scholarly journals Dl-3-n-Butylphthalide Reduces Cognitive Deficits and Alleviates Neuropathology in P301S Tau Transgenic Mice

2021 ◽  
Vol 15 ◽  
Author(s):  
Yanmin Chang ◽  
Yi Yao ◽  
Rong Ma ◽  
Zemin Wang ◽  
Junjie Hu ◽  
...  
Keyword(s):  
Transgenic Mice ◽  
Cognitive Deficits ◽  
Tau Protein ◽  
Animal Studies ◽  
Inflammatory Responses ◽  
Hyperphosphorylated Tau ◽  
Behavioral Deficits ◽  
Synaptic Loss ◽  
Underlying Mechanisms ◽  
P301s Mutation

Alzheimer’s disease (AD) is a destructive and burdensome neurodegenerative disease, one of the most common characteristics of which are neurofibrillary tangles (NFTs) that are composed of abnormal tau protein. Animal studies have suggested that dl-3-n-butylphthalide (dl-NBP) alleviates cognitive impairment in mouse models of APP/PS1 and SAMP8. However, the underlying mechanisms related to this remain unclear. In this study, we examined the effects of dl-NBP on learning and memory in P301S transgenic mice, which carry the human tau gene with the P301S mutation. We found that dl-NBP supplementation effectively improved behavioral deficits and rescued synaptic loss in P301S tau transgenic mice, compared with vehicle-treated P301S mice. Furthermore, we also found that it markedly inhibited the hyperphosphorylated tau at the Ser262 site and decreased the activity of MARK4, which was associated with tau at the Ser262 site. Finally, dl-NBP treatment exerted anti-inflammatory effects and reduced inflammatory responses in P301S mice. In conclusion, our results provide evidence that dl-NBP has a promising potential for the therapy of tauopathies, including AD.

scholarly journals Effects of resveratrol and morin on insoluble tau in tau transgenic mice

2018 ◽  
Vol 9 (1) ◽  
pp. 54-60 ◽  
Author(s):  
Kwun Chung Yu ◽  
Ping Kwan ◽  
Stanley K.K. Cheung ◽  
Amy Ho ◽  
Larry Baum
Keyword(s):  
Transgenic Mice ◽  
Motor Function ◽  
Tau Protein ◽  
Late Stage ◽  
Animal Studies ◽  
Paired Helical Filaments ◽  
Hyperphosphorylated Tau ◽  
Total Tau ◽  
Tau Aggregation ◽  
Do So

Abstract Tauopathies are neurodegenerative diseases, including Alzheimer’s disease (AD) and frontotemporal dementia (FTD), in which tau protein aggregates within neurons. An effective treatment is lacking and is urgently needed. We evaluated two structurally similar natural compounds, morin and resveratrol, for treating tauopathy in JNPL3 P301L mutant human tau overexpressing mice. Rotarod tests were performed to determine effects on motor function. After treatment from age 11 to 14 months, brains of 26 mice were collected to quantify aggregated hyperphosphorylated tau by Thioflavin T and immunohistochemistry (IHC) and to quantify total tau (HT7 antibody) and hyperphosphorylated tau (AT8 antibody) in homogenates and a fraction enriched for paired helical filaments. Resveratrol reduced the level of total hyperphosphorylated tau in IHC sections (p=0.036), and morin exhibited a tendency to do so (p=0.29), while the two drugs tended to increase the proportion of solubilizable tau that was hyperphosphorylated, as detected in blots. Neither resveratrol nor morin affected motor function. One explanation of these results is that the drugs might interrupt a late stage in tau aggregation, after small aggregates have formed but before further aggregation has occurred. Further animal studies would be informative to explore the possible efficacy of morin or resveratrol for treating tauopathies.

scholarly journals Zebrafish Models to Study New Pathways in Tauopathies

2021 ◽  
Vol 22 (9) ◽  
pp. 4626
Author(s):  
Clément Barbereau ◽  
Nicolas Cubedo ◽  
Tangui Maurice ◽  
Mireille Rossel
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Common Point ◽  
Transgenic Models ◽  
Synaptic Loss ◽  
Wide Range ◽  
Transgenic Lines ◽  
Functional Consequences ◽  
The Common

