scholarly journals Efficient propagation of misfolded tau between individual neurons occurs in absence of degeneration

2018 ◽  
Author(s):  
Grace I Hallinan ◽  
Mariana Vargas-Caballero ◽  
Jonathan West ◽  
Katrin Deinhardt
Keyword(s):  
Cell Death ◽  
Axonal Transport ◽  
Tau Protein ◽  
Neuronal Death ◽  
Early Event ◽  
Neuronal Dysfunction ◽  
Tau Pathology ◽  
Functional Consequences ◽  
Tau Aggregation ◽  
The Brain

AbstractIn Alzheimer’s disease, misfolded tau protein propagates through the brain in a prion-like manner along connected circuits. Tauopathy correlates with significant neuronal death, but the links between tau aggregation, propagation, neuronal dysfunction and death remain poorly understood, and the direct functional consequences for the neuron containing the tau aggregates are unclear. Here, by monitoring individual neurons within a minimal circuit, we demonstrate that misfolded tau efficiently spreads from presynaptic to postsynaptic neurons. Within postsynaptic cells, tau aggregates initially in distal axons, while proximal axons remain free of tau pathology. In the presence of tau aggregates neurons display axonal transport deficits, but remain viable and electrically competent. This shows that misfolded tau species are not immediately toxic to neurons, and suggests that propagation of misfolded tau is an early event in disease, occurring prior to neuronal dysfunction and cell death.

scholarly journals Antisense Oligonucleotide-Mediated Reduction of HDAC6 Does Not Reduce Tau Pathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Antonio Valencia ◽  
Veronica L. Reinhart Bieber ◽  
Bekim Bajrami ◽  
Galina Marsh ◽  
Stefan Hamann ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Antisense Oligonucleotide ◽  
Tau Phosphorylation ◽  
Histone Deacetylase 6 ◽  
Tau Pathology ◽  
Tau Aggregation ◽  
The Brain ◽  
Mediated Reduction ◽  
Tau Acetylation

Acetylation of tau protein is dysregulated in Alzheimer's Disease (AD). It has been proposed that acetylation of specific sites in the KXGS motif of tau can regulate phosphorylation of nearby residues and reduce the propensity of tau to aggregate. Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme involved in deacetylation of multiple targets, including tau, and it has been suggested that inhibition of HDAC6 would increase tau acetylation at the KXGS motifs and thus may present a viable therapeutic approach to treat AD. To directly test the contribution of HDAC6 to tau pathology, we intracerebroventricularly injected an antisense oligonucleotide (ASO) directed against HDAC6 mRNA into brains of P301S tau mice (PS19 model), which resulted in a 70% knockdown of HDAC6 protein in the brain. Despite a robust decrease in levels of HDAC6, no increase in tau acetylation was observed. Additionally, no change of tau phosphorylation or tau aggregation was detected upon the knockdown of HDAC6. We conclude that HDAC6 does not impact tau pathology in PS19 mice.

scholarly journals Pharmacological Modulators of Tau Aggregation and Spreading

2020 ◽  
Vol 10 (11) ◽  
pp. 858
Author(s):  
Antonio Dominguez-Meijide ◽  
Eftychia Vasili ◽  
Tiago Fleming Outeiro
Keyword(s):  
Tau Protein ◽  
Neurodegenerative Disorders ◽  
Molecular Mechanisms ◽  
Mechanisms Of Action ◽  
Tau Aggregation ◽  
The Brain ◽  
Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

scholarly journals Experimental evidence for the age dependence of tau protein spread in the brain

2019 ◽  
Vol 5 (6) ◽  
pp. eaaw6404 ◽  
Author(s):  
Susanne Wegmann ◽  
Rachel E. Bennett ◽  
Louis Delorme ◽  
Ashley B. Robbins ◽  
Miwei Hu ◽  
...  
Keyword(s):  
Tau Protein ◽  
Brain Region ◽  
Age Dependence ◽  
Tau Pathology ◽  
Related Factors ◽  
Age Related ◽  
Regional Vulnerability ◽  
Related Risk ◽  
Old Mice ◽  
The Brain

