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1.
bioRxiv ; 2024 Jun 03.
Article in English | MEDLINE | ID: mdl-38895239

ABSTRACT

Post-Acute Sequelae of COVID-19 (PASC) encompasses persistent neurological symptoms, including olfactory and autonomic dysfunction. Here, we report chronic neurological dysfunction in mice infected with a virulent mouse-adapted SARS-CoV-2 that does not infect the brain. Long after recovery from nasal infection, we observed loss of tyrosine hydroxylase (TH) expression in olfactory bulb glomeruli and neurotransmitter levels in the substantia nigra (SN) persisted. Vulnerability of dopaminergic neurons in these brain areas was accompanied by increased levels of proinflammatory cytokines and neurobehavioral changes. RNAseq analysis unveiled persistent microglia activation, as found in human neurodegenerative diseases. Early treatment with antivirals (nirmatrelvir and molnupiravir) reduced virus titers and lung inflammation but failed to prevent neurological abnormalities, as observed in patients. Together these results show that chronic deficiencies in neuronal function in SARS-CoV-2-infected mice are not directly linked to ongoing olfactory epithelium dysfunction. Rather, they bear similarity with neurodegenerative disease, the vulnerability of which is exacerbated by chronic inflammation.

2.
bioRxiv ; 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38895380

ABSTRACT

Neuroinflammation is a pathological feature of many neurodegenerative diseases, including Alzheimer's disease (AD)1,2 and amyotrophic lateral sclerosis (ALS)3, raising the possibility of common therapeutic targets. We previously established that cytoplasmic double-stranded RNA (cdsRNA) is spatially coincident with cytoplasmic pTDP-43 inclusions in neurons of patients with C9ORF72-mediated ALS4. CdsRNA triggers a type-I interferon (IFN-I)-based innate immune response in human neural cells, resulting in their death4. Here, we report that cdsRNA is also spatially coincident with pTDP-43 cytoplasmic inclusions in brain cells of patients with AD pathology and that type-I interferon response genes are significantly upregulated in brain regions affected by AD. We updated our machine-learning pipeline DRIAD-SP (Drug Repurposing In Alzheimer's Disease with Systems Pharmacology) to incorporate cryptic exon (CE) detection as a proxy of pTDP-43 inclusions and demonstrated that the FDA-approved JAK inhibitors baricitinib and ruxolitinib that block interferon signaling show a protective signal only in cortical brain regions expressing multiple CEs. Furthermore, the JAK family member TYK2 was a top hit in a CRISPR screen of cdsRNA-mediated death in differentiated human neural cells. The selective TYK2 inhibitor deucravacitinib, an FDA-approved drug for psoriasis, rescued toxicity elicited by cdsRNA. Finally, we identified CCL2, CXCL10, and IL-6 as candidate predictive biomarkers for cdsRNA-related neurodegenerative diseases. Together, we find parallel neuroinflammatory mechanisms between TDP-43 associated-AD and ALS and nominate TYK2 as a possible disease-modifying target of these incurable neurodegenerative diseases.

3.
Nat Commun ; 15(1): 4809, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844444

ABSTRACT

The direct access of olfactory afferents to memory-related cortical systems has inspired theories about the role of the olfactory pathways in the development of cortical neurodegeneration in Alzheimer's disease (AD). In this study, we used baseline olfactory identification measures with longitudinal flortaucipir and PiB PET, diffusion MRI of 89 cognitively normal older adults (73.82 ± 8.44 years; 56% females), and a transcriptomic data atlas to investigate the spatiotemporal spreading and genetic vulnerabilities of AD-related pathology aggregates in the olfactory system. We find that odor identification deficits are predominantly associated with tau accumulation in key areas of the olfactory pathway, with a particularly strong predictive power for longitudinal tau progression. We observe that tau spreads from the medial temporal lobe structures toward the olfactory system, not the reverse. Moreover, we observed a genetic background of odor perception-related genes that might confer vulnerability to tau accumulation along the olfactory system.


