IU Indianapolis ScholarWorks :: Browsing by Author "Vidal, Ruben"

Browsing by Author "Vidal, Ruben"

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A1 reactive astrocytes and a loss of TREM2 are associated with an early stage of pathology in a mouse model of cerebral amyloid angiopathy
(BMC, 2020-07-25) Taylor, Xavier; Cisternas, Pablo; You, Yanwen; You, Yingjian; Xiang, Shunian; Marambio, Yamil; Zhang, Jie; Vidal, Ruben; Lasagna-Reeves, Cristian A.; Anatomy and Cell Biology, School of Medicine
Background Cerebral amyloid angiopathy (CAA) is typified by the cerebrovascular deposition of amyloid. The mechanisms underlying the contribution of CAA to neurodegeneration are not currently understood. Although CAA is highly associated with the accumulation of amyloid beta (Aβ), other amyloids are known to associate with the vasculature. Alzheimer’s disease (AD) is characterized by parenchymal Aβ deposition, intracellular accumulation of tau, and significant neuroinflammation. CAA increases with age and is present in 85–95% of individuals with AD. A substantial amount of research has focused on understanding the connection between parenchymal amyloid and glial activation and neuroinflammation, while associations between vascular amyloid pathology and glial reactivity remain understudied. Methods Here, we dissect the glial and immune responses associated with early-stage CAA with histological, biochemical, and gene expression analyses in a mouse model of familial Danish dementia (FDD), a neurodegenerative disease characterized by the vascular accumulation of Danish amyloid (ADan). Findings observed in this CAA mouse model were complemented with primary culture assays. Results We demonstrate that early-stage CAA is associated with dysregulation in immune response networks and lipid processing, severe astrogliosis with an A1 astrocytic phenotype, and decreased levels of TREM2 with no reactive microgliosis. Our results also indicate how cholesterol accumulation and ApoE are associated with vascular amyloid deposits at the early stages of pathology. We also demonstrate A1 astrocytic mediation of TREM2 and microglia homeostasis. Conclusion The initial glial response associated with early-stage CAA is characterized by the upregulation of A1 astrocytes without significant microglial reactivity. Gene expression analysis revealed that several AD risk factors involved in immune response and lipid processing may also play a preponderant role in CAA. This study contributes to the increasing evidence that brain cholesterol metabolism, ApoE, and TREM2 signaling are major players in the pathogenesis of AD-related dementias, including CAA. Understanding the basis for possible differential effects of glial response, ApoE, and TREM2 signaling on parenchymal plaques versus vascular amyloid deposits provides important insight for developing future therapeutic interventions.
Abnormal iron metabolism in fibroblasts from a patient with the neurodegenerative disease hereditary ferritinopathy
(BMC, 2010-11-10) Barbeito, Ana G.; Levade, Thierry; Delisle, Marie B.; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
Background Nucleotide duplications in exon 4 of the ferritin light polypeptide (FTL) gene cause the autosomal dominant neurodegenerative disease neuroferritinopathy or hereditary ferritinopathy (HF). Pathologic examination of patients with HF has shown abnormal ferritin and iron accumulation in neurons and glia in the central nervous system (CNS) as well as in cells of other organ systems, including skin fibroblasts. To gain some understanding on the molecular basis of HF, we characterized iron metabolism in primary cultures of human skin fibroblasts from an individual with the FTL c.497_498dupTC mutation. Results Compared to normal controls, HF fibroblasts showed abnormal iron metabolism consisting of increased levels of ferritin polypeptides, divalent metal transporter 1, basal iron content and reactive oxygen species, and decreased levels of transferrin receptor-1 and IRE-IRP binding activity. Conclusions Our data indicates that HF fibroblasts replicate the abnormal iron metabolism observed in the CNS of patients with HF. We propose that HF fibroblasts are a unique cellular model in which to study the role of abnormal iron metabolism in the pathogenesis of HF without artifacts derived from over-expression or lack of endogenous translational regulatory elements.
