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Article: Clathrin mediated endocytosis in Alzheimer's disease: cell type specific involvement in amyloid beta pathology.

Jaye, Sierra / Sandau, Ursula S / Saugstad, Julie A

2024 Volume 16, Page(s) 1378576

Abstract: This review provides a comprehensive examination of the role of clathrin-mediated endocytosis (CME) in Alzheimer's disease (AD) pathogenesis, emphasizing its impact across various cellular contexts beyond neuronal dysfunction. In neurons, dysregulated ... ...

Abstract	This review provides a comprehensive examination of the role of clathrin-mediated endocytosis (CME) in Alzheimer's disease (AD) pathogenesis, emphasizing its impact across various cellular contexts beyond neuronal dysfunction. In neurons, dysregulated CME contributes to synaptic dysfunction, amyloid beta (Aβ) processing, and Tau pathology, highlighting its involvement in early AD pathogenesis. Furthermore, CME alterations extend to non-neuronal cell types, including astrocytes and microglia, which play crucial roles in Aβ clearance and neuroinflammation. Dysregulated CME in these cells underscores its broader implications in AD pathophysiology. Despite significant progress, further research is needed to elucidate the precise mechanisms underlying CME dysregulation in AD and its therapeutic implications. Overall, understanding the complex interplay between CME and AD across diverse cell types holds promise for identifying novel therapeutic targets and interventions.
Language	English
Publishing date	2024-04-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2558898-9
ISSN	1663-4365
ISSN	1663-4365
DOI	10.3389/fnagi.2024.1378576
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Article ; Online: Toward a better understanding of inflammatory microvesicles in alcohol use disorder.

Sandau, Ursula S / Loftis, Jennifer M

Journal of neuroscience research

2021 Volume 99, Issue 10, Page(s) 2364–2366

MeSH term(s)	Alcoholism/diagnosis ; Alcoholism/metabolism ; Animals ; Cell-Derived Microparticles/drug effects ; Cell-Derived Microparticles/metabolism ; Ethanol/administration & dosage ; Ethanol/toxicity ; Humans ; Inflammation Mediators/metabolism
Chemical Substances	Inflammation Mediators ; Ethanol (3K9958V90M)
Language	English
Publishing date	2021-07-22
Publishing country	United States
Document type	Letter ; Review
ZDB-ID	195324-2
ISSN	1097-4547 ; 0360-4012
ISSN (online)	1097-4547
ISSN	0360-4012
DOI	10.1002/jnr.24930
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Article ; Online: Analysis of the longitudinal stability of human plasma miRNAs and implications for disease biomarkers.

Sandau, Ursula S / Wiedrick, Jack T / McFarland, Trevor J / Galasko, Douglas R / Fanning, Zoe / Quinn, Joseph F / Saugstad, Julie A

Scientific reports

2024 Volume 14, Issue 1, Page(s) 2148

Abstract: There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal ... ...

Abstract	There is great interest in developing clinical biomarker assays that can aid in non-invasive diagnosis and/or monitoring of human diseases, such as cancer, cardiovascular disease, and neurological diseases. Yet little is known about the longitudinal stability of miRNAs in human plasma. Here we assessed the intraindividual longitudinal stability of miRNAs in plasma from healthy human adults, and the impact of common factors (e.g., hemolysis, age) that may confound miRNA data. We collected blood by venipuncture biweekly over a 3-month period from 22 research participants who had fasted overnight, isolated total RNA, then performed miRNA qPCR. Filtering and normalization of the qPCR data revealed amplification of 134 miRNAs, 74 of which had high test-retest reliability and low percentage level drift, meaning they were stable in an individual over the 3-month time period. We also determined that, of nuisance factors, hemolysis and tobacco use have the greatest impact on miRNA levels and variance. These findings support that many miRNAs show intraindividual longitudinal stability in plasma from healthy human adults, including some reported as candidate biomarkers for Alzheimer's disease.
MeSH term(s)	Adult ; Humans ; MicroRNAs/genetics ; Hemolysis ; Reproducibility of Results ; Plasma ; Biomarkers
Chemical Substances	MicroRNAs ; Biomarkers
Language	English
Publishing date	2024-01-25
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-024-52681-5
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Article: Differential Effects of APOE Genotype on MicroRNA Cargo of Cerebrospinal Fluid Extracellular Vesicles in Females With Alzheimer's Disease Compared to Males.