Subject(s)
Aging , Alzheimer Disease , Olfactory Perception , Positron-Emission Tomography , tau Proteins , Humans , Female , tau Proteins/metabolism , tau Proteins/genetics , Male , Aged , Olfactory Perception/physiology , Aging/physiology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/physiopathology , Aged, 80 and over , Olfactory Pathways/metabolism , Olfactory Pathways/diagnostic imaging , Smell/physiology , Brain/metabolism , Brain/diagnostic imaging , Temporal Lobe/metabolism , Temporal Lobe/diagnostic imaging , Middle Aged
4.
Acta Neuropathol ; 147(1): 56, 2024 03 13.
Article in English | MEDLINE | ID: mdl-38478117

ABSTRACT

The stimulator of interferon genes (STING) pathway has been implicated in neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). While prior studies have focused on STING within immune cells, little is known about STING within neurons. Here, we document neuronal activation of the STING pathway in human postmortem cortical and spinal motor neurons from individuals affected by familial or sporadic ALS. This process takes place selectively in the most vulnerable cortical and spinal motor neurons but not in neurons that are less affected by the disease. Concordant STING activation in layer V cortical motor neurons occurs in a mouse model of C9orf72 repeat-associated ALS and frontotemporal dementia (FTD). To establish that STING activation occurs in a neuron-autonomous manner, we demonstrate the integrity of the STING signaling pathway, including both upstream activators and downstream innate immune response effectors, in dissociated mouse cortical neurons and neurons derived from control human induced pluripotent stem cells (iPSCs). Human iPSC-derived neurons harboring different familial ALS-causing mutations exhibit increased STING signaling with DNA damage as a main driver. The elevated downstream inflammatory markers present in ALS iPSC-derived neurons can be suppressed with a STING inhibitor. Our results reveal an immunophenotype that consists of innate immune signaling driven by the STING pathway and occurs specifically within vulnerable neurons in ALS/FTD.


Subject(s)
Amyotrophic Lateral Sclerosis , Frontotemporal Dementia , Induced Pluripotent Stem Cells , Pick Disease of the Brain , Animals , Humans , Mice , Amyotrophic Lateral Sclerosis/genetics , Amyotrophic Lateral Sclerosis/metabolism , C9orf72 Protein/genetics , Frontotemporal Dementia/genetics , Frontotemporal Dementia/metabolism , Induced Pluripotent Stem Cells/metabolism , Motor Neurons/metabolism
5.
Comput Methods Programs Biomed ; 242: 107819, 2023 Dec.
Article in English | MEDLINE | ID: mdl-37774426

ABSTRACT

BACKGROUND AND OBJECTIVE: Competing risks data arise in both observational and experimental clinical studies with time-to-event outcomes, when each patient might follow one of the multiple mutually exclusive competing paths. Ignoring competing risks in the analysis can result in biased conclusions. In addition, possible confounding bias of the treatment-outcome relationship has to be addressed, when estimating treatment effects from observational data. In order to provide tools for estimation of average treatment effects on time-to-event outcomes in the presence of competing risks, we developed the R package causalCmprsk. We illustrate the package functionality in the estimation of effects of a right heart catheterization procedure on discharge and in-hospital death from observational data. METHODS: The causalCmprsk package implements an inverse probability weighting estimation approach, aiming to emulate baseline randomization and alleviate possible treatment selection bias. The package allows for different types of weights, representing different target populations. causalCmprsk builds on existing methods from survival analysis and adapts them to the causal analysis in non-parametric and semi-parametric frameworks. RESULTS: The causalCmprsk package has two main functions: fit.cox assumes a semiparametric structural Cox proportional hazards model for the counterfactual cause-specific hazards, while fit.nonpar does not impose any structural assumptions. In both frameworks, causalCmprsk implements estimators of (i) absolute risks for each treatment arm, e.g., cumulative hazards or cumulative incidence functions, and (ii) relative treatment effects, e.g., hazard ratios, or restricted mean time differences. The latter treatment effect measure translates the treatment effect from probability into more intuitive time domain and allows the user to quantify, for example, by how many days or months the treatment accelerates the recovery or postpones illness or death. CONCLUSIONS: The causalCmprsk package provides a convenient and useful tool for causal analysis of competing risks data. It allows the user to distinguish between different causes of the end of follow-up and provides several time-varying measures of treatment effects. The package is accompanied by a vignette that contains more details, examples and code, making the package accessible even for non-expert users.


