scholarly journals Common antigenic motif recognized by human VH5-51/VL4-1 tau antibodies with distinct functionalities

2018 ◽  
Author(s):  
Adrian Apetri ◽  
Rosa Crespo ◽  
Jarek Juraszek ◽  
Gabriel Pascual ◽  
Roosmarijn Janson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
B Cells ◽  
Crystal Structures ◽  
Tau Protein ◽  
Paired Helical Filaments ◽  
Memory B Cells ◽  
The Other ◽  
New Targets ◽  
Repeat Domain ◽  
Insert Region

ABSTRACTMisfolding and aggregation of tau protein are closely associated with the onset and progression of Alzheimer’s Disease (AD). By interrogating IgG+ memory B cells from asymptomatic donors with tau peptides, we have identified two somatically mutated VH5-51/VL4-1 antibodies. One of these, CBTAU-27.1, binds to the aggregation motif in the R3 repeat domain and blocks the aggregation of tau into paired helical filaments (PHFs) by sequestering monomeric tau. The other, CBTAU-28.1, binds to the N-terminal insert region and inhibits the spreading of tau seeds and mediates the uptake of tau aggregates into microglia by binding PHFs. Crystal structures revealed that the combination of VH5-51 and VL4-1 recognizes a common Pro-Xn-Lys motif driven by germline-encoded hotspot interactions while the specificity and thereby functionality of the antibodies are defined by the CDR3 regions. Affinity improvement led to improvement in functionality, identifying their epitopes as new targets for therapy and prevention of AD.

Targeting Tau Hyperphosphorylation via Kinase Inhibition: Strategy to Address Alzheimer's Disease

2020 ◽  
Vol 20 (12) ◽  
pp. 1059-1073 ◽  
Author(s):  
Ahmad Abu Turab Naqvi ◽  
Gulam Mustafa Hasan ◽  
Md. Imtaiyaz Hassan
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Glycogen Synthase ◽  
Paired Helical Filaments ◽  
Tau Hyperphosphorylation ◽  
Microtubule Stabilization ◽  
Extracellular Signal

Microtubule-associated protein tau is involved in the tubulin binding leading to microtubule stabilization in neuronal cells which is essential for stabilization of neuron cytoskeleton. The regulation of tau activity is accommodated by several kinases which phosphorylate tau protein on specific sites. In pathological conditions, abnormal activity of tau kinases such as glycogen synthase kinase-3 β (GSK3β), cyclin-dependent kinase 5 (CDK5), c-Jun N-terminal kinases (JNKs), extracellular signal-regulated kinase 1 and 2 (ERK1/2) and microtubule affinity regulating kinase (MARK) lead to tau hyperphosphorylation. Hyperphosphorylation of tau protein leads to aggregation of tau into paired helical filaments like structures which are major constituents of neurofibrillary tangles, a hallmark of Alzheimer’s disease. In this review, we discuss various tau protein kinases and their association with tau hyperphosphorylation. We also discuss various strategies and the advancements made in the area of Alzheimer's disease drug development by designing effective and specific inhibitors for such kinases using traditional in vitro/in vivo methods and state of the art in silico techniques.

Microtubules, Tau Protein,and Paired Helical Filaments in Alzheimer’s Disease

1995 ◽  
pp. 143-160
Author(s):  
E. Mandelkow ◽  
J. Biernat ◽  
B. Lichtenberg-Kraag ◽  
G. Drewes ◽  
H. Wille ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Paired Helical Filaments

scholarly journals Generation of Plasma Cells From Peripheral Blood Memory B Cells: Synergistic Effect of Interleukin-10 and CD27/CD70 Interaction

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 173-180 ◽  
Author(s):  
Kazunaga Agematsu ◽  
Haruo Nagumo ◽  
Yumiko Oguchi ◽  
Takayuki Nakazawa ◽  
Keitaro Fukushima ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Interleukin 10 ◽  
Memory B Cells ◽  
The Other ◽  
Cell Pool ◽  
Activation System ◽  
Antibody Secreting Cells

B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27− B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10–mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10–mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

scholarly journals Generation of Plasma Cells From Peripheral Blood Memory B Cells: Synergistic Effect of Interleukin-10 and CD27/CD70 Interaction

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 173-180 ◽  
Author(s):  
Kazunaga Agematsu ◽  
Haruo Nagumo ◽  
Yumiko Oguchi ◽  
Takayuki Nakazawa ◽  
Keitaro Fukushima ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Interleukin 10 ◽  
Memory B Cells ◽  
The Other ◽  
Cell Pool ◽  
Activation System ◽  
Antibody Secreting Cells

Abstract B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27− B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10–mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10–mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

scholarly journals Cell cycle-dependent phosphorylation and microtubule binding of tau protein stably transfected into Chinese hamster ovary cells.

1995 ◽  
Vol 6 (10) ◽  
pp. 1397-1410 ◽  
Author(s):  
U Preuss ◽  
F Döring ◽  
S Illenberger ◽  
E M Mandelkow
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Chinese Hamster Ovary ◽  
Chinese Hamster Ovary Cells ◽  
Protein A ◽  
Chinese Hamster ◽  
Paired Helical Filaments ◽  
Ovary Cells