Sandau, Ursula S / McFarland, Trevor J / Smith, Sierra J / Galasko, Douglas R / Quinn, Joseph F / Saugstad, Julie A

Frontiers in cell and developmental biology

2022 Volume 10, Page(s) 864022

Abstract: Multiple biological factors, including age, sex, and genetics, influence Alzheimer's disease (AD) risk. Of the 6.2 million Americans living with Alzheimer's dementia in 2021, 3.8 million are women and 2.4 million are men. The strongest genetic risk ... ...

Abstract	Multiple biological factors, including age, sex, and genetics, influence Alzheimer's disease (AD) risk. Of the 6.2 million Americans living with Alzheimer's dementia in 2021, 3.8 million are women and 2.4 million are men. The strongest genetic risk factor for sporadic AD is apolipoprotein E-e4 (APOE-e4). Female APOE-e4 carriers develop AD more frequently than age-matched males and have more brain atrophy and memory loss. Consequently, biomarkers that are sensitive to biological risk factors may improve AD diagnostics and may provide insight into underlying mechanistic changes that could drive disease progression. Here, we have assessed the effects of sex and APOE-e4 on the miRNA cargo of cerebrospinal fluid (CSF) extracellular vesicles (EVs) in AD. We used ultrafiltration (UF) combined with size exclusion chromatography (SEC) to enrich CSF EVs (e.g., Flotillin+). CSF EVs were isolated from female and male AD or controls (CTLs) that were either APOE-e3,4 or -e3,3 positive (n = 7/group, 56 total). MiRNA expression levels were quantified using a custom TaqMan™ array that assayed 190 miRNAs previously found in CSF, including 25 miRNAs that we previously validated as candidate AD biomarkers. We identified changes in the EV miRNA cargo that were affected by both AD and sex. In total, four miRNAs (miR-16-5p, -331-3p, -409-3p, and -454-3p) were significantly increased in AD vs. CTL, independent of sex and APOE-e4 status. Pathway analysis of the predicted gene targets of these four miRNAs with identified pathways was highly relevant to neurodegeneration (e.g., senescence and autophagy). There were also three miRNAs (miR-146b-5p, -150-5p, and -342-3p) that were significantly increased in females vs. males, independent of disease state and APOE-e4 status. We then performed a statistical analysis to assess the effect of APOE genotype in AD within each sex and found that APOE-e4 status affects different subsets of CSF EV miRNAs in females vs. males. Together, this study demonstrates the complexity of the biological factors associated with AD risk and the impact on EV miRNAs, which may contribute to AD pathophysiology.
Language	English
Publishing date	2022-04-27
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2737824-X
ISSN	2296-634X
ISSN	2296-634X
DOI	10.3389/fcell.2022.864022
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Article ; Online: Transient use of a systemic adenosine kinase inhibitor attenuates epilepsy development in mice.

Sandau, Ursula S / Yahya, Mayadah / Bigej, Ryan / Friedman, Joseph L / Saleumvong, Bounmy / Boison, Detlev

Epilepsia

2019 Volume 60, Issue 4, Page(s) 615–625

Abstract: Objective: Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct ... ...