Subject(s)
Models, Statistical , Humans , Hospital Mortality , Proportional Hazards Models , Survival Analysis , Probability
6.
Nat Commun ; 13(1): 7652, 2022 Dec 10.
Article in English | MEDLINE | ID: mdl-36496454

ABSTRACT

Metformin, a diabetes drug with anti-aging cellular responses, has complex actions that may alter dementia onset. Mixed results are emerging from prior observational studies. To address this complexity, we deploy a causal inference approach accounting for the competing risk of death in emulated clinical trials using two distinct electronic health record systems. In intention-to-treat analyses, metformin use associates with lower hazard of all-cause mortality and lower cause-specific hazard of dementia onset, after accounting for prolonged survival, relative to sulfonylureas. In parallel systems pharmacology studies, the expression of two AD-related proteins, APOE and SPP1, was suppressed by pharmacologic concentrations of metformin in differentiated human neural cells, relative to a sulfonylurea. Together, our findings suggest that metformin might reduce the risk of dementia in diabetes patients through mechanisms beyond glycemic control, and that SPP1 is a candidate biomarker for metformin's action in the brain.


Subject(s)
Dementia , Diabetes Mellitus, Type 2 , Metformin , Humans , Metformin/pharmacology , Metformin/therapeutic use , Drug Repositioning , Network Pharmacology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Sulfonylurea Compounds , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Dementia/drug therapy , Dementia/etiology , Medical Records
7.
J Alzheimers Dis ; 88(2): 721-729, 2022.
Article in English | MEDLINE | ID: mdl-35694921

ABSTRACT

BACKGROUND: Olfactory dysfunction is one of the earliest signs of Alzheimer's disease (AD), highlighting its potential use as a biomarker for early detection. It has also been linked to progression from mild cognitive impairment (MCI) to dementia. OBJECTIVE: To study olfactory function and its associations with markers of AD brain pathology in non-demented mutation carriers of an autosomal dominant AD (ADAD) mutation and non-carrier family members. METHODS: We analyzed cross-sectional data from 16 non-demented carriers of the Presenilin1 E280A ADAD mutation (mean age [SD]: 40.1 [5.3], and 19 non-carrier family members (mean age [SD]: 36.0 [5.5]) from Colombia, who completed olfactory and cognitive testing and underwent amyloid and tau positron emission tomography (PET) imaging. RESULTS: Worse olfactory identification performance was associated with greater age in mutation carriers (r = -0.52 p = 0.037). In carriers, worse olfactory identification performance was related to worse MMSE scores (r = 0.55, p = 0.024) and CERAD delayed recall (r = 0.63, p = 0.007) and greater cortical amyloid-ß (r = -0.53, p = 0.042) and tau pathology burden (entorhinal: r = -0.59, p = 0.016; inferior temporal: r = -0.52, p = 0.038). CONCLUSION: Worse performance on olfactory identification tasks was associated with greater age, a proxy for disease progression in this genetically vulnerable ADAD cohort. In addition, this is the first study to report olfactory dysfunction in ADAD mutation carriers with diagnosis of MCI and its correlation with abnormal accumulation of tau pathology in the entorhinal region. Taken together, our findings suggest that olfactory dysfunction has promise as an early marker of brain pathology and future risk for dementia.


Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Olfaction Disorders , Alzheimer Disease/diagnostic imaging , Alzheimer Disease/genetics , Amyloid beta-Peptides/metabolism , Biomarkers , Brain/pathology , Cognitive Dysfunction/diagnostic imaging , Cognitive Dysfunction/genetics , Cognitive Dysfunction/pathology , Cross-Sectional Studies , Humans , Magnetic Resonance Imaging/methods , Olfaction Disorders/etiology , Olfaction Disorders/genetics , Positron-Emission Tomography/methods , tau Proteins/genetics , tau Proteins/metabolism
8.
Int Forum Allergy Rhinol ; 12(4): 327-680, 2022 04.
Article in English | MEDLINE | ID: mdl-35373533

ABSTRACT

BACKGROUND: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O). METHODS: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus. RESULTS: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies. CONCLUSION: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further.