Activated endothelial cells induce a distinct type of astrocytic reactivity
(Springer Nature, 2022-03-29) Taylor, Xavier; Cisternas, Pablo; Jury, Nur; Martinez, Pablo; Huang, Xiaoqing; You, Yanwen; Redding-Ochoa, Javier; Vidal, Ruben; Zhang, Jie; Troncoso, Juan; Lasagna-Reeves, Cristian A.; Anatomy, Cell Biology and Physiology, School of Medicine
Reactive astrogliosis is a universal response of astrocytes to abnormal events and injuries. Studies have shown that proinflammatory microglia can polarize astrocytes (designated A1 astrocytes) toward a neurotoxic phenotype characterized by increased Complement Component 3 (C3) expression. It is still unclear if inflammatory stimuli from other cell types may also be capable of inducing a subset of C3+ neurotoxic astrocytes. Here, we show that a subtype of C3+ neurotoxic astrocytes is induced by activated endothelial cells that is distinct from astrocytes activated by microglia. Furthermore, we show that endothelial-induced astrocytes have upregulated expression of A1 astrocytic genes and exhibit a distinctive extracellular matrix remodeling profile. Finally, we demonstrate that endothelial-induced astrocytes are Decorin-positive and are associated with vascular amyloid deposits but not parenchymal amyloid plaques in mouse models and AD/CAA patients. These findings demonstrate the existence of potentially extensive and subtle functional diversity of C3+-reactive astrocytes.
Age-dependent formation of TMEM106B amyloid filaments in human brains
(Springer Nature, 2022) Schweighauser, Manuel; Arseni, Diana; Bacioglu, Mehtap; Huang, Melissa; Lövestam, Sofia; Shi, Yang; Yang, Yang; Zhang, Wenjuan; Kotecha, Abhay; Garringer, Holly J.; Vidal, Ruben; Hallinan, Grace I.; Newell, Kathy L.; Tarutani, Airi; Murayama, Shigeo; Miyazaki, Masayuki; Saito, Yuko; Yoshida, Mari; Hasegawa, Kazuko; Lashley, Tammaryn; Revesz, Tamas; Kovacs, Gabor G.; van Swieten, John; Takao, Masaki; Hasegawa, Masato; Ghetti, Bernardino; Spillantini, Maria Grazia; Ryskeldi-Falcon, Benjamin; Murzin, Alexey G.; Goedert, Michel; Scheres, Sjors H.W.; Pathology and Laboratory Medicine, School of Medicine
Many age-dependent neurodegenerative diseases, such as Alzheimer's and Parkinson's, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120-254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.
Amyloid and intracellular accumulation of BRI2
(Elsevier, 2017-04) Garringer, Holly J.; Sammeta, Neeraja; Oblak, Adrian; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
Familial British dementia (FBD) and familial Danish dementia (FDD) are caused by mutations in the BRI2 gene. These diseases are characterized clinically by progressive dementia and ataxia and neuropathologically by amyloid deposits and neurofibrillary tangles. Herein, we investigate BRI2 protein accumulation in FBD, FDD, Alzheimer disease and Gerstmann-Sträussler-Scheinker disease. In FBD and FDD, we observed reduced processing of the mutant BRI2 pro-protein, which was found accumulating intracellularly in the Golgi of neurons and glial cells. In addition, we observed an accumulation of a mature form of BRI2 protein in dystrophic neurites, surrounding amyloid cores. Accumulation of BRI2 was also observed in dystrophic neurites of Alzheimer disease and Gerstmann-Sträussler-Scheinker disease cases. Although it remains to be determined whether intracellular accumulation of BRI2 may lead to cell damage in these degenerative diseases, our study provides new insights into the role of mutant BRI2 in the pathogenesis of FBD and FDD and implicates BRI2 as a potential indicator of neuritic damage in diseases characterized by cerebral amyloid deposition.
