The association between tau aggregation and microglia in frontotemporal lobar dementia

Background: Alzheimer’s Disease (AD) is characterized by the presence of extracellular amyloid-β (Aβ) plaques and intraneuronal neurofibrillary tangles assembled by the microtubuleassociated protein tau. Increasing evidence demonstrated that tau pathology played an important role in AD progression. Resveratrol (RSV) has previously proved to exert neuroprotective effect against AD by inhibiting Aβ generation and Aβ-induced neurocytotoxicity, while its effect on tau pathology is still unknown. Method: The effect of RSV on tau aggregation was measured by Thioflavin T fluorescence and Transmission electron microscope imaging. The effect of RSV on tau oligomer-induced cytotoxicity was assessed by MTT assay and the uptake of extracellular tau by N2a cells was determined by immunocytochemistry. 6-month-old male PS19 mice were treated with RSV or vehicle by oral administration (gavage) once a day for 5 weeks. The cognitive performance was determined using Morris water maze test, object recognition test and Y-maze test. The levels of phosphorylated-tau, gliosis, proinflammatory cytokines such as TNF-α and IL-1β, and synaptic proteins including synaptophysin and PSD95 in the brains of the mice were evaluated by immunoblotting, immunostaining and ELISA, respectively. Results: RSV significantly inhibited tau aggregation and tau oligomer-induced cytotoxicity, and blocked the uptake of extracellular tau oligomers by N2a cells. When applied to PS19 mice, RSV treatment effectively rescued cognitive deficits, reducing the levels of phosphorylated tau, neuroinflammation and synapse loss in the brains of mice. Conclusion: These findings suggest that RSV has promising therapeutic potential for AD and other tauopathies.

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Recent Updates in the Alzheimer’s Disease Etiopathology and Possible Treatment Approaches: A Narrative Review of Current Clinical Trials

Current Molecular Pharmacology ◽

10.2174/1874467213666200422090135 ◽

2020 ◽

Vol 13 (4) ◽

pp. 273-294 ◽

Cited By ~ 2

Author(s):

Elahe Zarini-Gakiye ◽

Javad Amini ◽

Nima Sanadgol ◽

Gholamhassan Vaezi ◽

Kazem Parivar

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Clinical Trials ◽

Small Molecules ◽

Clinical Trial Design ◽

Treatment Approaches ◽

Drug Candidates ◽

Novel Treatments ◽

Approved Drugs ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is the most frequent subtype of incurable neurodegenerative dementias and its etiopathology is still not clearly elucidated. Objective: Outline the ongoing clinical trials (CTs) in the field of AD, in order to find novel master regulators. Methods: We strictly reviewed all scientific reports from Clinicaltrials.gov and PubMed databases from January 2010 to January 2019. The search terms were “Alzheimer's disease” or “dementia” and “medicine” or “drug” or “treatment” and “clinical trials” and “interventions”. Manuscripts that met the objective of this study were included for further evaluations. Results: Drug candidates have been categorized into two main groups including antibodies, peptides or hormones (such as Ponezumab, Interferon β-1a, Solanezumab, Filgrastim, Levemir, Apidra, and Estrogen), and naturally-derived ingredients or small molecules (such as Paracetamol, Ginkgo, Escitalopram, Simvastatin, Cilostazo, and Ritalin-SR). The majority of natural candidates acted as anti-inflammatory or/and anti-oxidant and antibodies exert their actions via increasing amyloid-beta (Aβ) clearance or decreasing Tau aggregation. Among small molecules, most of them that are present in the last phases act as specific antagonists (Suvorexant, Idalopirdine, Intepirdine, Trazodone, Carvedilol, and Risperidone) or agonists (Dextromethorphan, Resveratrol, Brexpiprazole) and frequently ameliorate cognitive dysfunctions. Conclusion: The presences of a small number of candidates in the last phase suggest that a large number of candidates have had an undesirable side effect or were unable to pass essential eligibility for future phases. Among successful treatment approaches, clearance of Aβ, recovery of cognitive deficits, and control of acute neuroinflammation are widely chosen. It is predicted that some FDA-approved drugs, such as Paracetamol, Risperidone, Escitalopram, Simvastatin, Cilostazoand, and Ritalin-SR, could also be used in off-label ways for AD. This review improves our ability to recognize novel treatments for AD and suggests approaches for the clinical trial design for this devastating disease in the near future.

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Kinetics of tau aggregation reveals patient specific tau characteristics among Alzheimer's cases

Brain Communications ◽

10.1093/braincomms/fcab096 ◽

2021 ◽

Author(s):

Tarun V Kamath ◽

Naomi Klickstein ◽

Caitlin Commins ◽

Analiese R Fernandes ◽

Derek H Oakley ◽

...