Subject(s)
Hypersensitivity , Smell , Consensus , Cost of Illness , Humans
9.
Lancet Neurol ; 20(9): 753-761, 2021 09.
Article in English | MEDLINE | ID: mdl-34339626

ABSTRACT

BACKGROUND: The mechanisms by which any upper respiratory virus, including SARS-CoV-2, impairs chemosensory function are not known. COVID-19 is frequently associated with olfactory dysfunction after viral infection, which provides a research opportunity to evaluate the natural course of this neurological finding. Clinical trials and prospective and histological studies of new-onset post-viral olfactory dysfunction have been limited by small sample sizes and a paucity of advanced neuroimaging data and neuropathological samples. Although data from neuropathological specimens are now available, neuroimaging of the olfactory system during the acute phase of infection is still rare due to infection control concerns and critical illness and represents a substantial gap in knowledge. RECENT DEVELOPMENTS: The active replication of SARS-CoV-2 within the brain parenchyma (ie, in neurons and glia) has not been proven. Nevertheless, post-viral olfactory dysfunction can be viewed as a focal neurological deficit in patients with COVID-19. Evidence is also sparse for a direct causal relation between SARS-CoV-2 infection and abnormal brain findings at autopsy, and for trans-synaptic spread of the virus from the olfactory epithelium to the olfactory bulb. Taken together, clinical, radiological, histological, ultrastructural, and molecular data implicate inflammation, with or without infection, in either the olfactory epithelium, the olfactory bulb, or both. This inflammation leads to persistent olfactory deficits in a subset of people who have recovered from COVID-19. Neuroimaging has revealed localised inflammation in intracranial olfactory structures. To date, histopathological, ultrastructural, and molecular evidence does not suggest that SARS-CoV-2 is an obligate neuropathogen. WHERE NEXT?: The prevalence of CNS and olfactory bulb pathosis in patients with COVID-19 is not known. We postulate that, in people who have recovered from COVID-19, a chronic, recrudescent, or permanent olfactory deficit could be prognostic for an increased likelihood of neurological sequelae or neurodegenerative disorders in the long term. An inflammatory stimulus from the nasal olfactory epithelium to the olfactory bulbs and connected brain regions might accelerate pathological processes and symptomatic progression of neurodegenerative disease. Persistent olfactory impairment with or without perceptual distortions (ie, parosmias or phantosmias) after SARS-CoV-2 infection could, therefore, serve as a marker to identify people with an increased long-term risk of neurological disease.


Subject(s)
COVID-19/complications , COVID-19/diagnostic imaging , Olfaction Disorders/diagnostic imaging , Olfaction Disorders/etiology , Olfactory Mucosa/diagnostic imaging , Brain/diagnostic imaging , Brain/physiopathology , Brain/virology , COVID-19/physiopathology , Humans , Neurodegenerative Diseases/diagnostic imaging , Neurodegenerative Diseases/etiology , Neurodegenerative Diseases/physiopathology , Olfaction Disorders/physiopathology , Olfaction Disorders/virology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Prospective Studies , Smell/physiology
10.
Sci Transl Med ; 13(601)2021 07 07.
Article in English | MEDLINE | ID: mdl-34233951

ABSTRACT

Triggers of innate immune signaling in the CNS of patients with amyotrophic lateral sclerosis and frontotemporal degeneration (ALS/FTD) remain elusive. We report the presence of cytoplasmic double-stranded RNA (cdsRNA), an established trigger of innate immunity, in ALS-FTD brains carrying C9ORF72 intronic hexanucleotide expansions that included genomically encoded expansions of the G4C2 repeat sequences. The presence of cdsRNA in human brains was coincident with cytoplasmic TAR DNA binding protein 43 (TDP-43) inclusions, a pathologic hallmark of ALS/FTD. Introducing cdsRNA into cultured human neural cells induced type I interferon (IFN-I) signaling and death that was rescued by FDA-approved JAK inhibitors. In mice, genomically encoded dsRNAs expressed exclusively in a neuronal class induced IFN-I and death in connected neurons non-cell-autonomously. Our findings establish that genomically encoded cdsRNAs trigger sterile, viral-mimetic IFN-I induction and propagated death within neural circuits and may drive neuroinflammation and neurodegeneration in patients with ALS/FTD.