The incidence of Alzheimer’s disease (AD), which is characterized by progressive cognitive decline that correlates with the spread of tau protein aggregation in the cortical mantle, is strongly age-related. It could be that age predisposes the brain for tau misfolding and supports the propagation of tau pathology. We tested this hypothesis using an experimental setup that allowed for exploration of age-related factors of tau spread and regional vulnerability. We virally expressed human tau locally in entorhinal cortex (EC) neurons of young or old mice and monitored the cell-to-cell tau protein spread by immunolabeling. Old animals showed more tau spreading in the hippocampus and adjacent cortical areas and accumulated more misfolded tau in EC neurons. No misfolding, at any age, was observed in the striatum, a brain region mostly unaffected by tangles. Age and brain region dependent tau spreading and misfolding likely contribute to the profound age-related risk for sporadic AD.

scholarly journals Mechanisms of secretion and spreading of pathological tau protein

2019 ◽  
Vol 77 (9) ◽  
pp. 1721-1744 ◽  
Author(s):  
Cecilia A. Brunello ◽  
Maria Merezhko ◽  
Riikka-Liisa Uronen ◽  
Henri J. Huttunen
Keyword(s):  
Tau Protein ◽  
Molecular Mechanisms ◽  
Recent Literature ◽  
General Mechanism ◽  
Cell Transfer ◽  
Tau Pathology ◽  
Cellular Mechanisms ◽  
Brain Areas ◽  
Cell To Cell Transfer ◽  
The Brain

Abstract Accumulation of misfolded and aggregated forms of tau protein in the brain is a neuropathological hallmark of tauopathies, such as Alzheimer’s disease and frontotemporal lobar degeneration. Tau aggregates have the ability to transfer from one cell to another and to induce templated misfolding and aggregation of healthy tau molecules in previously healthy cells, thereby propagating tau pathology across different brain areas in a prion-like manner. The molecular mechanisms involved in cell-to-cell transfer of tau aggregates are diverse, not mutually exclusive and only partially understood. Intracellular accumulation of misfolded tau induces several mechanisms that aim to reduce the cellular burden of aggregated proteins and also promote secretion of tau aggregates. However, tau may also be released from cells physiologically unrelated to protein aggregation. Tau secretion involves multiple vesicular and non-vesicle-mediated pathways, including secretion directly through the plasma membrane. Consequently, extracellular tau can be found in various forms, both as a free protein and in vesicles, such as exosomes and ectosomes. Once in the extracellular space, tau aggregates can be internalized by neighboring cells, both neurons and glial cells, via endocytic, pinocytic and phagocytic mechanisms. Importantly, accumulating evidence suggests that prion-like propagation of misfolding protein pathology could provide a general mechanism for disease progression in tauopathies and other related neurodegenerative diseases. Here, we review the recent literature on cellular mechanisms involved in cell-to-cell transfer of tau, with a particular focus in tau secretion.

Modulation of tau pathology in tau transgenic models

2010 ◽  
Vol 38 (4) ◽  
pp. 996-1000 ◽  
Author(s):  
Jean-Pierre Brion ◽  
Kunie Ando ◽  
Céline Heraud ◽  
Karelle Leroy
Keyword(s):  
Neuronal Death ◽  
Amyloid Β ◽  
Tau Proteins ◽  
Amyloid Β Peptide ◽  
Wild Type ◽  
Tau Pathology ◽  
Amyloid Pathology ◽  
Aβ Amyloid ◽  
Tau Aggregation ◽  
The Relationship

