles of circRNAs, miRNAs and mRNAs during B-cell differentiation. 175, 203, 219 and 207 circRNAs were specifically expressed in pro-B cells, pre-B cells, immature B cells and mature B cells, respectively. The circRNA-associated ceRNA networks constructed in two sequential stages of B-cell differentiation revealed the potential mechanism of circRNAs in these processes. This study is the first to explore circRNA profiles and circRNA-miRNA-mRNA networks in different B-cell developmental stages of mouse bone marrow, which contribute to further research on their mechanism in B-cell development and differentiation.

  https://www.ncbi.nlm.nih.gov/pubmed/38212848 https://doi.org/10.1186/s40478-023-01707-6

  More

• Molecular Signatures of Resilience to Alzheimer's Disease in Neocortical Layer 4 Neurons.

  Dharshini, S. A., Sanz-Ros, J., Pan, J., Tang, W., Vallejo, K., Otero-Garcia, M., Cobos, I.

  bioRxiv : the preprint server for biology

  ABSTRACT
  Mitosis is a critical criterion for meningioma grading. However, pathologists' assessment of mitoses is subject to significant inter-observer variation due to challenges in locating mitosis hotspots and accurately detecting mitotic figures. To address this issue, we leverage digital pathology and propose a computational strategy to enhance pathologists' mitosis assessment. The strategy has two components: (1) A depth-first search algorithm that quantifies the mathematically maximum mitotic count in 10 consecutive high-power fields, which can enhance the preciseness, especially in cases with borderline mitotic count. (2) Implementing a collaborative sphere to group a set of pathologists to detect mitoses under each high-power field, which can mitigate subjective random errors in mitosis detection originating from individual detection errors. By depth-first search algorithm (1) , we analyzed 19 meningioma slides and discovered that the proposed algorithm upgraded two borderline cases verified at consensus conferences. This improvement is attributed to the algorithm's ability to quantify the mitotic count more comprehensively compared to other conventional methods of counting mitoses. In implementing a collaborative sphere (2) , we evaluated the correctness of mitosis detection from grouped pathologists and/or pathology residents, where each member of the group annotated a set of 48 high-power field images for mitotic figures independently. We report that groups with sizes of three can achieve an average precision of 0.897 and sensitivity of 0.699 in mitosis detection, which is higher than an average pathologist in this study (precision: 0.750, sensitivity: 0.667). The proposed computational strategy can be integrated with artificial intelligence workflow, which envisions the future of achieving a rapid and robust mitosis assessment by interactive assisting algorithms that can ultimately benefit patient management.

  https://www.ncbi.nlm.nih.gov/pubmed/39574639 https://doi.org/10.1101/2024.11.03.621787

  More

• Majority voting of doctors improves appropriateness of AI reliance in pathology

  Gu, H., Yang, C., Magaki, S., Zarrin-Khameh, N., Lakis, N. S., Cobos, I., Khanlou, N., Zhang, X. R., Assi, J., Byers, J. T., Hamza, A., Han, K., Meyer, A., Mirbaha, H., Mohila, C. A., Stevens, T. M., Stone, S. L., Yan, W., Haeri, M., Chen, X.

  INTERNATIONAL JOURNAL OF HUMAN-COMPUTER STUDIES

  ABSTRACT
  Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

  https://www.ncbi.nlm.nih.gov/pubmed/37995687 https://doi.org/10.1016/j.ijhcs.2024.103315

  More

2023

• Lifelong restructuring of 3D genome architecture in cerebellar granule cells.

  Tan, L., Shi, J., Moghadami, S., Parasar, B., Wright, C. P., Seo, Y., Vallejo, K., Cobos, I., Duncan, L., Chen, R., Deisseroth, K.

  Science (New York, N.Y.)