Keyword(s):

Growth Phase ◽

Tau Proteins ◽

Patient Specific ◽

Lag Phase ◽

Plateau Phase ◽

Kinetic Assay ◽

Cellular Processes ◽

Morphological Differences ◽

Tau Aggregation ◽

Kinetics Of

Abstract The accumulation of tau aggregates throughout the human brain is the hallmark of a number of neurodegenerative conditions classified as tauopathies. Increasing evidence shows that tau aggregation occurs in a “prion-like” manner, in which a small amount of misfolded tau protein can induce other, naïve tau proteins to aggregate. Tau aggregates have been found to differ structurally among different tauopathies. Recently, however, we have suggested that tau oligomeric species may differ biochemically among individual patients with sporadic Alzheimer disease, and have also showed that the bioactivity of the tau species, measured using a cell-based bioassay, also varied among individuals. Here, we adopted a live-cell imaging approach to the standard cell-based bioassay to explore further whether the kinetics of aggregation also differentiated these patients. We found that aggregation can be observed to follow a consistent pattern in all cases, with a lag phase, a growth phase, and a plateau phase, which each provide quantitative parameters by which we characterize aggregation kinetics. The length of the lag phase and magnitude of the plateau phase are both dependent upon the concentration of seeding-competent tau, the relative enrichment of which differs among patients. The slope of the growth phase correlates with morphological differences in the tau aggregates, which may be reflective of underlying structural differences. This kinetic assay confirms and refines the concept of heterogeneity in the characteristics of tau proteopathic seeds among individuals with Alzheimer’s disease and is a method by which future studies may characterize longitudinal changes in tau aggregation and the cellular processes which may influence these changes.

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Arrayed CRISPR reveals genetic regulators of tau aggregation, autophagy and mitochondria in Alzheimer’s disease model

Scientific Reports ◽

10.1038/s41598-021-82658-7 ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Lishu Duan ◽

Mufeng Hu ◽

Joseph A. Tamm ◽

Yelena Y. Grinberg ◽

Fang Shen ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Drug Discovery ◽

Disease Model ◽

Mitochondrial Morphology ◽

Individual Gene ◽

Human Genes ◽

Future Drug ◽

Tau Aggregation

AbstractAlzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

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Borrelidin from Saltern-Derived Halophilic Nocardiopsis sp. Dissociates Amyloid-β and Tau Fibrils

Journal of Alzheimer s Disease Reports ◽

10.3233/adr-200247 ◽

2020 ◽

pp. 1-7

Author(s):

Jisu Shin ◽

Seung-Hoon Yang ◽

Young Eun Du ◽

Keunwan Park ◽

DaWon Kim ◽

...

Keyword(s):

Amyloid Β ◽

Thioflavin T ◽

Drug Candidate ◽

Ht22 Cells ◽

Aβ Aggregation ◽

Actinomycete Strain ◽

Direct Dissociation ◽

Aβ Fibrils ◽

Tau Aggregation

Background: Alzheimer’s disease (AD) is characterized by the aggregation of two pathological proteins, amyloid-β (Aβ) and tau, leading to neuronal and cognitive dysfunction. Clearance of either Aβ or tau aggregates by immunotherapy has become a potential therapy, as these aggregates are found in the brain ahead of the symptom onset. Given that Aβ and tau independently and cooperatively play critical roles in AD development, AD treatments might require therapeutic approaches to eliminate both aggregates together. Objective: We aimed to discover a chemical drug candidate from natural sources for direct dissociation of both insoluble Aβ and tau aggregates through in vitro assessments. Methods: We isolated four borrelidin chemicals from a saltern-derived halophilic actinomycete strain of rare genus Nocardiopsis and simulated their docking interactions with Aβ fibrils. Then, anti-cytotoxic, anti-Aβ, and anti-tau effects of borrelidins were examined by MTT assays with HT22 hippocampal cell line, thioflavin T assays, and gel electrophoresis. Results: When HT22 cells were exposed to Aβ aggregates, the treatment of borrelidins alleviates the Aβ-induced toxicity. These anti-cytotoxic effects can be derived from the inhibitory functions of borrelidins against the Aβ aggregation as shown in thioflavin T and gel electrophoretic analyses. Among them, especially borrelidin, which exhibits the highest probability of docking, not only dissociates Aβ aggregates but also directly regulates tau aggregation. Conclusion: Borrelidin dissociates insoluble Aβ and tau aggregates together and our findings support the view that it is possible to develop an alternative chemical approach mimicking anti-Aβ or anti-tau immunotherapy for clearance of both aggregates.

