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Article ; Online: Doxycycline for transgene control disrupts gut microbiome diversity without compromising acute neuroinflammatory response.

Koller, Emily J / Wood, Caleb A / Lai, Zoe / Borgenheimer, Ella / Hoffman, Kristi L / Jankowsky, Joanna L

2024 Volume 21, Issue 1, Page(s) 11

Abstract: The tetracycline transactivator (tTA) system provides controllable transgene expression through oral administration of the broad-spectrum antibiotic doxycycline. Antibiotic treatment for transgene control in mouse models of disease might have undesirable ...

Abstract	The tetracycline transactivator (tTA) system provides controllable transgene expression through oral administration of the broad-spectrum antibiotic doxycycline. Antibiotic treatment for transgene control in mouse models of disease might have undesirable systemic effects resulting from changes in the gut microbiome. Here we assessed the impact of doxycycline on gut microbiome diversity in a tTA-controlled model of Alzheimer's disease and then examined neuroimmune effects of these microbiome alterations following acute LPS challenge. We show that doxycycline decreased microbiome diversity in both transgenic and wild-type mice and that these changes persisted long after drug withdrawal. Despite the change in microbiome composition, doxycycline treatment had minimal effect on basal transcriptional signatures of inflammation the brain or on the neuroimmune response to LPS challenge. Our findings suggest that central neuroimmune responses may be less affected by doxycycline at doses needed for transgene control than by antibiotic cocktails at doses used for experimental microbiome disruption.
MeSH term(s)	Mice ; Animals ; Doxycycline/pharmacology ; Mice, Transgenic ; Gastrointestinal Microbiome ; Lipopolysaccharides ; Tetracycline/pharmacology ; Anti-Bacterial Agents/pharmacology ; Anti-Bacterial Agents/therapeutic use ; Trans-Activators/genetics ; Inflammation ; Transgenes
Chemical Substances	Doxycycline (N12000U13O) ; Lipopolysaccharides ; Tetracycline (F8VB5M810T) ; Anti-Bacterial Agents ; Trans-Activators
Language	English
Publishing date	2024-01-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-023-03004-4
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Article: The TMEM106B T186S coding variant increases neurite arborization and synaptic density in primary hippocampal neurons.

Nguyen, Quynh / Wood, Caleb A / Kim, Peter J / Jankowsky, Joanna L

Frontiers in neuroscience

2023 Volume 17, Page(s) 1275959

Abstract: The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer's disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with ... ...

Abstract	The lysosomal protein TMEM106B was identified as a risk modifier of multiple dementias including frontotemporal dementia and Alzheimer's disease. The gene comes in two major haplotypes, one associated with disease risk, and by comparison, the other with resilience. Only one coding polymorphism distinguishes the two alleles, a threonine-to-serine substitution at residue 185 (186 in mouse), that is inherited in disequilibrium with multiple non-coding variants. Transcriptional studies suggest synaptic, neuronal, and cognitive preservation in human subjects with the protective haplotype, while murine
Language	English
Publishing date	2023-10-13
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.2023.1275959
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Article ; Online: Correction: Temporal and spatially controlled APP transgene expression using Cre-dependent alleles.

Koller, Emily J / Comstock, Melissa / Bean, Jonathan C / Escobedo, Gabriel / Park, Kyung-Won / Jankowsky, Joanna L

Disease models & mechanisms

2023 Volume 16, Issue 3

Language	English
Publishing date	2023-03-08
Publishing country	England
Document type	Published Erratum
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.050136
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Article ; Online: Generation of a Dcx-CreER

Perez, Gabriella A / Park, Kyung-Won / Lanza, Denise / Cicardo, Jenna / Uddin, M Danish / Jankowsky, Joanna L

Genesis (New York, N.Y. : 2000)

2023 Volume 62, Issue 1, Page(s) e23584

Abstract: A wide variety of ... ...

Abstract	A wide variety of CreER
MeSH term(s)	Mice ; Animals ; Mice, Transgenic ; Neurons/metabolism ; Neural Stem Cells/metabolism ; Neurogenesis/genetics ; Brain
Language	English
Publishing date	2023-12-16
Publishing country	United States
Document type	Journal Article
ZDB-ID	2004544-X
ISSN	1526-968X ; 1526-954X
ISSN (online)	1526-968X
ISSN	1526-954X
DOI	10.1002/dvg.23584
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Article ; Online: Temporal and spatially controlled APP transgene expression using Cre-dependent alleles.

