scholarly journals Anti-Aβ antibodies bound to neuritic plaques enhance microglia activity and mitigate tau pathology

2020 ◽  
Vol 8 (1) ◽  
Author(s):  
Vanessa Laversenne ◽  
Sameer Nazeeruddin ◽  
Emma C. Källstig ◽  
Philippe Colin ◽  
Christel Voize ◽  
...  
Keyword(s):  
Mouse Model ◽  
Tau Protein ◽  
Hippocampal Formation ◽  
Dystrophic Neurites ◽  
Neuritic Plaques ◽  
Tau Pathology ◽  
Continuous Administration ◽  
Plaque Deposition ◽  
5Xfad Mice

AbstractThe brain pathology of Alzheimer’s disease (AD) is characterized by the misfolding and aggregation of both the amyloid beta (Aβ) peptide and hyperphosphorylated forms of the tau protein. Initial Aβ deposition is considered to trigger a sequence of deleterious events contributing to tau pathology, neuroinflammation and ultimately causing the loss of synapses and neurons. To assess the effect of anti-Aβ immunization in this context, we generated a mouse model by overexpressing the human tau protein in the hippocampus of 5xFAD mice. Aβ plaque deposition combined with human tau overexpression leads to an array of pathological manifestations including the formation of tau-positive dystrophic neurites and accumulation of hyperphosphorylated tau at the level of neuritic plaques. Remarkably, the presence of human tau reduces microglial clustering in proximity to the Aβ plaques, which may affect the barrier role of microglia. In this mouse model, continuous administration of anti-Aβ antibodies enhances the clustering of microglial cells even in the presence of tau. Anti-Aβ immunization increases plaque compaction, reduces the spread of tau in the hippocampal formation and prevents the formation of tau-positive dystrophic neurites. However, the treatment does not significantly reduce tau-induced neurodegeneration in the dentate gyrus. These results highlight that anti-Aβ immunization is able to enhance microglial activity around neuritic plaques, mitigating part of the tau-induced pathological manifestations.

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 A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer’s Disease

2018 ◽  
Author(s):  
Rubayat Islam Khan ◽  
Saif Shahriar Rahman Nirzhor ◽  
Barnaly Rashid
Keyword(s):  
Disease Progression ◽  
Tau Protein ◽  
Imaging Techniques ◽  
Memory Loss ◽  
Full Time ◽  
Tau Pathology ◽  
Synaptic Loss ◽  
Beta Peptides ◽  
Severe Change

One of the most commonly known chronic neurodegenerative disorders, Alzheimer’s disease (AD), manifests the common type of dementia in 60–80% of cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is~usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms such as memory loss, and eventually requiring full-time medical care. From a histopathological standpoint, the~defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT), and depositions of amyloid β-peptides (Aβ) in the brain. The~abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of Tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review: (1) we highlight the interplays existing between Tau pathology and AD; and (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging~techniques.

scholarly journals Role of misfolded tau in the onset and progression of brain toxicity after trauma

2020 ◽  
Author(s):  
Luisa Diomede ◽  
Elisa R. Zanier ◽  
Maria Monica Barzago ◽  
Gloria Vegliante ◽  
Margherita Romeo ◽  
...  
Keyword(s):  
Mouse Model ◽  
Transgenic Mice ◽  
Functional Decline ◽  
Vital Role ◽  
Misfolded Proteins ◽  
Tau Pathology ◽  
Knock Out ◽  
C Elegans

Abstract Background Traumatic brain injury (TBI) is associated with widespread tau pathology in about thirty percent of patients surviving late after injury. We previously found that TBI in mice induces a transmissible tau pathology (tauTBI), with late cognitive decline and synaptic dysfunction. However, it is not clear whether tauTBI is a marker of ongoing neurodegeneration or a driver of functional decline. We employed the nematode C. elegans, which can recognize pathogenic forms of misfolded proteins, to investigate whether tauTBI is the primary toxic culprit in post-TBI neurodegeneration. Methods We developed an original approach involving the administration of brain homogenates from TBI mice to C. elegans, a valuable model for rapidly investigating the pathogenic effects of misfolded proteins in vivo. Brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, as well as pre-aggregated recombinant tau were employed to test whether abnormal tau conformers play a causal role in driving toxicity in TBI. Results Worms given brain homogenates from chronic but not acute TBI mice, or from mice in which tauTBI had been transmitted by intracerebral inoculation, had impaired motility and neuromuscular synaptic transmission. Results were similar when worms were exposed to brain homogenates from transgenic mice overexpressing tau P301L, a tauopathy mouse model, suggesting that TBI-induced and mutant tau have similar toxic properties. Harsh protease digestion to eliminate the protein component of the homogenates or pre-incubation with anti-tau antibodies abolished the toxicity. Homogenates of chronic TBI brains from tau knock-out mice were not toxic to C. elegans, whereas pre-aggregated recombinant tau was sufficient to impair their motility. Conclusions These results support a vital role of abnormal tau species in chronic neurodegeneration after TBI supporting the idea that targeting pathological tau may point to a therapeutic opportunity in trauma, and set the groundwork for the development of a C. elegans-based platform for screening anti-tau compounds.