NFTs (neurofibrillary tangles) in Alzheimer's disease and in tauopathies are hallmark neuropathological lesions whose relationship with neuronal dysfunction, neuronal death and with other lesions [such as Aβ (amyloid β-peptide) pathology] are still imperfectly understood. Many transgenic mice overexpressing wild-type or mutant tau proteins have been generated to investigate the physiopathology of tauopathies. Most of the mice overexpressing wild-type tau do not develop NFTs, but can develop a severe axonopathy, whereas overexpression of mutant tau leads to NFT formation, synaptic loss and neuronal death in several models. The association between neuronal death and NFTs has, however, been challenged in some models showing a dissociation between tau aggregation and tau toxicity. Cross-breeding of mice developing NFTs with mice developing Aβ deposits increases NFT pathology, highlighting the relationship between tau and amyloid pathology. On the other hand, tau expression seems to be necessary for expression of a pathological phenotype associated with amyloid pathology. These findings suggest that there is a bilateral cross-talk between Aβ and tau pathology. These observations are discussed by the presentation of some relevant models developed recently.

scholarly journals Tau in the brain interstitial fluid is fragmented and seeding-competent

2020 ◽  
Author(s):  
Erica Barini ◽  
Gudrun Plotzky ◽  
Yulia Mordashova ◽  
Jonas Hoppe ◽  
Esther Rodriguez-Correa ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Interstitial Fluid ◽  
List Type ◽  
Fragmentation Pattern ◽  
Tau Pathology ◽  
Brain Areas ◽  
Brain Interstitial Fluid ◽  
Tau Aggregation ◽  
The Brain

SUMMARYIn Alzheimer disease, Tau pathology is thought to propagate from cell to cell throughout interconnected brain areas. However, the forms of Tau released into the brain interstitial fluid (ISF) in vivo during the development of Tauopathy and their pathological relevance remain unclear. Combining in vivo microdialysis and biochemical analysis, we find that human Tau (hTau) present in brain ISF is truncated and comprises at least 10 distinct fragments spanning the entire Tau protein. The fragmentation pattern is similar across different Tau transgenic models, pathological stages and brain areas. ISF hTau concentration decreases during Tauopathy progression, while its phosphorylation increases. ISF from mice with established Tauopathy induces Tau aggregation in HEK293-Tau biosensor cells and notably, only a small fraction of Tau, separated by ultracentrifugation, is seeding competent. These results indicate that only a subset of Tau accounts for ISF seeding competence and have the potential to contribute to the propagation of Tau pathology.Graphical abstractHighlights✓In transgenic mice, interstitial fluid comprises several Tau fragments spanning the entire Tau sequence.✓Interstitial fluid Tau concentration decreases with Tauopathy progression, while phosphorylation increases.✓Only interstitial fluid from mice with established Tauopathy is seeding competent in vitro.✓Interstitial fluid seeding competence is driven by less soluble, aggregated and phosphorylated Tau species.In BriefBarini et al. show that in the brain interstitial fluid of Tau transgenic mice, truncated Tau decreases, while its phosphorylation increases during the progression of pathology. A subset of less soluble, aggregated and phosphorylated ISF Tau induces Tau aggregation in cells.

scholarly journals Defined Tau Phosphospecies Differentially Inhibit Fast Axonal Transport Through Activation of Two Independent Signaling Pathways

2021 ◽  
Vol 13 ◽  
Author(s):  
Sarah L. Morris ◽  
Ming-Ying Tsai ◽  
Sarah Aloe ◽  
Karin Bechberger ◽  
Svenja König ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Axonal Transport ◽  
Glycogen Synthase ◽  
Tau Proteins ◽  
Protein Phosphatase 1 ◽  
Tau Pathology ◽  
Fast Axonal Transport ◽  
Functional Consequences ◽  
Health And Disease ◽  
And Function