  ABSTRACT
  The generation and differentiation of B lymphocytes (B cells) is a flexible process with many critical regulatory factors. Previous studies indicated that non-coding RNAs play multiple roles in the development of lymphocytes. However, little has been known about the circular RNA (circRNA) profiles and their competing endogenous RNA (ceRNA) networks in B-cell development and differentiation. Here, four B-cell subsets were purified from single-cell suspensions of mouse bone marrow. Then RNA sequencing (RNA-Seq) was used to display expression profiles of circRNAs, miRNAs and mRNAs during B-cell differentiation. 175, 203, 219 and 207 circRNAs were specifically expressed in pro-B cells, pre-B cells, immature B cells and mature B cells, respectively. The circRNA-associated ceRNA networks constructed in two sequential stages of B-cell differentiation revealed the potential mechanism of circRNAs in these processes. This study is the first to explore circRNA profiles and circRNA-miRNA-mRNA networks in different B-cell developmental stages of mouse bone marrow, which contribute to further research on their mechanism in B-cell development and differentiation.

  https://www.ncbi.nlm.nih.gov/pubmed/37676945 https://doi.org/10.1126/science.adh3253

  More

• Deregulation of ER-mitochondria contact formation and mitochondrial calcium homeostasis mediated by VDAC in fragile X syndrome.

  Geng, J., Khaket, T. P., Pan, J., Li, W., Zhang, Y., Ping, Y., Cobos Sillero, M. I., Lu, B.

  Developmental cell

  ABSTRACT
  Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

  https://www.ncbi.nlm.nih.gov/pubmed/37040696 https://doi.org/10.1016/j.devcel.2023.03.002

  More

• Sex-Specific Oligodendroglia Response in Alzheimer's Disease

  Bharani, K., Dharshini, A., Oberhauser, J., Cobos, I.

  ABSTRACT
  The generation and differentiation of B lymphocytes (B cells) is a flexible process with many critical regulatory factors. Previous studies indicated that non-coding RNAs play multiple roles in the development of lymphocytes. However, little has been known about the circular RNA (circRNA) profiles and their competing endogenous RNA (ceRNA) networks in B-cell development and differentiation. Here, four B-cell subsets were purified from single-cell suspensions of mouse bone marrow. Then RNA sequencing (RNA-Seq) was used to display expression profiles of circRNAs, miRNAs and mRNAs during B-cell differentiation. 175, 203, 219 and 207 circRNAs were specifically expressed in pro-B cells, pre-B cells, immature B cells and mature B cells, respectively. The circRNA-associated ceRNA networks constructed in two sequential stages of B-cell differentiation revealed the potential mechanism of circRNAs in these processes. This study is the first to explore circRNA profiles and circRNA-miRNA-mRNA networks in different B-cell developmental stages of mouse bone marrow, which contribute to further research on their mechanism in B-cell development and differentiation.

  https://www.ncbi.nlm.nih.gov/pubmed/35386709 https://doi.org/10.3389/fimmu.2022.812924

  More

• Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

  Torre, D., Fstkchyan, Y. S., Ho, J. S., Cheon, Y., Patel, R. S., Degrace, E. J., Mzoughi, S., Schwarz, M., Mohammed, K., Seo, J. S., Romero-Bueno, R., Demircioglu, D., Hasson, D., Tang, W., Mahajani, S. U., Campisi, L., Zheng, S., Song, W. S., Wang, Y. C., Shah, H., Francoeur, N., Soto, J., Salfati, Z., Weirauch, M. T., Warburton, P., Beaumont, K., Smith, M. L., Mulder, L., Villalta, S. A., Kessenbrock, K., Jang, C., Lee, D., De Rubeis, S., Cobos, I., Tam, O., Hammell, M. G., Seldin, M., Shi, Y., Basu, U., Sebastiano, V., Byun, M., Sebra, R., Rosenberg, B. R., Benner, C., Guccione, E., Marazzi, I.