Subject(s)
Amyotrophic Lateral Sclerosis , C9orf72 Protein , Frontotemporal Dementia , Amyotrophic Lateral Sclerosis/genetics , Animals , Brain/metabolism , C9orf72 Protein/genetics , DNA Repeat Expansion , Frontotemporal Dementia/genetics , Humans , Mice , RNA, Double-Stranded
11.
Alzheimers Dement ; 17(9): 1487-1498, 2021 09.
Article in English | MEDLINE | ID: mdl-33938131

ABSTRACT

INTRODUCTION: Despite strong evidence linking amyloid beta (Aß) to Alzheimer's disease, most clinical trials have shown no clinical efficacy for reasons that remain unclear. To understand why, we developed a quantitative systems pharmacology (QSP) model for seven therapeutics: aducanumab, crenezumab, solanezumab, bapineuzumab, elenbecestat, verubecestat, and semagacestat. METHODS: Ordinary differential equations were used to model the production, transport, and aggregation of Aß; pharmacology of the drugs; and their impact on plaque. RESULTS: The calibrated model predicts that endogenous plaque turnover is slow, with an estimated half-life of 2.75 years. This is likely why beta-secretase inhibitors have a smaller effect on plaque reduction. Of the mechanisms tested, the model predicts binding to plaque and inducing antibody-dependent cellular phagocytosis is the best approach for plaque reduction. DISCUSSION: A QSP model can provide novel insights to clinical results. Our model explains the results of clinical trials and provides guidance for future therapeutic development.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Computer Simulation , Network Pharmacology , Pharmaceutical Preparations , Alzheimer Disease/drug therapy , Alzheimer Disease/immunology , Amyloid Precursor Protein Secretases/therapeutic use , Amyloid beta-Peptides/drug effects , Amyloid beta-Peptides/metabolism , Antibodies, Monoclonal, Humanized/therapeutic use , Humans
12.
Nat Commun ; 12(1): 1033, 2021 02 15.
Article in English | MEDLINE | ID: mdl-33589615

ABSTRACT

Clinical trials of novel therapeutics for Alzheimer's Disease (AD) have consumed a large amount of time and resources with largely negative results. Repurposing drugs already approved by the Food and Drug Administration (FDA) for another indication is a more rapid and less expensive option. We present DRIAD (Drug Repurposing In AD), a machine learning framework that quantifies potential associations between the pathology of AD severity (the Braak stage) and molecular mechanisms as encoded in lists of gene names. DRIAD is applied to lists of genes arising from perturbations in differentiated human neural cell cultures by 80 FDA-approved and clinically tested drugs, producing a ranked list of possible repurposing candidates. Top-scoring drugs are inspected for common trends among their targets. We propose that the DRIAD method can be used to nominate drugs that, after additional validation and identification of relevant pharmacodynamic biomarker(s), could be readily evaluated in a clinical trial.


Subject(s)
Alzheimer Disease/drug therapy , Drugs, Investigational/pharmacology , Machine Learning , Nerve Tissue Proteins/genetics , Neuroprotective Agents/pharmacology , Nootropic Agents/pharmacology , Prescription Drugs/pharmacology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cerebral Cortex/pathology , Drug Repositioning , Drugs, Investigational/chemistry , Gene Expression Profiling , Gene Expression Regulation , High-Throughput Screening Assays , Humans , Nerve Tissue Proteins/antagonists & inhibitors , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Neurons/pathology , Neuroprotective Agents/chemistry , Nootropic Agents/chemistry , Pharmacogenetics/methods , Pharmacogenetics/statistics & numerical data , Polypharmacology , Prescription Drugs/chemistry , Primary Cell Culture , Severity of Illness Index
13.
Neuron ; 107(2): 219-233, 2020 07 22.
Article in English | MEDLINE | ID: mdl-32640192

ABSTRACT

The main neurological manifestation of COVID-19 is loss of smell or taste. The high incidence of smell loss without significant rhinorrhea or nasal congestion suggests that SARS-CoV-2 targets the chemical senses through mechanisms distinct from those used by endemic coronaviruses or other common cold-causing agents. Here we review recently developed hypotheses about how SARS-CoV-2 might alter the cells and circuits involved in chemosensory processing and thereby change perception. Given our limited understanding of SARS-CoV-2 pathogenesis, we propose future experiments to elucidate disease mechanisms and highlight the relevance of this ongoing work to understanding how the virus might alter brain function more broadly.


