scholarly journals Neuronal Models for Studying Tau Pathology

2010 ◽  
Vol 2010 ◽  
pp. 1-11
Author(s):  
Thorsten Koechling ◽  
Filip Lim ◽  
Felix Hernandez ◽  
Jesus Avila
Keyword(s):  
Tau Protein ◽  
Human Population ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Peptide ◽  
Tau Pathology ◽  
Histological Characteristics ◽  
The Brain ◽  
Phosphorylated Tau Protein ◽  
Genetically Modified Animals

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder leading to dementia in the aged human population. It is characterized by the presence of two main pathological hallmarks in the brain: senile plaques containing -amyloid peptide and neurofibrillary tangles (NFTs), consisting of fibrillar polymers of abnormally phosphorylated tau protein. Both of these histological characteristics of the disease have been simulated in genetically modified animals, which today include numerous mouse, fish, worm, and fly models of AD. The objective of this review is to present some of the main animal models that exist for reproducing symptoms of the disorder and their advantages and shortcomings as suitable models of the pathological processes. Moreover, we will discuss the results and conclusions which have been drawn from the use of these models so far and their contribution to the development of therapeutic applications for AD.

AADVAC1, AN ACTIVE IMMUNOTHERAPY FOR ALZHEIMER’S DISEASE AND NON ALZHEIMER TAUOPATHIES: AN OVERVIEW OF PRECLINICAL AND CLINICAL DEVELOPMENT

2018 ◽  
pp. 1-7
Author(s):  
P. Novak ◽  
N. Zilka ◽  
M. Zilkova ◽  
B. Kovacech ◽  
R. Skrabana ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Therapeutic Potential ◽  
Phase 1 ◽  
Primary Progressive Aphasia ◽  
Tau Proteins ◽  
Active Immunotherapy ◽  
Tau Pathology

Neurofibrillary tau protein pathology is closely associated with the progression and phenotype of cognitive decline in Alzheimer’s disease and other tauopathies, and a high-priority target for disease-modifying therapies. Herein, we provide an overview of the development of AADvac1, an active immunotherapy against tau pathology, and tau epitopes that are potential targets for immunotherapy. The vaccine leads to the production of antibodies that target conformational epitopes in the microtubule-binding region of tau, with the aim to prevent tau aggregation and spreading of pathology, and promote tau clearance. The therapeutic potential of the vaccine was evaluated in transgenic rats and mice expressing truncated, non mutant tau protein, which faithfully replicate of human tau pathology. Treatment with AADvac1 resulted in reduction of neurofibrillary pathology and insoluble tau in their brains, and amelioration of their deleterious phenotype. The vaccine was highly immunogenic in humans, inducing production of IgG antibodies against the tau peptide in 29/30 treated elderly patients with mild-to-moderate Alzheimer’s. These antibodies were able to recognise insoluble tau proteins in Alzheimer patients’ brains. Treatment with AADvac1 proved to be remarkably safe, with injection site reactions being the only adverse event tied to treatment. AADvac1 is currently being investigated in a phase 2 study in Alzheimer’s disease, and a phase 1 study in non-fluent primary progressive aphasia, a neurodegenerative disorder with a high tau pathology component.

scholarly journals Tauopathy Analysis in P301S Mouse Model of Alzheimer Disease Immunized with DNA and MVA Poxvirus-Based Vaccines Expressing Human Full-Length 4R2N or 3RC Tau Proteins

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 127
Author(s):  
Juan García-Arriaza ◽  
María Q. Marín ◽  
Jesús Merchán-Rubira ◽  
Sara M. Mascaraque ◽  
Miguel Medina ◽  
...  
Keyword(s):  
Mouse Model ◽  
Immune Responses ◽  
B Cell ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Innate Immune ◽  
Full Length ◽  
Tau Proteins ◽  
Β Amyloid