Tau protein is subject to phosphorylation by multiple kinases at more than 80 different sites. Some of these sites are associated with tau pathology and neurodegeneration, but other sites are modified in normal tau as well as in pathological tau. Although phosphorylation of tau at residues in the microtubule-binding repeats is thought to reduce tau association with microtubules, the functional consequences of other sites are poorly understood. The AT8 antibody recognizes a complex phosphoepitope site on tau that is detectable in a healthy brain but significantly increased in Alzheimer’s disease (AD) and other tauopathies. Previous studies showed that phosphorylation of tau at the AT8 site leads to exposure of an N-terminal sequence that promotes activation of a protein phosphatase 1 (PP1)/glycogen synthase 3 (GSK3) signaling pathway, which inhibits kinesin-1-based anterograde fast axonal transport (FAT). This finding suggests that phosphorylation may control tau conformation and function. However, the AT8 includes three distinct phosphorylated amino acids that may be differentially phosphorylated in normal and disease conditions. To evaluate the effects of specific phosphorylation sites in the AT8 epitope, recombinant, pseudophosphorylated tau proteins were perfused into the isolated squid axoplasm preparation to determine their effects on axonal signaling pathways and FAT. Results from these studies suggest a mechanism where specific phosphorylation events differentially impact tau conformation, promoting activation of independent signaling pathways that differentially affect FAT. Implications of findings here to our understanding of tau function in health and disease conditions are discussed.

scholarly journals The Norepinephrine Metabolite DOPEGAL Confers Locus Coeruleus Tau Vulnerability and Propagation via Asparagine Endopeptidase

2019 ◽  
Author(s):  
Seong Su Kang ◽  
Xia Liu ◽  
Eun Hee Ahn ◽  
Jie Xiang ◽  
Fredric P. Manfredsson ◽  
...  
Keyword(s):  
Monoamine Oxidase ◽  
Locus Coeruleus ◽  
Selective Vulnerability ◽  
Monoamine Oxidase A ◽  
Noradrenergic Neurons ◽  
Tau Pathology ◽  
Intact Cells ◽  
Tau Aggregation ◽  
The Brain

AbstractAberrant Tau inclusions in the locus coeruleus (LC) are the earliest detectable Alzheimer’s disease (AD)-like neuropathology in the human brain; however, why LC neurons are selectively vulnerable to developing early Tau pathology and degenerating later in disease and whether the LC might seed the stereotypical spread of Tau pathology to the rest of the brain remain unclear. Here we show that 3,4-dihydroxyphenylglycolaldehyde (DOPEGAL), which is produced exclusively in noradrenergic neurons by monoamine oxidase A (MAO-A) metabolism of norepinephrine (NE), activates asparagine endopeptidase (AEP) that cleaves Tau at residue N368 into aggregation- and propagation-prone forms, thereby leading to LC degeneration and the spread of Tau pathology. DOPEGAL triggers AEP-cleaved Tau aggregationin vitroand in intact cells, resulting in LC neurotoxicity and propagation of pathology to the forebrain. Thus, our findings reveal a novel molecular mechanism underlying the selective vulnerability of LC neurons in AD.

scholarly journals Braiding Braak and Braak: Staging patterns and model selection in network neurodegeneration

2021 ◽  
Author(s):  
Prama Putra ◽  
Travis Thompson ◽  
Alain Goriely
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Tau Proteins ◽  
Histopathological Analysis ◽  
Braak Staging ◽  
New Methods ◽  
Tau Aggregation ◽  
The Brain ◽  
And Diffusion

AbstractA hallmark of Alzheimer’s disease is the aggregation of insoluble amyloid-beta plaques and tau protein neurofibrillary tangles. A key histopathological observation is that tau protein aggregates follow a clear progression pattern through the brain; characterized by six distinct stages. This so-called ‘Braak staging pattern’ has become the gold standard for Alzheimer’s disease progression. It has also been suggested, via a histopathological analysis, that soluble seed-competent tau seeding precedes tau aggregation in the same manner. Mathematical models such as prion-like propagation on networks have the ability to capture key feature of the dynamics. Here, we study the staging of tau proteins using a model of proteopathy that include both local growth due to autocatalytic effects and diffusion along axonal pathways. We develop new methods to capture the staging patterns and use these as a qualitative criterion to identify the best model for diffusion process on networks and to identify possible parameter regimes. Our analysis provides a systematic way to study Braak staging in neurodegenerative processes.

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