Subject(s)
Betacoronavirus , Coronavirus Infections/physiopathology , Olfaction Disorders/physiopathology , Pneumonia, Viral/physiopathology , Smell/physiology , Taste Disorders/physiopathology , Taste/physiology , Animals , COVID-19 , Coronavirus Infections/epidemiology , Humans , Olfaction Disorders/epidemiology , Olfaction Disorders/virology , Olfactory Bulb/physiopathology , Olfactory Bulb/virology , Olfactory Mucosa/physiopathology , Olfactory Mucosa/virology , Pandemics , Pneumonia, Viral/epidemiology , SARS-CoV-2 , Taste Disorders/epidemiology , Taste Disorders/virology
14.
medRxiv ; 2020 Jun 16.
Article in English | MEDLINE | ID: mdl-32587994

ABSTRACT

Post-infectious anosmias typically follow death of olfactory sensory neurons (OSNs) with a months-long recovery phase associated with parosmias. While profound anosmia is the leading symptom associated with COVID-19 infection, many patients regain olfactory function within days to weeks without distortions. Here, we demonstrate that sterile induction of anti-viral type I interferon signaling in the mouse olfactory epithelium is associated with diminished odor discrimination and reduced odor-evoked local field potentials. RNA levels of all class I, class II, and TAAR odorant receptors are markedly reduced in OSNs in a non-cell autonomous manner. We find that people infected with COVID-19 rate odors with lower intensities and have odor discrimination deficits relative to people that tested negative for COVID-19. Taken together, we propose that inflammatory-mediated loss of odorant receptor expression with preserved circuit integrity accounts for the profound anosmia and rapid recovery of olfactory function without parosmias caused by COVID-19.

15.
Cell ; 178(5): 1159-1175.e17, 2019 08 22.
Article in English | MEDLINE | ID: mdl-31442405

ABSTRACT

Expansion of CAG trinucleotide repeats in ATXN1 causes spinocerebellar ataxia type 1 (SCA1), a neurodegenerative disease that impairs coordination and cognition. While ATXN1 is associated with increased Alzheimer's disease (AD) risk, CAG repeat number in AD patients is not changed. Here, we investigated the consequences of ataxin-1 loss of function and discovered that knockout of Atxn1 reduced CIC-ETV4/5-mediated inhibition of Bace1 transcription, leading to increased BACE1 levels and enhanced amyloidogenic cleavage of APP, selectively in AD-vulnerable brain regions. Elevated BACE1 expression exacerbated Aß deposition and gliosis in AD mouse models and impaired hippocampal neurogenesis and olfactory axonal targeting. In SCA1 mice, polyglutamine-expanded mutant ataxin-1 led to the increase of BACE1 post-transcriptionally, both in cerebrum and cerebellum, and caused axonal-targeting deficit and neurodegeneration in the hippocampal CA2 region. These findings suggest that loss of ataxin-1 elevates BACE1 expression and Aß pathology, rendering it a potential contributor to AD risk and pathogenesis.


Subject(s)
Alzheimer Disease/pathology , Amyloid Precursor Protein Secretases/metabolism , Ataxin-1/metabolism , Brain/metabolism , Alzheimer Disease/metabolism , Amyloid Precursor Protein Secretases/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Ataxin-1/deficiency , Ataxin-1/genetics , Brain/pathology , CA2 Region, Hippocampal/metabolism , CA2 Region, Hippocampal/pathology , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Disease Models, Animal , Female , Gene Frequency , Humans , Male , Mice , Mice, Transgenic , Neurogenesis , Proto-Oncogene Proteins c-ets/genetics , Proto-Oncogene Proteins c-ets/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription, Genetic , Trinucleotide Repeats/genetics , Up-Regulation
16.
Sci Data ; 6: 190016, 2019 02 19.
Article in English | MEDLINE | ID: mdl-30778261