Abstract	Objective: Over one-third of all patients with epilepsy are refractory to treatment and there is an urgent need to develop new drugs that can prevent the development and progression of epilepsy. Epileptogenesis is characterized by distinct histopathologic and biochemical changes, which include astrogliosis and increased expression of the adenosine-metabolizing enzyme adenosine kinase (ADK; EC 2.7.1.20). Increased expression of ADK contributes to epileptogenesis and is therefore a target for therapeutic intervention. We tested the prediction that the transient use of an ADK inhibitor administered during the latent phase of epileptogenesis can mitigate the development of epilepsy. Methods: We used the intrahippocampal kainic acid (KA) mouse model of temporal lobe epilepsy, which is characterized by ipsilateral hippocampal sclerosis with granule cell dispersion and the development of recurrent hippocampal paroxysmal discharges (HPDs). KA-injected mice were treated with the ADK inhibitor 5-iodotubercidin (5-ITU, 1.6 mg/kg, b.i.d., i.p.) during the latent phase of epileptogenesis from day 3-8 after injury; the period when gradual increases in hippocampal ADK expression begin to manifest. HPDs were assessed at 6 and 9 weeks after KA administration followed by epilepsy histopathology including assessment of granule cell dispersion, astrogliosis, and ADK expression. Results: 5-ITU significantly reduced the percent time in seizures by at least 80% in 56% of mice at 6 weeks post-KA. This reduction in seizure activity was maintained in 40% of 5-ITU-treated mice at 9 weeks. 5-ITU also suppressed granule cell dispersion and prevented maladaptive ADK increases in these protected mice. Significance: Our results show that the transient use of a small-molecule ADK inhibitor, given during the early stages of epileptogenesis, has antiepileptogenic disease-modifying properties, which provides the rationale for further investigation into the development of a novel class of antiepileptogenic ADK inhibitors with increased efficacy for epilepsy prevention.
MeSH term(s)	Adenosine Kinase/antagonists & inhibitors ; Animals ; Anticonvulsants/pharmacology ; Brain/drug effects ; Enzyme Inhibitors/pharmacology ; Epilepsy ; Male ; Mice ; Mice, Inbred C57BL ; Tubercidin/analogs & derivatives ; Tubercidin/pharmacology
Chemical Substances	Anticonvulsants ; Enzyme Inhibitors ; 5-iodotubercidin (24386-93-4) ; Adenosine Kinase (EC 2.7.1.20) ; Tubercidin (M351LCX45Y)
Language	English
Publishing date	2019-02-27
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	216382-2
ISSN	1528-1167 ; 0013-9580
ISSN (online)	1528-1167
ISSN	0013-9580
DOI	10.1111/epi.14674
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Zs.A 517: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 475: Show issues

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Article ; Online: Identification of miRNAs That Mediate Protective Functions of Anti-Cancer Drugs During White Matter Ischemic Injury.

Baltan, Selva / Sandau, Ursula S / Brunet, Sylvain / Bastian, Chinthasagar / Tripathi, Ajai / Nguyen, Hung / Liu, Helen / Saugstad, Julie A / Zarnegarnia, Yalda / Dutta, Ranjan

ASN neuro

2021 Volume 13, Page(s) 17590914211042220

Abstract: We have previously shown that two anti-cancer drugs, CX-4945 and MS-275, protect and preserve white matter (WM) architecture and improve functional recovery in a model of WM ischemic injury. While both compounds promote recovery, CX-4945 is a selective ... ...

Abstract	We have previously shown that two anti-cancer drugs, CX-4945 and MS-275, protect and preserve white matter (WM) architecture and improve functional recovery in a model of WM ischemic injury. While both compounds promote recovery, CX-4945 is a selective Casein kinase 2 (CK2) inhibitor and MS-275 is a selective Class I histone deacetylase (HDAC) inhibitor. Alterations in microRNAs (miRNAs) mediate some of the protective actions of these drugs. In this study, we aimed to (1) identify miRNAs expressed in mouse optic nerves (MONs); (2) determine which miRNAs are regulated by oxygen glucose deprivation (OGD); and (3) determine the effects of CX-4945 and MS-275 treatment on miRNA expression. RNA isolated from MONs from control and OGD-treated animals with and without CX-4945 or MS-275 treatment were quantified using NanoString nCounter
MeSH term(s)	Animals ; Antineoplastic Agents/pharmacology ; Apoptosis ; Glucose ; Mice ; MicroRNAs/genetics ; White Matter
Chemical Substances	Antineoplastic Agents ; MicroRNAs ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2021-10-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2485467-0
ISSN	1759-0914 ; 1759-0914
ISSN (online)	1759-0914
ISSN	1759-0914
DOI	10.1177/17590914211042220
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Article: Cerebrospinal Fluid MicroRNA Changes in Cognitively Normal Veterans With a History of Deployment-Associated Mild Traumatic Brain Injury.

Lusardi, Theresa A / Sandau, Ursula S / Sakhanenko, Nikita A / Baker, Sarah Catherine B / Wiedrick, Jack T / Lapidus, Jodi A / Raskind, Murray A / Li, Ge / Peskind, Elaine R / Galas, David J / Quinn, Joseph F / Saugstad, Julie A

Frontiers in neuroscience

2021 Volume 15, Page(s) 720778

Abstract: A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer's disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of ... ...