Tauopathies represent a vast family of neurodegenerative diseases, the most well-known of which is Alzheimer’s disease. The symptoms observed in patients include cognitive deficits and locomotor problems and can lead ultimately to dementia. The common point found in all these pathologies is the accumulation in neural and/or glial cells of abnormal forms of Tau protein, leading to its aggregation and neurofibrillary tangles. Zebrafish transgenic models have been generated with different overexpression strategies of human Tau protein. These transgenic lines have made it possible to highlight Tau interacting factors or factors which may limit the neurotoxicity induced by mutations and hyperphosphorylation of the Tau protein in neurons. Several studies have tested neuroprotective pharmacological approaches. On few-days-old larvae, modulation of various signaling or degradation pathways reversed the deleterious effects of Tau mutations, mainly hTauP301L and hTauA152T. Live imaging and live tracking techniques as well as behavioral follow-up enable the analysis of the wide range of Tau-related phenotypes from synaptic loss to cognitive functional consequences.

scholarly journals Host Tau Genotype Specifically Regulates and Designs Tau Seeding and Spreading Following Intracerebral Injection of Identical Tau ADInoculum

2021 ◽  
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
José Antonio del Rio ◽  
Isidro Ferrer
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Host Cells ◽  
Intracerebral Injection ◽  
Molecular Response ◽  
Knock Out ◽  
Ca1 Neurons ◽  
Variable Expression ◽  
Gsk 3Β ◽  
P301s Mutation

Abstract BackgroundSeveral studies have demonstrated the capacity for seeding and spreading of tau-enriched fractions of brain homogenates from AD and other human and mouse tauopathies following intracerebral inoculation into transgenic mice bearing human tau or mutant human tau and into WT mice. However, little attention has been paid about the importance of host tau in tau seeding. MethodsThe brains of four adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), P301S (human 4Rtau expressing the P301S mutation), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWt (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD case. ResultsNo tau deposits were identified in inoculated mtWT mice. Involvement of CA1 neurons was higher and that of oligodendrocytes lower in inoculated hTau when compared with inoculated WT and P301S mice. tau-P Ser422, PHF1, and MAP2-P immunoreactivity was moderate or weak in WT and P301S, but strong i in inoculated hTau mice. p38-P and SAPK/JNK-P were observed in recruited phospho-tau deposits in inoculated WT, P301S, and hTau mice. However, CK1-δ, GSK-3β-P Ser9, AKT-P Ser473, PKAα/β-P Tyr197, and CLK1 were identified in neurons with tau deposits only in inoculated hTau. Finally, 3Rtau deposits predominated in inoculated WT and P301S, and 4Rtau deposits in hTau transgenic mice. ConclusionsOur results reveal that a) host tau is mandatory for tau seeding and spreading following tau inoculation; b) tau seeding and spreading is characterized by major genotype-dependent biochemical changes linked to post-translational tau modifications including tau phosphorylation and tau nitration at different sites, c) it is accompanied by genotype-dependent activation of various kinases thus pointing to a complex molecular response in the receptive host cells; d) tau seeding and spreading is accompanied by modifications in tau splicing with variable expression of new 3Rtau and 4Rtau isoforms; e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits are dependent on the host tau genotypes injected with identical AD tau inoculum.

scholarly journals Insights into Disease-Associated Tau Impact on Mitochondria

2020 ◽  
Vol 21 (17) ◽  
pp. 6344 ◽  
Author(s):  
Leonora Szabo ◽  
Anne Eckert ◽  
Amandine Grimm
Keyword(s):  
Cognitive Deficits ◽  
Tau Protein ◽  
Frontotemporal Lobar Degeneration ◽  
Therapeutic Interventions ◽  
Mitochondrial Proteins ◽  
Early Event ◽  
Substantial Evidence ◽  
Mitochondrial Functions ◽  
Underlying Mechanisms ◽  
The Brain

