Tauopathies: New Perspectives and Challenges

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Neurobiology and Clinical Neuroscience".

Deadline for manuscript submissions: closed (31 March 2024) | Viewed by 9203

Special Issue Editors


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Guest Editor
UK Dementia Research Institute, University of Edinburgh, Edinburgh EH16 4SB, UK
Interests: functional genomics; genetics; tauopathy; organoids; iPSC modeling; frontotemporal dementia; progressive supranuclear palsy; Parkinson’s disease

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Guest Editor
1. Center for Genomic Medicine, Chemical Neurobiology Laboratory, Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA
2. Department of Neurology, Harvard Medical School, Boston, MA 02115, USA
Interests: biochemistry & molecular biology; neuroscience; proteinopathies; neurodegeneration; tauopathies; stem cell biology; iPSC-derived cellular models

Special Issue Information

Dear Colleagues,

Tauopathies are a fascinating and vast assembly of neurodegenerative diseases, spanning multiple distinct neuropathological features, cellular phenotypes and clinical presentations. This diversity and complexity make tauopathies particularly challenging to model. Regardless, recent advancements in animal and cellular models have accelerated our knowledge and understanding of these diseases. In parallel, the development and application of new technologies to study and characterize these models have expanded our horizons for what is possible to know. However, we still have a long way to go with regard to untangling the complexity and pleiotropy of MAPT, tau and tauopathies, and developing effective therapies and treatments.

We invite authors from any area of the tauopathy field to submit original research or review articles pertaining to this special issue. Studies and opinions on new approaches and technologies that have changed our perspective of the field, where we are currently lacking in our efforts and understanding, and the challenges we face to make meaningful progress are encouraged.

Dr. Kathryn Bowles
Dr. Maria Catarina Silva
Guest Editors

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Keywords

  • tauopathy
  • MAPT
  • animal models
  • iPSC
  • genetics
  • biomarkers
  • neuropathology
  • FTD
  • PSP
  • AD

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Published Papers (4 papers)

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Research

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16 pages, 1546 KiB  
Article
MAPT Mutations V337M and N297K Alter Organelle Trafficking in Frontotemporal Dementia Patient-Specific Motor Neurons
by Christiane Hartmann, Marie Anskat, Marc Ehrlich, Jared Sterneckert, Arun Pal and Andreas Hermann
Biomedicines 2024, 12(3), 641; https://doi.org/10.3390/biomedicines12030641 - 13 Mar 2024
Cited by 1 | Viewed by 1529
Abstract
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have [...] Read more.
Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by the progressive loss of neurons mainly in the frontal and temporal lobes of the brain. Mutations (e.g., V337M, N297K) in the microtubule-associated protein TAU (MAPT) are responsible 5–20% of familial FTD cases and have been associated with defects in organelle trafficking that plays a critical role in the proper function of cells, including transport of essential molecules and degradation of waste products. Due to the critical role of TAU mutations in microtubule stabilization and organelle transportation, it is of great interest to study these molecular mechanisms to develop effective therapeutic strategies. Therefore, herein, we analyzed mitochondrial and lysosomal trafficking in disease-specific spinal motor neurons by using live cell imaging in undirected (uncompartmentalized) and directed (compartmentalized) cell culture systems. While V337M neurons only expressed 3R TAU, the N297K mutant neurons expressed both 3R and 4R TAU. Axonal trafficking was affected differentially in V337M and N297 MAPT mutated neurons. These findings suggest that the MAPT mutations V337M and N297K impaired axon physiology differentially, which highlights the need for mutation- and/or 3R/4R TAU-specific therapeutic approaches. Full article
(This article belongs to the Special Issue Tauopathies: New Perspectives and Challenges)
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0 pages, 2873 KiB  
Article
Cell States and Interactions of CD8 T Cells and Disease-Enriched Microglia in Human Brains with Alzheimer’s Disease
by Mai Yamakawa and Jessica E. Rexach
Biomedicines 2024, 12(2), 308; https://doi.org/10.3390/biomedicines12020308 - 29 Jan 2024
Cited by 1 | Viewed by 2436
Abstract
Alzheimer’s disease (AD) is a multi-stage neurodegenerative disorder characterized by beta-amyloid accumulation, hyperphosphorylated Tau deposits, neurodegeneration, neuroinflammation, and cognitive impairment. Recent studies implicate CD8 T cells as neuroimmune responders to the accumulation of AD pathology in the brain and potential contributors to toxic [...] Read more.
Alzheimer’s disease (AD) is a multi-stage neurodegenerative disorder characterized by beta-amyloid accumulation, hyperphosphorylated Tau deposits, neurodegeneration, neuroinflammation, and cognitive impairment. Recent studies implicate CD8 T cells as neuroimmune responders to the accumulation of AD pathology in the brain and potential contributors to toxic neuroinflammation. However, more evidence is needed to understand lymphocytes in disease, including their functional states, molecular mediators, and interacting cell types in diseased brain tissue. The scarcity of lymphocytes in brain tissue samples has limited the unbiased profiling of disease-associated cell types, cell states, drug targets, and relationships to common AD genetic risk variants based on transcriptomic analyses. However, using recent large-scale, high-quality single-nuclear sequencing datasets from over 84 Alzheimer’s disease and control cases, we leverage single-nuclear RNAseq data from 800 lymphocytes collected from 70 individuals to complete unbiased molecular profiling. We demonstrate that effector memory CD8 T cells are the major lymphocyte subclass enriched in the brain tissues of individuals with AD dementia. We define disease-enriched interactions involving CD8 T cells and multiple brain cell subclasses including two distinct microglial disease states that correlate, respectively, to beta-amyloid and tau pathology. We find that beta-amyloid-associated microglia are a major hub of multicellular cross-talk gained in disease, including interactions involving both vulnerable neuronal subtypes and CD8 T cells. We reproduce prior reports that amyloid-response microglia are depleted in APOE4 carriers. Overall, these human-based studies provide additional support for the potential relevance of effector memory CD8 T cells as a lymphocyte population of interest in AD dementia and provide new candidate interacting partners and drug targets for further functional study. Full article
(This article belongs to the Special Issue Tauopathies: New Perspectives and Challenges)
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21 pages, 1703 KiB  
Article
The Impact of Muscarinic Antagonism on Psychosis-Relevant Behaviors and Striatal [11C] Raclopride Binding in Tau Mouse Models of Alzheimer’s Disease
by Heidy Jimenez, Joseph Carrion, Leslie Adrien, Adam Wolin, John Eun, Ezra Cinamon, Eric H. Chang, Peter Davies, An Vo and Jeremy Koppel
Biomedicines 2023, 11(8), 2091; https://doi.org/10.3390/biomedicines11082091 - 25 Jul 2023
Cited by 2 | Viewed by 1658
Abstract
Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with [...] Read more.
Psychosis that occurs over the course of Alzheimer’s disease (AD) is associated with increased caregiver burden and a more rapid cognitive and functional decline. To find new treatment targets, studies modeling psychotic conditions traditionally employ agents known to induce psychosis, utilizing outcomes with cross-species relevance, such as locomotive activity and sensorimotor gating, in rodents. In AD, increased burdens of tau pathology (a diagnostic hallmark of the disease) and treatment with anticholinergic medications have, separately, been reported to increase the risk of psychosis. Recent evidence suggests that muscarinic antagonists may increase extracellular tau. Preclinical studies in AD models have not previously utilized muscarinic cholinergic antagonists as psychotomimetic agents. In this report, we utilize a human–mutant–tau model (P301L/COMTKO) and an over-expressed non-mutant human tau model (htau) in order to compare the impact of antimuscarinic (scopolamine 10 mg/kg/day) treatment with dopaminergic (reboxetine 20 mg/kg/day) treatment, for 7 days, on locomotion and sensorimotor gating. Scopolamine increased spontaneous locomotion, while reboxetine reduced it; neither treatment impacted sensorimotor gating. In the P301L/COMTKO, scopolamine treatment was associated with decreased muscarinic M4 receptor expression, as quantified with RNA-seq, as well as increased dopamine receptor D2 signaling, as estimated with Micro-PET [11C] raclopride binding. Scopolamine also increased soluble tau in the striatum, an effect that partially mediated the observed increases in locomotion. Studies of muscarinic agonists in preclinical tau models are warranted to determine the impact of treatment—on both tau and behavior—that may have relevance to AD and other tauopathies. Full article
(This article belongs to the Special Issue Tauopathies: New Perspectives and Challenges)
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Review