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a progressive memory loss and cognitive decline that has been associated with an accumulation in the brain of intracellular neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau protein, and extracellular senile plaques formed by β-amyloid peptides. Currently, there is no cure for AD and after the failure of anti β-amyloid therapies, active and passive tau immunotherapeutic approaches have been developed in order to prevent, reduce or ideally reverse the disease. Vaccination is one of the most effective approaches to prevent diseases and poxviruses, particularly modified vaccinia virus Ankara (MVA), are one of the most promising viral vectors used as vaccines against several human diseases. Thus, we present here the generation and characterization of the first MVA vectors expressing human tau genes; the full-length 4R2N tau protein or a 3RC tau fragment containing 3 tubulin-binding motifs and the C-terminal region (termed MVA-Tau4R2N and MVA-Tau3RC, respectively). Both MVA-Tau recombinant viruses efficiently expressed the human tau 4R2N or 3RC proteins in cultured cells, being detected in the cytoplasm of infected cells and co-localized with tubulin. These MVA-Tau vaccines impacted the innate immune responses with a differential recruitment of innate immune cells to the peritoneal cavity of infected mice. However, no tau-specific T cell or humoral immune responses were detected in vaccinated mice. Immunization of transgenic P301S mice, a mouse model for tauopathies, with a DNA-Tau prime/MVA-Tau boost approach showed no significant differences in the hyperphosphorylation of tau, motor capacity and survival rate, when compared to non-vaccinated mice. These findings showed that a well-established and potent protocol of T and B cell activation based on DNA/MVA prime/boost regimens using DNA and MVA vectors expressing tau full-length 4R2N or 3RC proteins is not sufficient to trigger tau-specific T and B cell immune responses and to induce a protective effect against tauopathy in this P301S murine model. In the pursuit of AD vaccines, our results highlight the need for novel optimized tau immunogens and additional modes of presentation of tau protein to the immune system.

scholarly journals Quantitative Assessment of Hippocampal Tau Pathology in AD and PART

2020 ◽  
Vol 70 (11) ◽  
pp. 1808-1811 ◽  
Author(s):  
Lei Zhang ◽  
Yankai Jiang ◽  
Jie Zhu ◽  
Huazheng Liang ◽  
Xiangyang He ◽  
...  
Keyword(s):  
Tau Protein ◽  
Quantitative Assessment ◽  
Hippocampal Formation ◽  
Selective Vulnerability ◽  
Tau Pathology ◽  
Regional Patterns ◽  
Mathematical Algorithm ◽  
Age Related ◽  
Distinguishing Features ◽  
Phosphorylated Tau Protein

Abstract To quantitatively assess the distribution pattern of hippocampal tau pathology in Alzheimer’s disease (AD) and primary age-related tauopathy (PART), we investigated the distribution of phosphorylated tau protein (AT8) in 6 anatomically defined subregions of the hippocampal formation and developed a mathematical algorithm to compare the patterns of tau deposition in PART and AD. We demonstrated regional patterns of selective vulnerability as distinguishing features of PART and AD in functionally relevant structures of the hippocampus. In AD cases, tau pathology was high in both CA1 and subiculum, followed by CA2/3, entorhinal cortex (EC), CA4, and dentate gyrus (DG). In PART, the severity of tau pathology in CA1 and subiculum was high, followed by EC, CA2/3, CA4, and DG. There are significant differences between sector DG and CA1, DG and subiculum in both AD and PART.

scholarly journals Mutual Relationship between Tau and Central Insulin Signalling: Consequences for AD and Tauopathies?

2018 ◽  
Vol 107 (2) ◽  
pp. 181-195 ◽  
Author(s):  
Maud Gratuze ◽  
Aurélie Joly-Amado ◽  
Didier Vieau ◽  
Luc Buée ◽  
David Blum
Keyword(s):  
Tau Protein ◽  
Energy Homeostasis ◽  
Neurodegenerative Disorder ◽  
Insulin Signalling ◽  
Positive Outcome ◽  
Insulin Resistant ◽  
Increased Risk ◽  
Multiple Levels ◽  
The Brain