Koller, Emily J / Comstock, Melissa / Bean, Jonathan C / Escobedo, Gabriel / Park, Kyung-Won / Jankowsky, Joanna L

Disease models & mechanisms

2022 Volume 15, Issue 5

Abstract: Although a large number of mouse models have been made to study Alzheimer's disease, only a handful allow experimental control over the location or timing of the protein being used to drive pathology. Other fields have used the Cre and the tamoxifen- ... ...

Abstract	Although a large number of mouse models have been made to study Alzheimer's disease, only a handful allow experimental control over the location or timing of the protein being used to drive pathology. Other fields have used the Cre and the tamoxifen-inducible CreER driver lines to achieve precise spatial and temporal control over gene deletion and transgene expression, yet these tools have not been widely used in studies of neurodegeneration. Here, we describe two strategies for harnessing the wide range of Cre and CreER driver lines to control expression of disease-associated amyloid precursor protein (APP) in modeling Alzheimer's amyloid pathology. We show that CreER-based spatial and temporal control over APP expression can be achieved with existing lines by combining a Cre driver with a tetracycline-transactivator (tTA)-dependent APP responder using a Cre-to-tTA converter line. We then describe a new mouse line that places APP expression under direct control of Cre recombinase using an intervening lox-stop-lox cassette. Mating this allele with a CreER driver allows both spatial and temporal control over APP expression, and with it, amyloid onset. This article has an associated First Person interview with the first author of the paper.
MeSH term(s)	Alleles ; Amyloid beta-Protein Precursor/genetics ; Amyloid beta-Protein Precursor/metabolism ; Animals ; Humans ; Integrases/metabolism ; Mice ; Mice, Transgenic ; Tetracycline/pharmacology ; Transgenes
Chemical Substances	Amyloid beta-Protein Precursor ; Cre recombinase (EC 2.7.7.-) ; Integrases (EC 2.7.7.-) ; Tetracycline (F8VB5M810T)
Language	English
Publishing date	2022-05-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2451104-3
ISSN	1754-8411 ; 1754-8403
ISSN (online)	1754-8411
ISSN	1754-8403
DOI	10.1242/dmm.049330
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Article ; Online: Practical considerations for choosing a mouse model of Alzheimer's disease.

Jankowsky, Joanna L / Zheng, Hui

Molecular neurodegeneration

2017 Volume 12, Issue 1, Page(s) 89

Abstract: Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of β-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been ... ...

Abstract	Alzheimer's disease (AD) is behaviorally identified by progressive memory impairment and pathologically characterized by the triad of β-amyloid plaques, neurofibrillary tangles, and neurodegeneration. Genetic mutations and risk factors have been identified that are either causal or modify the disease progression. These genetic and pathological features serve as basis for the creation and validation of mouse models of AD. Efforts made in the past quarter-century have produced over 100 genetically engineered mouse lines that recapitulate some aspects of AD clinicopathology. These models have been valuable resources for understanding genetic interactions that contribute to disease and cellular reactions that are engaged in response. Here we focus on mouse models that have been widely used stalwarts of the field or that are recently developed bellwethers of the future. Rather than providing a summary of each model, we endeavor to compare and contrast the genetic approaches employed and to discuss their respective advantages and limitations. We offer a critical account of the variables which may contribute to inconsistent findings and the factors that should be considered when choosing a model and interpreting the results. We hope to present an insightful review of current AD mouse models and to provide a practical guide for selecting models best matched to the experimental question at hand.
MeSH term(s)	Alzheimer Disease/genetics ; Alzheimer Disease/pathology ; Amyloid beta-Protein Precursor/genetics ; Animals ; Cerebral Amyloid Angiopathy/genetics ; Cognitive Dysfunction/genetics ; Disease Models, Animal ; Humans ; Mice ; Mice, Knockout ; Mice, Transgenic ; Neurodegenerative Diseases/genetics ; Neurofibrillary Tangles ; Plaque, Amyloid
Chemical Substances	Amyloid beta-Protein Precursor
Language	English
Publishing date	2017-12-22
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ISSN	1750-1326
ISSN (online)	1750-1326
DOI	10.1186/s13024-017-0231-7
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Article ; Online: An automated respiratory data pipeline for waveform characteristic analysis.