Tau protein, a neuronal microtubule-associated protein, is phosphorylated in situ and hyperphosphorylated when aggregated into the paired helical filaments of Alzheimer's disease. To study the phosphorylation of tau protein in vivo, we have stably transfected htau40, the largest human tau isoform, into Chinese hamster ovary cells. The distribution and phosphorylation of tau was monitored by gel shift, autoradiography, immunofluorescence, and immunoblotting, using the antibodies Tau-1, AT8, AT180, and PHF-1, which are sensitive to the phosphorylation of Ser202, Thr205, Thr231, Ser235, Ser396, and Ser404 and are used in the diagnosis of Alzheimer tau. In interphase cells, tau becomes phosphorylated to some extent, partly at these sites; most of the tau is associated with microtubules. In mitosis, the above Ser/Thr-Pro sites become almost completely phosphorylated, causing a pronounced shift in M(r) and an antibody reactivity similar to that of Alzheimer tau. Moreover, a substantial fraction of tau is found in the cytoplasm detached from microtubules. Autoradiographs of metabolically labeled Chinese hamster ovary cells in interphase and mitosis confirmed that tau protein is more highly phosphorylated during mitosis. The understanding of tau phosphorylation under physiological conditions might help elucidate possible mechanisms for the hyperphosphorylation in Alzheimer's disease.

scholarly journals Tau protein and its role in Alzheimer’s disease physiopathology: a literature review

2021 ◽  
Author(s):  
Larissa Rosa Stork ◽  
Lucca Stephani Ribeiro ◽  
Izabella Savergnini Deprá ◽  
Luísa D’Ávila Camargo ◽  
Maria Angélica Santos Novaes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Paired Helical Filaments ◽  
Tau Proteins ◽  
Molecular Aspects ◽  
Cellular Cytoskeleton

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by a double proteinopathy: deposition of amyloid-β into plaques and hyperphosphorylation of Tau protein. Objectives: To understand the genetic and molecular aspects of Tau protein and its relationship with Alzheimer’s disease. Methods: We conducted a systematic literature search using Pubmed/ MEDLINE and ClinicalKey databases, applying the descriptors: “Alzheimer Disease” AND “Tau proteins’’ AND Tauopathies, during July and August of 2020. The inclusion criteria were English and Portuguese articles published between 2015 and 2020, with human limited study and free full text, excluding images, books, clinical tests, and narrative reviews. After analyzing titles and abstracts, we selected 12 articles and included 7 additional studies. Results: Mapt, the encoder gene of Tau, is located in the 17q21.3 locus and presents 16 exons that, when transcripted, originates 12 copies of mRNA by alternative splicing and 6 Tau’s isoforms. Tau is a microtubule-associated protein (MAP) responsible for cellular cytoskeleton stabilization and maintenance, promoting neuronal axonal transport. A kinase-phosphatase imbalance turns Tau hyperphosphorylated, disassociating it from tubulin and grouping it into insoluble paired helical filaments, which originates neurofibrillary tangles. The tauopathy’s progress causes neurotransmitter destabilization and neuronal death, inducing AD symptomatic manifestations. Conclusions: Due to the gradual worsening of the disease to more debilitating stages, studies focused on deepening the knowledge of genetic and molecular aspects of Tau protein are viable and promising alternatives to improve the quality of patient’s lives.

scholarly journals Tau Protein Interaction Partners and Their Roles in Alzheimer’s Disease and Other Tauopathies

2021 ◽  
Vol 22 (17) ◽  
pp. 9207 ◽  
Author(s):  
Jakub Sinsky ◽  
Karoline Pichlerova ◽  
Jozef Hanes
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Critical Role ◽  
Neuronal Loss ◽  
Paired Helical Filaments ◽  
Normal Function ◽  
Tau Proteins ◽  
Proper Function ◽  
Interaction Partners

Tau protein plays a critical role in the assembly, stabilization, and modulation of microtubules, which are important for the normal function of neurons and the brain. In diseased conditions, several pathological modifications of tau protein manifest. These changes lead to tau protein aggregation and the formation of paired helical filaments (PHF) and neurofibrillary tangles (NFT), which are common hallmarks of Alzheimer’s disease and other tauopathies. The accumulation of PHFs and NFTs results in impairment of physiological functions, apoptosis, and neuronal loss, which is reflected as cognitive impairment, and in the late stages of the disease, leads to death. The causes of this pathological transformation of tau protein haven’t been fully understood yet. In both physiological and pathological conditions, tau interacts with several proteins which maintain their proper function or can participate in their pathological modifications. Interaction partners of tau protein and associated molecular pathways can either initiate and drive the tau pathology or can act neuroprotective, by reducing pathological tau proteins or inflammation. In this review, we focus on the tau as a multifunctional protein and its known interacting partners active in regulations of different processes and the roles of these proteins in Alzheimer’s disease and tauopathies.

scholarly journals Successful aggregation of Tau protein labelled on its native cysteines

2017 ◽  
Author(s):  
Martina Radli ◽  
Romy E Verdonschot ◽  
Luca Ferrari ◽  
Stefan GD Rüdiger
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Small Molecules ◽  
Tau Protein ◽  
Structural Changes ◽  
Fluorescent Dyes ◽  
Fibril Formation ◽  
Structural Rearrangements ◽  
Repeat Domain ◽  
Fluorescence Dyes

AbstractThe formation of fibrillar tangles of the Tau protein is crucial in the development of Alzheimer’s disease. Biophysical methods based on labelling of the cysteines of Tau with fluorescence dyes would allow to study fibril formation with an ‘internal eye’. However, the two native cysteines of Tau at positions 291 and 322 are located in the repeat domain, which is involved in forming the fibrils. The contribution of both cysteines to this process is unclear. Here we show that blocking natural cysteines using large fluorescent dyes does not interfere with Tau fibrillation so that FRET can be used to follow structural changes during the process. We anticipate that cysteine-labelled Tau enables following structural rearrangements during fibril formation in detail. This may also allow to monitor the effect of drugs, small molecules and proteins on the process.

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