  Molecular cell

  ABSTRACT
  The cerebellum contains most of the neurons in the human brain, and exhibits unique modes of development, malformation, and aging. For example, granule cells-the most abundant neuron type-develop unusually late and exhibit unique nuclear morphology. Here, by developing our high-resolution single-cell 3D genome assay Dip-C into population-scale (Pop-C) and virus-enriched (vDip-C) modes, we were able to resolve the first 3D genome structures of single cerebellar cells, create life-spanning 3D genome atlases for both human and mouse, and jointly measure transcriptome and chromatin accessibility during development. We found that while the transcriptome and chromatin accessibility of human granule cells exhibit a characteristic maturation pattern within the first year of postnatal life, 3D genome architecture gradually remodels throughout life into a non-neuronal state with ultra-long-range intra-chromosomal contacts and specific inter-chromosomal contacts. This 3D genome remodeling is conserved in mice, and robust to heterozygous deletion of chromatin remodeling disease-associated genes ( Chd8 or Arid1b ). Together these results reveal unexpected and evolutionarily-conserved molecular processes underlying the unique development and aging of the mammalian cerebellum.

  https://www.ncbi.nlm.nih.gov/pubmed/37995687 https://doi.org/10.1016/j.molcel.2023.10.036

  More

• Cerebellar Granule Cells Develop Non-neuronal 3D Genome Architecture over the Lifespan.

  Tan, L., Shi, J., Moghadami, S., Wright, C. P., Parasar, B., Seo, Y., Vallejo, K., Cobos, I., Duncan, L., Chen, R., Deisseroth, K.

  bioRxiv : the preprint server for biology

  ABSTRACT
  [Figure: see text].

  https://www.ncbi.nlm.nih.gov/pubmed/36865235 https://doi.org/10.1101/2023.02.25.530020

  More

2022

• Swollen axons impair neuronal circuits

  Cobos, I., Palop, J. J.

  NATURE

  ABSTRACT
  Though SARS-CoV-2 primarily targets the respiratory system, patients and survivors can suffer neurological symptoms1-3. Yet, an unbiased understanding of the cellular and molecular processes affected in the brains of COVID-19 patients is still missing. Here, we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control (including 1 terminal influenza) and 8 COVID-19 patients. While a systematic analysis yields no molecular traces of SARS-CoV-2 in the brain, we observe broad cellular perturbations which predict that choroid plexus barrier cells sense and relay peripheral inflammation into the brain and show that peripheral T cells infiltrate the parenchyma. We discover COVID-19 disease-associated microglia and astrocyte subpopulations that share features with pathological cell states reported in human neurodegenerative disease4-6. Synaptic signaling of upper-layer excitatory neurons-evolutionarily expanded in humans7 and linked to cognitive function8-are preferentially affected in COVID-19. Across cell types, COVID-19 perturbations overlap with those in chronic brain disorders and reside in genetic variants associated with cognition, schizophrenia, and depression. Our findings and public dataset provide a molecular framework to understand COVID-19 related neurological disease observed now and which may emerge later.

  https://www.ncbi.nlm.nih.gov/pubmed/34153974 https://doi.org/10.1038/s41586-021-03710-0

  More

• Human Astrocytes Exhibit Tumor Microenvironment-, Age-, and Sex-Related Transcriptomic Signatures.

  Krawczyk, M. C., Haney, J. R., Pan, L., Caneda, C., Khankan, R. R., Reyes, S. D., Chang, J. W., Morselli, M., Vinters, H. V., Wang, A. C., Cobos, I., Gandal, M. J., Bergsneider, M., Kim, W., Liau, L. M., Yong, W., Jalali, A., Deneen, B., Grant, G. A., Mathern, G. W., Fallah, A., Zhang, Y.