scholarly journals A Closer Look into the Role of Protein Tau in the Identification of Promising Therapeutic Targets for Alzheimer’s Disease

2018 ◽  
Author(s):  
Rubayat Islam Khan ◽  
Saif Shahriar Rahman Nirzhor ◽  
Barnaly Rashid
Keyword(s):  
Disease Progression ◽  
Tau Protein ◽  
Imaging Techniques ◽  
Memory Loss ◽  
Full Time ◽  
Tau Pathology ◽  
Synaptic Loss ◽  
Beta Peptides ◽  
Severe Change

One of the most commonly known chronic neurodegenerative disorders is Alzheimer’s disease (AD) that manifests the common type of dementia in 60-80% of AD cases. From a clinical standpoint, a patent cognitive decline and a severe change in personality, as caused by a loss of neurons, is usually evident in AD with about 50 million people affected in 2016. The disease progression in patients is distinguished by a gradual plummet in cognitive functions, eliciting symptoms like memory loss, and eventually requiring full-time medical care. From a pathophysiological standpoint, the defining characteristics are intracellular aggregations of hyper-phosphorylated tau protein, known as neurofibrillary tangles (NFT) and depositions of amyloid β-peptides (Aβ) in the brain. The abnormal phosphorylation of tau protein is attributed to a wide gamut of neurological disorders known as tauopathies. In addition to the hyperphosphorylated tau lesions, neuroinflammatory processes could occur in a sustained manner through astro-glial activation, resulting in the disease progression. Recent findings have suggested a strong interplay between the mechanism of tau phosphorylation, disruption of microtubules, and synaptic loss and pathology of AD. The mechanisms underlying these interactions along with their respective consequences in Tau pathology are still ill-defined. Thus, in this review, (1) we highlight the interplays existing between Tau pathology and AD and, (2) take a closer look into its role while identifying some promising therapeutic advances including state of the art imaging techniques.

scholarly journals Human tau pathology transmits glial tau aggregates in the absence of neuronal tau

2019 ◽  
Vol 217 (2) ◽  
Author(s):  
Sneha Narasimhan ◽  
Lakshmi Changolkar ◽  
Dawn M. Riddle ◽  
Alexandra Kats ◽  
Anna Stieber ◽  
...  
Keyword(s):  
White Matter ◽  
Mouse Model ◽  
Mouse Brain ◽  
Tau Protein ◽  
Corticobasal Degeneration ◽  
Cell Loss ◽  
Tau Pathology ◽  
Abnormal Accumulation ◽  
Nontg Mouse ◽  
Functional Consequences

Tauopathies are characterized by abnormal accumulation of tau protein in neurons and glia. In Alzheimer’s disease (AD), tau aggregates in neurons, while in corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP), tau also aggregates in astrocytes and oligodendrocytes. We previously demonstrated that human CBD and PSP tauopathy lysates (CBD-tau and PSP-tau) contain distinct tau strains that propagate neuronal and glial tau aggregates in nontransgenic (nonTg) mouse brain. Yet the mechanism of glial tau transmission is unknown. Here, we developed a novel mouse model to knock down tau in neurons to test for glial tau transmission. While oligodendroglial tau pathology propagated across the mouse brain in the absence of neuronal tau pathology, astrocytic tau pathology did not. Oligodendroglial tau aggregates propagated along white matter tracts independently of neuronal axons, and resulted in oligodendrocyte cell loss. Thus, glial tau pathology has significant functional consequences independent of neuronal tau pathology.