ABSTRACT

The immortalized human ReNcell VM cell line represents a reproducible and easy-to-propagate cell culture system for studying the differentiation of neural progenitors. To better characterize the starting line and its subsequent differentiation, we assessed protein and phospho-protein levels and cell morphology over a 15-day period during which ReNcell progenitors differentiated into neurons, astrocytes and oligodendrocytes. Five of the resulting datasets measured protein levels or states of phosphorylation based on tandem-mass-tag (TMT) mass spectrometry and four datasets characterized cellular phenotypes using high-content microscopy. Proteomic analysis revealed reproducible changes in pathways responsible for cytoskeletal rearrangement, cell phase transitions, neuronal migration, glial differentiation, neurotrophic signalling and extracellular matrix regulation. Proteomic and imaging data revealed accelerated differentiation in cells treated with the poly-selective CDK and GSK3 inhibitor kenpaullone or the HMG-CoA reductase inhibitor mevastatin, both of which have previously been reported to promote neural differentiation. These data provide in-depth information on the ReNcell progenitor state and on neural differentiation in the presence and absence of drugs, setting the stage for functional studies.


Subject(s)
Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Neurogenesis , Proteome/analysis , Cell Line , Cell Movement , Humans , Neurogenesis/physiology , Neurons/cytology , Tandem Mass Spectrometry
17.
J Pediatr Hematol Oncol ; 40(5): e273-e277, 2018 07.
Article in English | MEDLINE | ID: mdl-29771861

ABSTRACT

The dose-limiting toxicity for vincristine is peripheral neuropathy which can be potentiated with concurrent usage of azole antifungals. The current retrospective study assessed the incidence of concurrent vincristine and azole antifungal usage to determine if it led to increased neurotoxicity for the Kaiser Northern California pediatric acute lymphoblastic leukemia (ALL) and Hodgkin lymphoma patient population. Data were obtained from the electronic medical record (2007 to 2014). In total, 130 subjects received at least one dose of vincristine for ALL or Hodgkin lymphoma (median age 9, 88% ALL, 58% male, 47% Caucasian). Thirty one percent of patients received concurrent antifungal usage (fluconazole, 78%; voriconazole, 10%; fluconazole/voriconazole, 12%); however, concurrent antifungal usage accounted for <15% of vincristine doses. Grade 2 or greater neuropathy occurred in 51% of patients; grade 3 neuropathy was present in 8% of patients. No difference in the incidence of grade 2 or greater neuropathy was observed with the concurrent use of antifungal therapy (P=0.35), sex (P=0.59), type of cancer (P=0.41), ethnicity (P=0.29), or age (P=0.39), but was higher with increasing amount of vincristine doses (P=0.004). These results suggest that concurrent azole antifungal usage with vincristine for patients with ALL and Hodgkin lymphoma was low in the Kaiser Northern California population and limited usage as needed may be reasonable and safe.


Subject(s)
Antifungal Agents/adverse effects , Hodgkin Disease , Peripheral Nervous System Diseases , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Vincristine/adverse effects , Adolescent , Adult , Antifungal Agents/administration & dosage , California , Child , Child, Preschool , Female , Hodgkin Disease/drug therapy , Hodgkin Disease/epidemiology , Humans , Infant , Male , Peripheral Nervous System Diseases/chemically induced , Peripheral Nervous System Diseases/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology , Retrospective Studies , Vincristine/administration & dosage
19.
J Neurosci ; 37(41): 9880-9888, 2017 10 11.
Article in English | MEDLINE | ID: mdl-28899917