  The Journal of neuroscience : the official journal of the Society for Neuroscience

  ABSTRACT
  The specification of inhibitory neurons has been described for the mouse and human brain, and many studies have shown that pluripotent stem cells (PSCs) can be used to create interneurons invitro. It is unclear whether invitro methods to produce human interneurons generate all the subtypes found in brain, and how similar invitro and invivo interneurons are. We applied single-nuclei and single-cell transcriptomics to model interneuron development from human cortex and interneurons derived from PSCs. We provide a direct comparison of various invitro interneuron derivation methods to determine the homogeneity achieved. We find that PSC-derived interneurons capture stages of development prior to mid-gestation, and represent a minority of potential subtypes found in brain. Comparison with those found in fetal or adult brain highlighted decreased expression of synapse-related genes. These analyses highlight the potential to tailor the method of generation to drive formation of particular subtypes.

  https://www.ncbi.nlm.nih.gov/pubmed/34987109 https://doi.org/10.1523/JNEUROSCI.0407-21.2021

  More

• Swollen axons impair neuronal circuits

  Cobos, I., Palop, J. J. J.

  NATURE

  ABSTRACT
  Primary age-related tauopathy (PART) is a neurodegenerative pathology with features distinct from but also overlapping with Alzheimer disease (AD). While both exhibit Alzheimer-type temporal lobe neurofibrillary degeneration alongside amnestic cognitive impairment, PART develops independently of amyloid-β (Aβ) plaques. The pathogenesis of PART is not known, but evidence suggests an association with genes that promote tau pathology and others that protect from Aβ toxicity. Here, we performed a genetic association study in an autopsy cohort of individuals with PART (n = 647) using Braak neurofibrillary tangle stage as a quantitative trait. We found some significant associations with candidate loci associated with AD (SLC24A4, MS4A6A, HS3ST1) and progressive supranuclear palsy (MAPT and EIF2AK3). Genome-wide association analysis revealed a novel significant association with a single nucleotide polymorphism on chromosome 4 (rs56405341) in a locus containing three genes, including JADE1 which was significantly upregulated in tangle-bearing neurons by single-soma RNA-seq. Immunohistochemical studies using antisera targeting JADE1 protein revealed localization within tau aggregates in autopsy brains with four microtubule-binding domain repeats (4R) isoforms and mixed 3R/4R, but not with 3R exclusively. Co-immunoprecipitation in post-mortem human PART brain tissue revealed a specific binding of JADE1 protein to four repeat tau lacking N-terminal inserts (0N4R). Finally, knockdown of the Drosophila JADE1 homolog rhinoceros (rno) enhanced tau-induced toxicity and apoptosis in vivo in a humanized 0N4R mutant tau knock-in model, as quantified by rough eye phenotype and terminal deoxynucleotidyl transferase dUTP nick end-labeling (TUNEL) in the fly brain. Together, these findings indicate that PART has a genetic architecture that partially overlaps with AD and other tauopathies and suggests a novel role for JADE1 as a modifier of neurofibrillary degeneration.

  https://www.ncbi.nlm.nih.gov/pubmed/36450951 https://doi.org/10.1038/d41586-022-03800-7

  More

• Divergent Cortical Tau Positron Emission Tomography Patterns Among Patients With Preclinical Alzheimer Disease.