Lusk, Savannah / Ward, Christopher S / Chang, Andersen / Twitchell-Heyne, Avery / Fattig, Shaun / Allen, Genevera / Jankowsky, Joanna L / Ray, Russell S

The Journal of physiology

2023 Volume 601, Issue 21, Page(s) 4767–4806

Abstract: Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic and degenerative diseases converging on autonomic control failure. A lack of tools for high-throughput analysis of respiratory datasets ... ...

Abstract	Comprehensive and accurate analysis of respiratory and metabolic data is crucial to modelling congenital, pathogenic and degenerative diseases converging on autonomic control failure. A lack of tools for high-throughput analysis of respiratory datasets remains a major challenge. We present Breathe Easy, a novel open-source pipeline for processing raw recordings and associated metadata into operative outcomes, publication-worthy graphs and robust statistical analyses including QQ and residual plots for assumption queries and data transformations. This pipeline uses a facile graphical user interface for uploading data files, setting waveform feature thresholds and defining experimental variables. Breathe Easy was validated against manual selection by experts, which represents the current standard in the field. We demonstrate Breathe Easy's utility by examining a 2-year longitudinal study of an Alzheimer's disease mouse model to assess contributions of forebrain pathology in disordered breathing. Whole body plethysmography has become an important experimental outcome measure for a variety of diseases with primary and secondary respiratory indications. Respiratory dysfunction, while not an initial symptom in many of these disorders, often drives disability or death in patient outcomes. Breathe Easy provides an open-source respiratory analysis tool for all respiratory datasets and represents a necessary improvement upon current analytical methods in the field. KEY POINTS: Respiratory dysfunction is a common endpoint for disability and mortality in many disorders throughout life. Whole body plethysmography in rodents represents a high face-value method for measuring respiratory outcomes in rodent models of these diseases and disorders. Analysis of key respiratory variables remains hindered by manual annotation and analysis that leads to low throughput results that often exclude a majority of the recorded data. Here we present a software suite, Breathe Easy, that automates the process of data selection from raw recordings derived from plethysmography experiments and the analysis of these data into operative outcomes and publication-worthy graphs with statistics. We validate Breathe Easy with a terabyte-scale Alzheimer's dataset that examines the effects of forebrain pathology on respiratory function over 2 years of degeneration.
MeSH term(s)	Animals ; Mice ; Humans ; Longitudinal Studies ; Software ; Respiration ; Plethysmography
Language	English
Publishing date	2023-10-03
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, Non-U.S. Gov't
ZDB-ID	3115-x
ISSN	1469-7793 ; 0022-3751
ISSN (online)	1469-7793
ISSN	0022-3751
DOI	10.1113/JP284363
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Article ; Online: TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy.

Edwards, George A / Wood, Caleb A / He, Yang / Nguyen, Quynh / Kim, Peter J / Gomez-Gutierrez, Ruben / Park, Kyung-Won / Xu, Yong / Zurhellen, Cody / Al-Ramahi, Ismael / Jankowsky, Joanna L

Acta neuropathologica

2024 Volume 147, Issue 1, Page(s) 61

Abstract: TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone ... ...

Abstract	TMEM106B is a risk modifier of multiple neurological conditions, where a single coding variant and multiple non-coding SNPs influence the balance between susceptibility and resilience. Two key questions that emerge from past work are whether the lone T185S coding variant contributes to protection, and if the presence of TMEM106B is helpful or harmful in the context of disease. Here, we address both questions while expanding the scope of TMEM106B study from TDP-43 to models of tauopathy. We generated knockout mice with constitutive deletion of TMEM106B, alongside knock-in mice encoding the T186S knock-in mutation (equivalent to the human T185S variant), and crossed both with a P301S transgenic tau model to study how these manipulations impacted disease phenotypes. We found that TMEM106B deletion accelerated cognitive decline, hind limb paralysis, tau pathology, and neurodegeneration. TMEM106B deletion also increased transcriptional correlation with human AD and the functional pathways enriched in KO:tau mice aligned with those of AD. In contrast, the coding variant protected against tau-associated cognitive decline, synaptic impairment, neurodegeneration, and paralysis without affecting tau pathology. Our findings reveal that TMEM106B is a critical safeguard against tau aggregation, and that loss of this protein has a profound effect on sequelae of tauopathy. Our study further demonstrates that the coding variant is functionally relevant and contributes to neuroprotection downstream of tau pathology to preserve cognitive function.
MeSH term(s)	Animals ; Humans ; Mice ; Disease Models, Animal ; Membrane Proteins/genetics ; Mice, Knockout ; Mice, Transgenic ; Mutation ; Nerve Tissue Proteins/genetics ; Paralysis/genetics ; Polymorphism, Single Nucleotide ; tau Proteins/genetics ; tau Proteins/metabolism ; Tauopathies/pathology
Chemical Substances	Membrane Proteins ; Nerve Tissue Proteins ; tau Proteins ; TMEM106B protein, human ; Tmem106b protein, mouse
Language	English
Publishing date	2024-03-25
Publishing country	Germany
Document type	Journal Article
ZDB-ID	1079-0
ISSN	1432-0533 ; 0001-6322
ISSN (online)	1432-0533
ISSN	0001-6322
DOI	10.1007/s00401-024-02701-5
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Article ; Online: TMEM106B regulates microglial proliferation and survival in response to demyelination.