Abstract	A history of traumatic brain injury (TBI) increases the odds of developing Alzheimer's disease (AD). The long latent period between injury and dementia makes it difficult to study molecular changes initiated by TBI that may increase the risk of developing AD. MicroRNA (miRNA) levels are altered in TBI at acute times post-injury (<4 weeks), and in AD. We hypothesized that miRNA levels in cerebrospinal fluid (CSF) following TBI in veterans may be indicative of increased risk for developing AD. Our population of interest is cognitively normal veterans with a history of one or more mild TBI (mTBI) at a chronic time following TBI. We measured miRNA levels in CSF from three groups of participants: (1) community controls with no lifetime history of TBI (ComC); (2) deployed Iraq/Afghanistan veterans with no lifetime history of TBI (DepC), and (3) deployed Iraq/Afghanistan veterans with a history of repetitive blast mTBI (DepTBI). CSF samples were collected at the baseline visit in a longitudinal, multimodal assessment of Gulf War veterans, and represent a heterogenous group of male veterans and community controls. The average time since the last blast mTBI experienced was 4.7 ± 2.2 years [1.5 - 11.5]. Statistical analysis of TaqMan
Language	English
Publishing date	2021-09-09
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2411902-7
ISSN	1662-453X ; 1662-4548
ISSN (online)	1662-453X
ISSN	1662-4548
DOI	10.3389/fnins.2021.720778
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Article ; Online: Recommendations for reproducibility of cerebrospinal fluid extracellular vesicle studies.

Journal of extracellular vesicles

2023 Volume 13, Issue 1, Page(s) e12397

Abstract: Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the ... ...

Abstract	Cerebrospinal fluid (CSF) is a clear, transparent fluid derived from blood plasma that protects the brain and spinal cord against mechanical shock, provides buoyancy, clears metabolic waste and transports extracellular components to remote sites in the brain. Given its contact with the brain and the spinal cord, CSF is the most informative biofluid for studies of the central nervous system (CNS). In addition to other components, CSF contains extracellular vesicles (EVs) that carry bioactive cargoes (e.g., lipids, nucleic acids, proteins), and that can have biological functions within and beyond the CNS. Thus, CSF EVs likely serve as both mediators of and contributors to communication in the CNS. Accordingly, their potential as biomarkers for CNS diseases has stimulated much excitement for and attention to CSF EV research. However, studies on CSF EVs present unique challenges relative to EV studies in other biofluids, including the invasive nature of CSF collection, limited CSF volumes and the low numbers of EVs in CSF as compared to plasma. Here, the objectives of the International Society for Extracellular Vesicles CSF Task Force are to promote the reproducibility of CSF EV studies by providing current reporting and best practices, and recommendations and reporting guidelines, for CSF EV studies. To accomplish this, we created and distributed a world-wide survey to ISEV members to assess methods considered 'best practices' for CSF EVs, then performed a detailed literature review for CSF EV publications that was used to curate methods and resources. Based on responses to the survey and curated information from publications, the CSF Task Force herein provides recommendations and reporting guidelines to promote the reproducibility of CSF EV studies in seven domains: (i) CSF Collection, Processing, and Storage; (ii) CSF EV Separation/Concentration; (iii) CSF EV Size and Number Measurements; (iv) CSF EV Protein Studies; (v) CSF EV RNA Studies; (vi) CSF EV Omics Studies and (vii) CSF EV Functional Studies.
MeSH term(s)	Biomarkers/metabolism ; Brain/metabolism ; Extracellular Vesicles/metabolism ; Proteins/metabolism ; Reproducibility of Results
Chemical Substances	Biomarkers ; Proteins
Language	English
Publishing date	2023-12-29
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2683797-3
ISSN	2001-3078 ; 2001-3078
ISSN (online)	2001-3078
ISSN	2001-3078
DOI	10.1002/jev2.12397
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Article ; Online: Correcting deregulated Fxyd1 expression rescues deficits in neuronal arborization and potassium homeostasis in MeCP2 deficient male mice.

Matagne, Valerie / Wondolowski, Joyce / Frerking, Matthew / Shahidullah, Mohammad / Delamere, Nicholas A / Sandau, Ursula S / Budden, Sarojini / Ojeda, Sergio R

Brain research

2018 Volume 1697, Page(s) 45–52

Abstract: Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because ... ...