Abnormal tau protein aggregation in the brain is a hallmark of tauopathies, such as frontotemporal lobar degeneration and Alzheimer’s disease. Substantial evidence has been linking tau to neurodegeneration, but the underlying mechanisms have yet to be clearly identified. Mitochondria are paramount organelles in neurons, as they provide the main source of energy (adenosine triphosphate) to these highly energetic cells. Mitochondrial dysfunction was identified as an early event of neurodegenerative diseases occurring even before the cognitive deficits. Tau protein was shown to interact with mitochondrial proteins and to impair mitochondrial bioenergetics and dynamics, leading to neurotoxicity. In this review, we discuss in detail the different impacts of disease-associated tau protein on mitochondrial functions, including mitochondrial transport, network dynamics, mitophagy and bioenergetics. We also give new insights about the effects of abnormal tau protein on mitochondrial neurosteroidogenesis, as well as on the endoplasmic reticulum-mitochondria coupling. A better understanding of the pathomechanisms of abnormal tau-induced mitochondrial failure may help to identify new targets for therapeutic interventions.

scholarly journals Host Tau Genotype Specifically Regulates and Designs Tau Seeding and Spreading Following Intracerebral Injection of Identical Tau AD Inoculum

2021 ◽  
Author(s):  
Pol Andrés-Benito ◽  
Margarita Carmona ◽  
Mónica Jordán ◽  
José Antonio del Rio ◽  
Isidro Ferrer
Keyword(s):  
Transgenic Mice ◽  
Tau Protein ◽  
Host Cells ◽  
Intracerebral Injection ◽  
Molecular Response ◽  
Knock Out ◽  
Ca1 Neurons ◽  
Variable Expression ◽  
Gsk 3Β ◽  
P301s Mutation

Abstract Background: Several studies have demonstrated the capacity for seeding and spreading of tau-enriched fractions of brain homogenates from AD and other human and mouse tauopathies following intracerebral inoculation into transgenic mice bearing human tau or mutant human tau and into WT mice. However, little attention has been paid about the importance of host tau in tau seeding. Methods: The brains of four adult murine genotypes expressing different forms of tau—WT (murine 4Rtau), P301S (human 4Rtau expressing the P301S mutation), hTau (homozygous transgenic mice knock-out for murine tau protein and heterozygous expressing human forms of 3Rtau and 4Rtau proteins), and mtWt (homozygous transgenic mice knock-out for murine tau protein)—were analyzed following unilateral hippocampal inoculation of sarkosyl-insoluble tau fractions from the same AD case. Results: No tau deposits were identified in inoculated mtWT mice. Involvement of CA1 neurons was higher and that of oligodendrocytes lower in inoculated hTau when compared with inoculated WT and P301S mice. tau-P Ser422, PHF1, and MAP2-P immunoreactivity was moderate or weak in WT and P301S, but strong in inoculated hTau mice. p38-P and SAPK/JNK-P were observed in recruited phospho-tau deposits in inoculated WT, P301S, and hTau mice. However, CK1-δ, GSK-3β-P Ser9, AKT-P Ser473, PKAα/β-P Tyr197, and CLK1 were identified in neurons with tau deposits only in inoculated hTau. Finally, 3Rtau deposits predominated in inoculated WT and P301S, and 4Rtau deposits in hTau transgenic mice. Conclusions: Our results reveal that a) host tau is mandatory for tau seeding and spreading following tau inoculation; b) tau seeding and spreading is characterized by major genotype-dependent biochemical changes linked to post-translational tau modifications including tau phosphorylation and tau nitration at different sites, c) it is accompanied by genotype-dependent activation of various kinases thus pointing to a complex molecular response in the receptive host cells; d) tau seeding and spreading is accompanied by modifications in tau splicing with variable expression of new 3Rtau and 4Rtau isoforms; e) selective regional and cellular vulnerabilities, and different molecular compositions of the deposits are dependent on the host tau genotypes injected with identical AD tau inoculum.