scholarly journals BAG1 Overexpression Stabilizes High Molecular Tau Protein – a Crucial Role of the Co-chaperone in Tau Pathology

2021 ◽  
Vol 9 (2) ◽  
pp. 77
Author(s):  
Sandra Caecilie Signore ◽  
Fred Silvester Wouters ◽  
Matthias Schmitz ◽  
Mathias Baehr ◽  
Pawel Kermer
Keyword(s):  
Tau Protein ◽  
Crucial Role ◽  
Protein A ◽  
Tau Pathology

scholarly journals Mislocalization and clearance of neuronal Rhes as a novel hallmark of tauopathies

2020 ◽  
Author(s):  
Alexander J. Ehrenberg ◽  
Kun Leng ◽  
Israel Hernandez ◽  
Caroline Lew ◽  
William W. Seeley ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Hippocampal Formation ◽  
Tau Pathology ◽  
Farnesyltransferase Inhibitor ◽  
Post Translational Modifications ◽  
Single Nucleus ◽  
Tau Aggregation

ABSTRACTThe farnesyltransferase inhibitor lonafarnib reduces tau inclusion burden and atrophy in familial tauopathy models by inhibiting farnesylation on the Ras GTPase, Rhes, and activating autophagy. While hinting at a role of Rhes in tau aggregation, it is unclear how translatable these results are for sporadic forms of tauopathy. We used a combination of quantitative pathology using multiplex immunofluorescence for Rhes, several tau post-translational modifications, and single nucleus RNA sequence analysis to interrogate Rhes presence and distribution in human cortical neurons and Rhes relation to tau and TDP-43 changes. snRNA data suggest that Rhes is found in all cortical neuron subpopulations, not only in striatum cells. Histologic investigation in hippocampal formation from multiple postmortem cases in five different tauopathies and healthy controls and TDP-43 proteinopathy showed that nearly all neurons in control brains display a pattern of diffuse cytoplasmic Rhes positivity. However, in the presence of abnormal tau, but not TDP-43 inclusions, the patterns of neuronal cytoplasmic Rhes tend to present as either punctiform or fully absent. Our findings reinforce the relevance of the link between Rhes changes and tau pathology suggested by in vivo and in vitro models of tauopathy and support a potential clinical application of lonafarnib to tauopathies.

Acupuncture Inhibits the Increase in Alpha-Synuclein by Modulating SGK1 in an MPTP Induced Parkinsonism Mouse Model

2019 ◽  
Vol 47 (03) ◽  
pp. 527-539
Author(s):  
Sujung Yeo ◽  
Sabina Lim
Keyword(s):  
Mouse Model ◽  
Dopaminergic Neurons ◽  
Lewy Bodies ◽  
Cell Loss ◽  
Alpha Synuclein ◽  
Control Group ◽  
Dystrophic Neurites ◽  
Dopaminergic Cell ◽  
Acupuncture Stimulation

Parkinson’s disease (PD), a progressive neurodegenerative disease, is caused by the loss of dopaminergic neurons in the substantia nigra (SN). It is characterized by the formation of intracytoplasmic Lewy bodies that are primarily composed of the protein alpha-synuclein ([Formula: see text]-syn) along with dystrophic neurites. Acupuncture stimulation results in an enhanced survival of dopaminergic neurons in the SN in parkinsonism animal models. We investigated the role of acupuncture in inhibiting the increase in [Formula: see text]-syn expression that is related with dopaminergic cell loss in the SN in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) parkinsonism mouse model. In this model, acupuncture stimulation at GB34 and LR3 attenuated the decrease in tyrosine hydroxylase. Moreover, acupuncture stimulation attenuated the increase in [Formula: see text]-syn. We identified that serum- and glucocorticoid-dependent kinase 1 (SGK1) is evidently downregulated in chronic MPTP-intoxication and acupuncture stimulation maintained SGK1 expression at levels similar to the control group. For an examination of the expression correlation between SGK1 and [Formula: see text]-syn, SH-SY5Y cells were knocked down with SGK1 siRNA then, the downregulation of dopaminergic cells and the increase in the expression of [Formula: see text]-syn were observed. Our findings indicate that the acupuncture-mediated inhibition in the [Formula: see text]-syn increase induced by MPTP may be responsible for modulating SGK1 expression.

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