  Young, C. B., Winer, J. R., Younes, K., Cody, K. A., Betthauser, T. J., Johnson, S. C., Schultz, A., Sperling, R. A., Greicius, M. D., Cobos, I., Poston, K. L., Mormino, E. C., Alzheimers Disease Neuroimaging Initiative and the Harvard Aging Brain Study, Weiner, M. W., Aisen, P., Petersen, R., Jack, C. R., Jagust, W., Trojanowki, J. Q., Toga, A. W., Beckett, L., Green, R. C., Saykin, A. J., Morris, J. C., Perrin, R. J., Shaw, L. M., Khachaturian, Z., Carrillo, M., Potter, W., Barnes, L., Bernard, M., Gonzalez, H., Ho, C., Hsiao, J. K., Jackson, J., Masliah, E., Masterman, D., Okonkwo, O., Ryan, L., Silverberg, N., Fleisher, A., Sacrey, D. T., Fockler, J., Conti, C., Veitch, D., Neuhaus, J., Jin, C., Nosheny, R., Ashford, M., Flenniken, D., Kormos, A., Montine, T., Rafii, M., Raman, R., Jimenez, G., Donohue, M., Gessert, D., Salazar, J., Zimmerman, C., Cabrera, Y., Walter, S., Miller, G., Coker, G., Clanton, T., Hergesheimer, L., Smith, S., Adegoke, O., Mahboubi, P., Moore, S., Pizzola, J., Shaffer, E., Harvey, D., Forghanian-Arani, A., Borowski, B., Ward, C., Schwarz, C., Jones, D., Gunter, J., Kantarci, K., Senjem, M., Vemuri, P., Reid, R., Fox, N. C., Malone, I., Thompson, P., Thomopoulos, S. I., Nir, T. M., Jahanshad, N., DeCarli, C., Knaack, A., Fletcher, E., Tosun-Turgut, D., Chen, S. R., Choe, M., Crawford, K., Yuschkevich, P. A., Das, S., Koeppe, R. A., Reiman, E. M., Chen, K., Mathis, C., Landau, S., Cairns, N. J., Householder, E., Franklin, E., Bernhardt, H., Taylor-Reinwald, L., Korecka, M., Figurski, M., Neu, S., Nho, K., Risacher, S. L., Apostolova, L. G., Shen, L., Foroud, T. M., Nudelman, K., Faber, K., Wilmes, K., Thal, L., Johnson, K. A., Sperling, R. A.

  JAMA neurology

  ABSTRACT
  Astrocytes are critical for the development and function of synapses. There are notable species differences between human astrocytes and commonly used animal models. Yet, it is unclear whether astrocytic genes involved in synaptic function are stable or exhibit dynamic changes associated with disease states and age in humans, which is a barrier in understanding human astrocyte biology and its potential involvement in neurological diseases. To better understand the properties of human astrocytes, we acutely purified astrocytes from the cerebral cortices of over 40 humans across various ages, sexes, and disease states. We performed RNA sequencing to generate transcriptomic profiles of these astrocytes and identified genes associated with these biological variables. We found that human astrocytes in tumor-surrounding regions downregulate genes involved in synaptic function and sensing of signals in the microenvironment, suggesting involvement of peri-tumor astrocytes in tumor-associated neural circuit dysfunction. In aging, we also found downregulation of synaptic regulators and upregulation of markers of cytokine signaling, while in maturation we identified changes in ionic transport with implications for calcium signaling. In addition, we identified subtle sexual dimorphism in human cortical astrocytes, which has implications for observed sex differences across many neurological disorders. Overall, genes involved in synaptic function exhibit dynamic changes in the peritumor microenvironment and aging. This data provides powerful new insights into human astrocyte biology in several biologically relevant states, that will aid in generating novel testable hypotheses about homeostatic and reactive astrocytes in humans.SIGNIFICANCE STATEMENTAstrocytes are an abundant class of cells playing integral roles at synapses. Astrocyte dysfunction is implicated in a variety of human neurological diseases. Yet our knowledge of astrocytes is largely based on mouse studies. Direct knowledge of human astrocyte biology remains limited. Here, we present transcriptomic profiles of human cortical astrocytes, and we identified molecular differences associated with age, sex, and disease state. We found that peritumor and aging astrocytes downregulate genes involved in astrocyte-synapse interactions. These data provide necessary insight into human astrocyte biology that will improve our understanding of human disease.

  https://www.ncbi.nlm.nih.gov/pubmed/35435938 https://doi.org/10.1001/jamaneurol.2022.0676

  More

• Whole-Transcriptome Profiling and circRNA-miRNA-mRNA Regulatory Networks in B-Cell Development.

  Pan, J., Hu, S., Ren, X., Hu, H., Deng, X., Yu, B., Cobos, I., Chen, X., Zhang, W.

  Frontiers in immunology

  ABSTRACT
  [Figure: see text].

  https://www.ncbi.nlm.nih.gov/pubmed/35386709 https://doi.org/10.3389/fimmu.2022.812924

  More