Abstract	Rett syndrome (RTT) is a neurodevelopmental disorder caused by mutations in the MECP2 gene. In the absence of MeCP2, expression of FXYD domain-containing transport regulator 1 (FXYD1) is deregulated in the frontal cortex (FC) of mice and humans. Because Fxyd1 is a membrane protein that controls cell excitability by modulating Na
MeSH term(s)	Animals ; Cell Membrane/metabolism ; Disease Models, Animal ; Gene Expression Regulation ; Homeostasis ; Male ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Methyl-CpG-Binding Protein 2/genetics ; Methyl-CpG-Binding Protein 2/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Neuronal Plasticity/genetics ; Neurons/metabolism ; Phenotype ; Phosphoproteins/genetics ; Phosphoproteins/metabolism ; Potassium/metabolism ; Rett Syndrome/genetics ; Rett Syndrome/physiopathology ; Sodium-Potassium-Exchanging ATPase/metabolism
Chemical Substances	Mecp2 protein, mouse ; Membrane Proteins ; Methyl-CpG-Binding Protein 2 ; Phosphoproteins ; phospholemman (135541-82-1) ; Sodium-Potassium-Exchanging ATPase (EC 7.2.2.13) ; Potassium (RWP5GA015D)
Language	English
Publishing date	2018-06-12
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1200-2
ISSN	1872-6240 ; 0006-8993
ISSN (online)	1872-6240
ISSN	0006-8993
DOI	10.1016/j.brainres.2018.06.013
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Zs.A 161: Show issues

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Article ; Online: Performance of Validated MicroRNA Biomarkers for Alzheimer's Disease in Mild Cognitive Impairment.

Sandau, Ursula S / Wiedrick, Jack T / Smith, Sierra J / McFarland, Trevor J / Lusardi, Theresa A / Lind, Babett / Harrington, Christina A / Lapidus, Jodi A / Galasko, Douglas R / Quinn, Joseph F / Saugstad, Julie A

Journal of Alzheimer's disease : JAD

2020 Volume 78, Issue 1, Page(s) 245–263

Abstract: Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI).: Objective: To assess whether a set of ... ...

Abstract	Background: Cerebrospinal fluid (CSF) microRNA (miRNA) biomarkers of Alzheimer's disease (AD) have been identified, but have not been evaluated in prodromal AD, including mild cognitive impairment (MCI). Objective: To assess whether a set of validated AD miRNA biomarkers in CSF are also sensitive to early-stage pathology as exemplified by MCI diagnosis. Methods: We measured the expression of 17 miRNA biomarkers for AD in CSF samples from AD, MCI, and cognitively normal controls (NC). We then examined classification performance of the miRNAs individually and in combination. For each miRNA, we assessed median expression in each diagnostic group and classified markers as trending linearly, nonlinearly, or lacking any trend across the three groups. For trending miRNAs, we assessed multimarker classification performance alone and in combination with apolipoprotein E ɛ4 allele (APOEɛ4) genotype and amyloid-β42 to total tau ratio (Aβ42:T-Tau). We identified predicted targets of trending miRNAs using pathway analysis. Results: Five miRNAs showed a linear trend of decreasing median expression across the ordered diagnoses (control to MCI to AD). The trending miRNAs jointly predicted AD with area under the curve (AUC) of 0.770, and MCI with AUC of 0.705. Aβ42:T-Tau alone predicted MCI with AUC of 0.758 and the AUC improved to 0.813 (p = 0.051) after adding the trending miRNAs. Multivariate correlation of the five trending miRNAs with Aβ42:T-Tau was weak. Conclusion: Selected miRNAs combined with Aβ42:T-Tau improved classification performance (relative to protein biomarkers alone) for MCI, despite a weak correlation with Aβ42:T-Tau. Together these data suggest that that these miRNAs carry novel information relevant to AD, even at the MCI stage. Preliminary target prediction analysis suggests novel roles for these biomarkers.
MeSH term(s)	Aged ; Aged, 80 and over ; Alzheimer Disease/cerebrospinal fluid ; Amyloid beta-Peptides/cerebrospinal fluid ; Apolipoprotein E4 ; Biomarkers/cerebrospinal fluid ; Case-Control Studies ; Cognitive Dysfunction/cerebrospinal fluid ; Disease Progression ; Female ; Humans ; Male ; MicroRNAs/cerebrospinal fluid ; Middle Aged ; Neuropsychological Tests ; tau Proteins/cerebrospinal fluid
Chemical Substances	Amyloid beta-Peptides ; Apolipoprotein E4 ; Biomarkers ; MicroRNAs ; tau Proteins
Language	English
Publishing date	2020-08-29
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1440127-7
ISSN	1875-8908 ; 1387-2877
ISSN (online)	1875-8908
ISSN	1387-2877
DOI	10.3233/JAD-200396
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