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Exosomes induce endolysosomal permeabilization as a gateway by which exosomal tau seeds escape into the cytosol

Acta Neuropathologica ◽

10.1007/s00401-020-02254-3 ◽

2021 ◽

Author(s):

Juan Carlos Polanco ◽

Gabriel Rhys Hand ◽

Adam Briner ◽

Chuanzhou Li ◽

Jürgen Götz

Keyword(s):

Critical Role ◽

Membrane Integrity ◽

Lysosomal Degradation ◽

Escape Route ◽

Cellular Invasion ◽

Endosomal Membrane ◽

Late Endosomes ◽

Endosomal Membranes ◽

Endosomal Pathway ◽

Tau Aggregation

AbstractThe microtubule-associated protein tau has a critical role in Alzheimer’s disease and other tauopathies. A proposed pathomechanism in the progression of tauopathies is the trans-synaptic spreading of tau seeds, with a role for exosomes which are secretory nanovesicles generated by late endosomes. Our previous work demonstrated that brain-derived exosomes isolated from tau transgenic rTg4510 mice encapsulate tau seeds with the ability to induce tau aggregation in recipient cells. We had also shown that exosomes can hijack the endosomal pathway to spread through interconnected neurons. Here, we reveal how tau seeds contained within internalized exosomes exploit mechanisms of lysosomal degradation to escape the endosome and induce tau aggregation in the cytosol of HEK293T-derived ‘tau biosensor cells’. We found that the majority of the exosome-containing endosomes fused with lysosomes to form endolysosomes. Exosomes induced their permeabilization, irrespective of the presence of tau seeds, or whether the exosomal preparations originated from mouse brains or HEK293T cells. We also found that permeabilization is a conserved mechanism, operating in both non-neuronal tau biosensor cells and primary neurons. However, permeabilization of endolysosomes only occurred in a small fraction of cells, which supports the notion that permeabilization occurs by a thresholded mechanism. Interestingly, tau aggregation was only induced in cells that exhibited permeabilization, presenting this as an escape route of exosomal tau seeds into the cytosol. Overexpression of RAB7, which is required for the formation of endolysosomes, strongly increased tau aggregation. Conversely, inhibition of lysosomal function with alkalinizing agents, or by knocking-down RAB7, decreased tau aggregation. Together, we conclude that the enzymatic activities of lysosomes permeabilize exosomal and endosomal membranes, thereby facilitating access of exosomal tau seeds to cytosolic tau to induce its aggregation. Our data underscore the importance of endosomal membrane integrity in mechanisms of cellular invasion by misfolded proteins that are resistant to lysosomal degradation.

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Correction to: Amyloid β-protein oligomers promote the uptake of tau fibril seeds potentiating intracellular tau aggregation

Alzheimer s Research & Therapy ◽

10.1186/s13195-021-00824-5 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Woo Shik Shin ◽

Jing Di ◽

Qin Cao ◽

Binsen Li ◽

Paul M. Seidler ◽

...

Keyword(s):

Amyloid Β ◽

Amyloid Β Protein ◽

Β Protein ◽

Tau Aggregation

An amendment to this paper has been published and can be accessed via the original article.

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“Don’t Phos Over Tau”: recent developments in clinical biomarkers and therapies targeting tau phosphorylation in Alzheimer’s disease and other tauopathies

Molecular Neurodegeneration ◽

10.1186/s13024-021-00460-5 ◽

2021 ◽

Vol 16 (1) ◽

Author(s):

Yuxing Xia ◽

Stefan Prokop ◽

Benoit I. Giasson

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Cerebrospinal Fluid ◽

Kinase Inhibitors ◽

Tau Phosphorylation ◽

Phosphorylated Tau ◽

Clinical Biomarkers ◽

Early Results ◽

Recent Developments ◽

Tau Aggregation

AbstractPhosphorylation is one of the most prevalent post-translational modifications found in aggregated tau isolated from Alzheimer’s disease (AD) patient brains. In tauopathies like AD, increased phosphorylation or hyperphosphorylation can contribute to microtubule dysfunction and is associated with tau aggregation. In this review, we provide an overview of the structure and functions of tau protein as well as the physiologic roles of tau phosphorylation. We also extensively survey tau phosphorylation sites identified in brain tissue and cerebrospinal fluid from AD patients compared to age-matched healthy controls, which may serve as disease-specific biomarkers. Recently, new assays have been developed to measure minute amounts of specific forms of phosphorylated tau in both cerebrospinal fluid and plasma, which could potentially be useful for aiding clinical diagnosis and monitoring disease progression. Additionally, multiple therapies targeting phosphorylated tau are in various stages of clinical trials including kinase inhibitors, phosphatase activators, and tau immunotherapy. With promising early results, therapies that target phosphorylated tau could be useful at slowing tau hyperphosphorylation and aggregation in AD and other tauopathies.

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