MiR-335-5p Inhibits β-Amyloid (Aβ) Accumulation to Attenuate Cognitive Deficits Through Targeting c-jun-N-terminal Kinase 3 in Alzheimer’s Disease

2020 ◽  
Vol 17 (1) ◽  
pp. 93-101 ◽  
Author(s):  
Dan Wang ◽  
Zhifu Fei ◽  
Song Luo ◽  
Hai Wang
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transgenic Mice ◽  
Western Blot ◽  
Mrna Expression ◽  
Cognitive Deficits ◽  
Protein Levels ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
The Relationship

Objectives: Alzheimer's disease (AD), also known as senile dementia, is a common neurodegenerative disease characterized by progressive cognitive impairment and personality changes. Numerous evidences have suggested that microRNAs (miRNAs) are involved in the pathogenesis and development of AD. However, the exact role of miR-335-5p in the progression of AD is still not clearly clarified. Methods: The protein and mRNA levels were measured by western blot and RNA extraction and quantitative real-time PCR (qRT-PCR), respectively. The relationship between miR-335-5p and c-jun-N-terminal kinase 3 (JNK3) was confirmed by dual-luciferase reporter assay. SH-SY5Y cells were transfected with APP mutant gene to establish the in vitro AD cell model. Flow cytometry and western blot were performed to evaluate cell apoptosis. The APP/PS1 transgenic mice were used as an in vivo AD model. Morris water maze test was performed to assess the effect of miR- 335-5p on the cognitive deficits in APP/PS1 transgenic mice. Results: The JNK3 mRNA expression and protein levels of JNK3 and β-Amyloid (Aβ) were significantly up-regulated, and the mRNA expression of miR-335-5p was down-regulated in the brain tissues of AD patients. The expression levels of miR-335-5p and JNK3 were significantly inversely correlated. Further, the dual Luciferase assay verified the relationship between miR-335- 5p and JNK3. Overexpression of miR-335-5p significantly decreased the protein levels of JNK3 and Aβ and inhibited apoptosis in SH-SY5Y/APPswe cells, whereas the inhibition of miR-335-5p obtained the opposite results. Moreover, the overexpression of miR-335-5p remarkably improved the cognitive abilities of APP/PS1 mice. Conclusion: The results revealed that the increased JNK3 expression, negatively regulated by miR-335-5p, may be a potential mechanism that contributes to Aβ accumulation and AD progression, indicating a novel approach for AD treatment.

scholarly journals Infectious disease-associated encephalopathies

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Maria C. Barbosa-Silva ◽  
Maiara N. Lima ◽  
Denise Battaglini ◽  
Chiara Robba ◽  
Paolo Pelosi ◽  
...  
Keyword(s):  
Infectious Disease ◽  
Cognitive Deficits ◽  
Brain Function ◽  
Cell Activation ◽  
Therapeutic Strategies ◽  
Barrier Dysfunction ◽  
Glial Cell Activation ◽  
The Central Nervous System ◽  
Underlying Mechanisms

AbstractInfectious diseases may affect brain function and cause encephalopathy even when the pathogen does not directly infect the central nervous system, known as infectious disease-associated encephalopathy. The systemic inflammatory process may result in neuroinflammation, with glial cell activation and increased levels of cytokines, reduced neurotrophic factors, blood–brain barrier dysfunction, neurotransmitter metabolism imbalances, and neurotoxicity, and behavioral and cognitive impairments often occur in the late course. Even though infectious disease-associated encephalopathies may cause devastating neurologic and cognitive deficits, the concept of infectious disease-associated encephalopathies is still under-investigated; knowledge of the underlying mechanisms, which may be distinct from those of encephalopathies of non-infectious cause, is still limited. In this review, we focus on the pathophysiology of encephalopathies associated with peripheral (sepsis, malaria, influenza, and COVID-19), emerging therapeutic strategies, and the role of neuroinflammation. Graphic abstract

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