Alzheimer disease (AD) is a progressive neurodegenerative disorder mainly characterized by cognitive deficits and neuropathological changes such as Tau lesions and amyloid plaques, but also associated with non-cognitive symptomatology. Metabolic and neuroendocrine abnormalities, such as alterations in body weight, brain insulin impairments, and lower brain glucose metabolism, which often precede clinical diagnosis, have been extensively reported in AD patients. However, the origin of these symptoms and their relation to pathology and cognitive impairments remain misunderstood. Insulin is a hormone involved in the control of energy homeostasis both peripherally and centrally, and insulin-resistant state has been linked to increased risk of dementia. It is now well established that insulin resistance can exacerbate Tau lesions, mainly by disrupting the balance between Tau kinases and phosphatases. On the other hand, the emerging literature indicates that Tau protein can also modulate insulin signalling in the brain, thus creating a detrimental vicious circle. The following review will highlight our current understanding of the role of insulin in the brain and its relation to Tau protein in the context of AD and tauopathies. Considering that insulin signalling is prone to be pharmacologically targeted at multiple levels, it constitutes an appealing approach to improve both insulin brain sensitivity and mitigate brain pathology with expected positive outcome in terms of cognition.

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 Folate and Methylation Status in Relation to Phosphorylated Tau Protein(181P) and β-Amyloid(1–42) in Cerebrospinal Fluid

2007 ◽  
Vol 53 (6) ◽  
pp. 1129-1136 ◽  
Author(s):  
Rima Obeid ◽  
Mariz Kasoha ◽  
Jean-Pierre Knapp ◽  
Panagiotis Kostopoulos ◽  
George Becker ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Tau Protein ◽  
Neurological Diseases ◽  
Methylation Status ◽  
Age Groups ◽  
Phosphorylated Tau ◽  
Β Amyloid ◽  
Folate And Vitamin B12 ◽  
The Brain ◽  
Phosphorylated Tau Protein

Abstract Background: Increased plasma total homocysteine (tHcy) is a risk factor for neurological diseases, but the underlying pathophysiology has not been adequately explained. Methods: We evaluated concentrations of tHcy, S-adenosyl homocysteine (SAH), S-adenosyl methionine (SAM), folate, and vitamin B12 in cerebrospinal fluid (CSF) and plasma or serum from 182 patients with different neurological disorders. We measured concentrations of phosphorylated tau protein (P-tau)(181P) and β-amyloid(1–42) in the CSF. Results: Aging was associated with higher concentrations of tHcy and SAH in the CSF, in addition to lower concentrations of CSF folate and lower SAM:SAH ratio. Concentrations of CSF SAH and CSF folate correlated significantly with those of P-tau (r = 0.46 and r = −0.28, respectively). Moreover, P-tau correlated negatively with SAM:SAH ratio (r = −0.40, P <0.001). The association between SAH and higher P-tau was observed in 3 age groups (<41, 41–60, and >60 years). CSF tHcy was predicted by concentrations of CSF cystathionine (β = 0.478), folate (β = −0.403), albumin (β = 0.349), and age (β = 0.298). Conclusions: tHcy concentration in the brain is related to age, B vitamins, and CSF albumin. Increase of CSF SAH is related to increased CSF P-tau; decreased degradation of P-tau might be a plausible explanation. Disturbed methyl group metabolism may be the link between hyperhomocysteinemia and neurodegeneration. Lowering tHcy and SAH might protect the brain by preventing P-tau accumulation.

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.

scholarly journals Phosphorylated Tau protein in the myenteric plexus of the ileum and colon of normothermic rats and during synthetic torpor

2021 ◽  
Author(s):  
R Chiocchetti ◽  
T Hitrec ◽  
F Giancola ◽  
J Sadeghinezhad ◽  
F Squarcio ◽  
...  
Keyword(s):  
Tau Protein ◽  
Myenteric Plexus ◽  
Cholinergic Neurons ◽  
Cellular Mechanism ◽  
Enteric Neurons ◽  
Neuronal Homeostasis ◽  
Core Body ◽  
The Brain ◽  
Phosphorylated Tau Protein ◽  
Tau Expression