ABSTRACT

Activity-dependent synaptic plasticity plays a critical role in the refinement of circuitry during postnatal development and may be disrupted in conditions that cause intellectual disability, such as Down syndrome (DS). To test this hypothesis, visual cortical plasticity was assessed in Ts65Dn mice that harbor a chromosomal duplication syntenic to human chromosome 21q. We find that Ts65Dn mice demonstrate a defect in ocular dominance plasticity (ODP) following monocular deprivation. This phenotype is similar to that of transgenic mice that express amyloid precursor protein (APP), which is duplicated in DS and in Ts65DN mice; however, normalizing APP gene copy number in Ts65Dn mice fails to rescue plasticity. Ts1Rhr mice harbor a duplication of the telomeric third of the Ts65Dn-duplicated sequence and demonstrate the same ODP defect, suggesting a gene or genes sufficient to drive the phenotype are located in that smaller duplication. In addition, we find that Ts65Dn mice demonstrate an abnormality in olfactory system connectivity, a defect in the refinement of connections to second-order neurons in the olfactory bulb. Ts1Rhr mice do not demonstrate a defect in glomerular refinement, suggesting that distinct genes or sets of genes underlie visual and olfactory system phenotypes. Importantly, these data suggest that developmental plasticity and connectivity are impaired in sensory systems in DS model mice, that such defects may contribute to functional impairment in DS, and that these phenotypes, present in male and female mice, provide novel means for examining the genetic and molecular bases for neurodevelopmental impairment in model mice in vivoSIGNIFICANCE STATEMENT Our understanding of the basis for intellectual impairment in Down syndrome is hindered by the large number of genes duplicated in Trisomy 21 and a lack of understanding of the effect of disease pathology on the function of neural circuits in vivo This work describes early postnatal developmental abnormalities in visual and olfactory sensory systems in Down syndrome model mice, which provide insight into defects in the function of neural circuits in vivo and provide an approach for exploring the genetic and molecular basis for impairment in the disease. In addition, these findings raise the possibility that basic dysfunction in primary sensory circuitry may illustrate mechanisms important for global learning and cognitive impairment in Down syndrome patients.


Subject(s)
Down Syndrome/physiopathology , Olfactory Pathways/physiopathology , Smell , Vision, Ocular , Visual Pathways/physiopathology , Animals , Blindness/physiopathology , Cytoskeletal Proteins/genetics , Dominance, Ocular , Female , Male , Mice , Mice, Inbred C3H , Mice, Inbred C57BL , Nerve Tissue Proteins/genetics , Neuronal Plasticity , Visual Cortex/physiopathology
20.
J Clin Invest ; 127(2): 681-694, 2017 Feb 01.
Article in English | MEDLINE | ID: mdl-28112682

ABSTRACT

Olfactory dysfunction is broadly associated with neurodevelopmental and neurodegenerative diseases and predicts increased mortality rates in healthy individuals. Conventional measurements of olfactory health assess odor processing pathways within the brain and provide a limited understanding of primary odor detection. Quantification of the olfactory sensory neurons (OSNs), which detect odors within the nasal cavity, would provide insight into the etiology of olfactory dysfunction associated with disease and mortality. Notably, OSNs are continually replenished by adult neurogenesis in mammals, including humans, so OSN measurements are primed to provide specialized insights into neurological disease. Here, we have evaluated a PET radiotracer, [11C]GV1-57, that specifically binds mature OSNs and quantifies the mature OSN population in vivo. [11C]GV1-57 monitored native OSN population dynamics in rodents, detecting OSN generation during postnatal development and aging-associated neurodegeneration. [11C]GV1-57 additionally measured rates of neuron regeneration after acute injury and early-stage OSN deficits in a rodent tauopathy model of neurodegenerative disease. Preliminary assessment in nonhuman primates suggested maintained uptake and saturable binding of [18F]GV1-57 in primate nasal epithelium, supporting its translational potential. Future applications for GV1-57 include monitoring additional diseases or conditions associated with olfactory dysregulation, including cognitive decline, as well as monitoring effects of neuroregenerative or neuroprotective therapeutics.


Subject(s)
Aging , Olfaction Disorders/diagnostic imaging , Olfactory Nerve/diagnostic imaging , Olfactory Pathways/diagnostic imaging , Positron-Emission Tomography/methods , Tauopathies/diagnostic imaging , Animals , Male , Olfaction Disorders/physiopathology , Olfactory Nerve/physiopathology , Olfactory Pathways/physiopathology , Radioactive Tracers , Rats , Rats, Sprague-Dawley , Tauopathies/physiopathology
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