Zhang, Tingting / Pang, Weilun / Feng, Tuancheng / Guo, Jennifer / Wu, Kenton / Nunez Santos, Mariela / Arthanarisami, Akshayakeerthi / Nana, Alissa L / Nguyen, Quynh / Kim, Peter J / Jankowsky, Joanna L / Seeley, William W / Hu, Fenghua

Science advances

2023 Volume 9, Issue 18, Page(s) eadd2676

Abstract: TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that ...

Abstract	TMEM106B, a lysosomal transmembrane protein, has been closely associated with brain health. Recently, an intriguing link between TMEM106B and brain inflammation has been discovered, but how TMEM106B regulates inflammation is unknown. Here, we report that TMEM106B deficiency in mice leads to reduced microglia proliferation and activation and increased microglial apoptosis in response to demyelination. We also found an increase in lysosomal pH and a decrease in lysosomal enzyme activities in TMEM106B-deficient microglia. Furthermore, TMEM106B loss results in a significant decrease in the protein levels of TREM2, an innate immune receptor essential for microglia survival and activation. Specific ablation of TMEM106B in microglia results in similar microglial phenotypes and myelination defects in mice, supporting the idea that microglial TMEM106B is critical for proper microglial activities and myelination. Moreover, the
MeSH term(s)	Humans ; Mice ; Animals ; Microglia/metabolism ; Mice, Knockout ; Brain/metabolism ; Demyelinating Diseases/genetics ; Demyelinating Diseases/metabolism ; Cell Proliferation ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Nerve Tissue Proteins/genetics ; Nerve Tissue Proteins/metabolism ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/metabolism
Chemical Substances	TMEM106B protein, human ; Membrane Proteins ; Nerve Tissue Proteins ; Trem2 protein, mouse ; Membrane Glycoproteins ; Receptors, Immunologic
Language	English
Publishing date	2023-05-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	2810933-8
ISSN	2375-2548 ; 2375-2548
ISSN (online)	2375-2548
ISSN	2375-2548
DOI	10.1126/sciadv.add2676
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Article: TMEM106B coding variant is protective and deletion detrimental in a mouse model of tauopathy.

Edwards, George A / Wood, Caleb A / Nguyen, Quynh / Kim, Peter J / Gomez-Gutierrez, Ruben / Park, Kyung-Won / Zurhellen, Cody / Al-Ramahi, Ismael / Jankowsky, Joanna L

bioRxiv : the preprint server for biology

2023

Abstract: TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimerâ€™s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding ... ...

Abstract	TMEM106B is a risk modifier for a growing list of age-associated dementias including Alzheimerâ€™s and frontotemporal dementia, yet its function remains elusive. Two key questions that emerge from past work are whether the conservative T185S coding variant found in the minor haplotype contributes to protection, and whether the presence of TMEM106B is helpful or harmful in the context of disease. Here we address both issues while extending the testbed for study of TMEM106B from models of TDP to tauopathy. We show that TMEM106B deletion accelerates cognitive decline, hindlimb paralysis, neuropathology, and neurodegeneration. TMEM106B deletion also increases transcriptional overlap with human AD, making it a better model of disease than tau alone. In contrast, the coding variant protects against tau-associated cognitive decline, neurodegeneration, and paralysis without affecting tau pathology. Our findings show that the coding variant contributes to neuroprotection and suggest that TMEM106B is a critical safeguard against tau aggregation.
Language	English
Publishing date	2023-03-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.23.533978
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