AbstractTau protein is of primary importance for neuronal homeostasis and when hyperphosphorylated (PP-Tau), it tends to aggregate in neurofibrillary tangles, as is the case with tauopathies, a class of neurodegenerative disorders. Reversible PP-Tau accumulation occurs in the brain of hibernating rodents and it was recently observed in rats (a non-hibernator) during synthetic torpor (ST), a pharmacological-induced torpor-like condition. To date, the expression of PP-Tau in the rat enteric nervous system (ENS) is still unknown. The present study immunohistochemically investigates the PP-Tau expression in the myenteric plexus of the ileum and colon of normothermic rats (CTRL) and during ST, focusing on the two major subclasses of enteric neurons, i.e., cholinergic and nitrergic.Results showed that both groups of rats expressed PP-Tau, with a significantly increased percentage of PP-Tau immunoreactive (IR) neurons in ST vs. CTRL. In all rats, the majority of PP-Tau-IR neurons were cholinergic. In ST rats, the percentage of PP-Tau-IR neurons expressing a nitrergic phenotype increased, although with no significant differences between groups. In addition, the ileum of ST rats showed a significant decrease in the percentage of nitrergic neurons. In conclusion, our findings suggest an adaptive response of ENS to very low core body temperatures, with changes involving PP-tau expression in enteric neurons, especially the ileal nitrergic subpopulation. In addition, the high presence of PP-Tau in cholinergic neurons, specifically, is very interesting and deserves further investigation. Altogether, these data strengthen the hypothesis of a common cellular mechanism triggered by ST, natural hibernation and tauopathies occurring in ENS neurons.

scholarly journals Administration of Mucuna Beans (Mucuna Pruriences (L.) DC. Var. Utilis) Improves Cognition and Neuropathology of 3×Tg-AD Mice

2021 ◽  
Author(s):  
Fumiko Konishi ◽  
Tadasu Furusho ◽  
Yoshiyuki Soeda ◽  
Jun Yamauchi ◽  
Shoko Kobayashi ◽  
...  
Keyword(s):  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Control Group ◽  
Phosphorylated Tau ◽  
Aβ Oligomers ◽  
Amyloid Beta Peptides ◽  
Beta Peptides ◽  
Hyperphosphorylated Tau Protein ◽  
Ad Prevention ◽  
The Brain

Abstract Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of extracellular amyloid-beta peptides (Aβ) resulting in senile plaques and intracellular hyperphosphorylated tau protein resulting in neurofibrillary tangles (NFTs). Mucuna beans (Mucuna pruriences (L.) DC. var. utilis) are unique plants containing 3%–9% L-3,4-dihydroxyphenylalanine (L-DOPA). Here we investigated the effect of the administration of Mucuna beans on AD prevention by feeding triple-transgenic mice (3×Tg-AD mice) with a diet containing Mucuna beans for 13 months. The levels of Aβ oligomers and detergent-insoluble phosphorylated tau decreased in the brain of mice fed with Mucuna beans (Mucuna group) compared to those of the Control group. Aβ accumulation and phosphorylated tau accumulation in the brain in the Mucuna group were also reduced. In addition, administration of Mucuna beans improved cognitive function. These results suggest that administration of Mucuna beans may have a preventive effect on AD development in 3×Tg-AD mice.

scholarly journals Looking at Alzheimer’s Disease Pathogenesis from the Nuclear Side

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1261
Author(s):  
Laura D’Andrea ◽  
Ramona Stringhi ◽  
Monica Di Luca ◽  
Elena Marcello
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Apoe Ε4 ◽  
Hyperphosphorylated Tau Protein ◽  
Ε4 Allele ◽  
Therapeutic Tools

Alzheimer’s disease (AD) is a neurodegenerative disorder representing the most common form of dementia. It is biologically characterized by the deposition of extracellular amyloid-β (Aβ) senile plaques and intracellular neurofibrillary tangles, constituted by hyperphosphorylated tau protein. The key protein in AD pathogenesis is the amyloid precursor protein (APP), which is cleaved by secretases to produce several metabolites, including Aβ and APP intracellular domain (AICD). The greatest genetic risk factor associated with AD is represented by the Apolipoprotein E ε4 (APOE ε4) allele. Importantly, all of the above-mentioned molecules that are strictly related to AD pathogenesis have also been described as playing roles in the cell nucleus. Accordingly, evidence suggests that nuclear functions are compromised in AD. Furthermore, modulation of transcription maintains cellular homeostasis, and alterations in transcriptomic profiles have been found in neurodegenerative diseases. This report reviews recent advancements in the AD players-mediated gene expression. Aβ, tau, AICD, and APOE ε4 localize in the nucleus and regulate the transcription of several genes, part of which is involved in AD pathogenesis, thus suggesting that targeting nuclear functions might provide new therapeutic tools for the disease.

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