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14 pages, 2639 KiB  
Review
Pick’s Disease, Seeding an Answer to the Clinical Diagnosis Conundrum
by Nicole Tamvaka, Sireesha Manne, Naveen Kondru and Owen A. Ross
Biomedicines 2023, 11(6), 1646; https://doi.org/10.3390/biomedicines11061646 - 6 Jun 2023
Cited by 3 | Viewed by 2399
Abstract
Pick’s disease (PiD) is a devastating neurodegenerative disease that is characterized by dementia, frontotemporal lobar degeneration, and the aggregation of 3R tau in pathognomonic inclusions known as Pick bodies. The term PiD has adopted many meanings since its conception in 1926, but it [...] Read more.
Pick’s disease (PiD) is a devastating neurodegenerative disease that is characterized by dementia, frontotemporal lobar degeneration, and the aggregation of 3R tau in pathognomonic inclusions known as Pick bodies. The term PiD has adopted many meanings since its conception in 1926, but it is currently used as a strictly neuropathological term, since PiD patients cannot be diagnosed during life. Due to its rarity, PiD remains significantly understudied, and subsequently, the etiology and pathomechanisms of the disease remain to be elucidated. The study of PiD and the preferential 3R tau accumulation that is unique to PiD is imperative in order to expand the current understanding of the disease and inform future studies and therapeutic development, since the lack of intervention strategies for tauopathies remains an unmet need. Yet, the lack of an antemortem diagnostic test for the disease has further complicated the study of PiD. The development of a clinical diagnostic assay for PiD will be a vital step in the study of the disease that will greatly contribute to therapeutic research, clinical trial design and patient recruitment and ultimately improve patient outcomes. Seed aggregation assays have shown great promise for becoming ante mortem clinical diagnostic tools for many proteinopathies, including tauopathies. Future research on adapting and optimizing current seed aggregation assays to successfully detect 3R tau pathogenic forms from PiD samples will be critical in establishing a 3R tau specific seed aggregation assay that can be used for clinical diagnosis and treatment evaluation. Full article
(This article belongs to the Special Issue Tauopathies: New Perspectives and Challenges)
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