Correction to: Cryo-EM structures of tau filaments from Alzheimer’s disease with PET ligand APN-1607
(SpringerLink, 2021-06) Shi, Yang; Murzin, Alexey G.; Falcon, Benjamin; Epstein, Alexander; Machin, Jonathan; Tempest, Paul; Newell, Kathy L.; Vidal, Ruben; Garringer, Holly J.; Sahara, Naruhiko; Higuchi, Makoto; Ghetti, Bernardino; Jang, Ming‑Kuei; Scheres, Sjors H.W; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Correction to: Acta Neuropathologica 10.1007/s00401-021-02294-3
Cross-β helical filaments of Tau and TMEM106B in gray and white matter of multiple system tauopathy with presenile dementia
(Springer, 2023) Hoq, Md. Rejaul; Bharath, Sakshibeedu R.; Hallinan, Grace I.; Fernandez, Anllely; Vago, Frank S.; Ozcan, Kadir A.; Li, Daoyi; Garringer, Holly J.; Vidal, Ruben; Ghetti, Bernardino; Jiang, Wen; Pathology and Laboratory Medicine, School of Medicine
Cryo-EM structures and functional characterization of homo- and heteropolymers of human ferritin variants
(Nature, 2020-11-26) Irimia-Dominguez, Jose; Sun, Chen; Li, Kunpeng; Muhoberac, Barry B.; Hallinan, Grace I.; Garringer, Holly J.; Ghetti, Bernardino; Jiang, Wen; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
The role of abnormal brain iron metabolism in neurodegenerative diseases is still insufficiently understood. Here, we investigate the molecular basis of the neurodegenerative disease hereditary ferritinopathy (HF), in which dysregulation of brain iron homeostasis is the primary cause of neurodegeneration. We mutagenized ferritin's three-fold pores (3FPs), i.e. the main entry route for iron, to investigate ferritin's iron management when iron must traverse the protein shell through the disrupted four-fold pores (4FPs) generated by mutations in the ferritin light chain (FtL) gene in HF. We assessed the structure and properties of ferritins using cryo-electron microscopy and a range of functional analyses in vitro. Loss of 3FP function did not alter ferritin structure but led to a decrease in protein solubility and iron storage. Abnormal 4FPs acted as alternate routes for iron entry and exit in the absence of functional 3FPs, further reducing ferritin iron-storage capacity. Importantly, even a small number of MtFtL subunits significantly compromises ferritin solubility and function, providing a rationale for the presence of ferritin aggregates in cell types expressing different levels of FtLs in patients with HF. These findings led us to discuss whether modifying pores could be used as a pharmacological target in HF.
Cryo-EM structures of amyloid-β 42 filaments from human brains
(American Association for the Advancement of Science, 2022) Yang, Yang; Arseni, Diana; Zhang, Wenjuan; Huang, Melissa; Lövestam, Sofia; Schweighauser, Manuel; Kotecha, Abhay; Murzin, Alexey G.; Peak-Chew, Sew Y.; Macdonald, Jennifer; Lavenir, Isabelle; Garringer, Holly J.; Gelpi, Ellen; Newell, Kathy L.; Kovacs, Gabor G.; Vidal, Ruben; Ghetti, Bernardino; Falcon, Benjamin; Scheres, Sjors H.W.; Goedert, Michel; Pathology and Laboratory Medicine, School of Medicine
Filament assembly of amyloid-β peptides ending at residue 42 (Aβ42) is a central event in Alzheimer’s disease. Here, we report the cryo–electron microscopy (cryo-EM) structures of Aβ42 filaments from human brains. Two structurally related S-shaped protofilament folds give rise to two types of filaments. Type I filaments were found mostly in the brains of individuals with sporadic Alzheimer’s disease, and type II filaments were found in individuals with familial Alzheimer’s disease and other conditions. The structures of Aβ42 filaments from the brain differ from those of filaments assembled in vitro. By contrast, in AppNL-F knock-in mice, Aβ42 deposits were made of type II filaments. Knowledge of Aβ42 filament structures from human brains may lead to the development of inhibitors of assembly and improved imaging agents.
Cryo-EM structures of amyloid-β and tau filaments in Down syndrome
(Springer Nature, 2024) Fernandez, Anllely; Hoq, Md Rejaul; Hallinan, Grace I.; Li, Daoyi; Bharath, Sakshibeedu R.; Vago, Frank S.; Zhang, Xiaoqi; Ozcan, Kadir A.; Newell, Kathy L.; Garringer, Holly J.; Jiang, Wen; Ghetti, Bernardino; Vidal, Ruben; Pathology and Laboratory Medicine, School of Medicine
Adult individuals with Down syndrome (DS) develop Alzheimer disease (AD). Whether there is a difference between AD in DS and AD regarding the structure of amyloid-β (Aβ) and tau filaments is unknown. Here we report the structure of Aβ and tau filaments from two DS brains. We found two Aβ40 filaments (types IIIa and IIIb) that differ from those previously reported in sporadic AD and two types of Aβ42 filaments (I and II) identical to those found in sporadic and familial AD. Tau filaments (paired helical filaments and straight filaments) were identical to those in AD, supporting the notion of a common mechanism through which amyloids trigger aggregation of tau. This knowledge is important for understanding AD in DS and assessing whether adults with DS could be included in AD clinical trials.

Browsing by Author "Vidal, Ruben"

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