scholarly journals Identification of biomolecules for Alzheimer's disease using docking analysis of tau protein

2021 ◽  
pp. 192-203
Author(s):  
Mansi Agrahari ◽  
Kanu Megha ◽  
Kajal Dahiya ◽  
Ila Sharma ◽  
Ankur Sharma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Active Site ◽  
Protein A ◽  
Three Dimensional ◽  
Docking Studies ◽  
Dimensional Structure ◽  
Docking Analysis ◽  
Bioinformatic Tools

Objective: In-silico methods to find and characterize the ligands against the active site of tau protein which could assist in the therapeutics of Alzheimer's disease. Methods: The aid of various bioinformatic tools such as phylogenetic analysis, homology modeling, and active site prediction led to the molecular docking analysis of the major malefactor for Alzheimer’s disease ‘microtubule- associated tau protein’. A three-dimensional structure of microtubule-related tau protein was created, and the Ramachandran plot was acquired for quality appraisal. Results: Procheck showed 62.95 of residues in the most preferred region with 20% residues in the additional allowed region and 5.7 % in the disallowed region of microtubule-associated tau protein. Screenings of the particles were done dependent on Lipinski's standard of five. Conclusion: Genistein, Hesperidin, and epigallocatechin-3 are the potential ligands in regulating microtubule-related tau protein and Epigallocatechin-3 gallate is the most potent among them and the most elevated negative free vitality of official with the maximum interacting surface territory throughout docking studies.

Computer-aided methods for 3-D visualization of serial sections and thick biological specimens

1992 ◽  
Vol 50 (2) ◽  
pp. 1060-1061
Author(s):  
Mark Ellisman ◽  
Maryann Martone ◽  
Gabriel Soto ◽  
Eleizer Masliah ◽  
David Hessler ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Three Dimensional ◽  
Neuritic Plaque ◽  
Dimensional Structure ◽  
Data Sets ◽  
Molecular Physiology ◽  
Research Activities ◽  
Computer Aided ◽  
Dimensional Reconstruction

Structurally-oriented biologists examine cells, tissues, organelles and macromolecules in order to gain insight into cellular and molecular physiology by relating structure to function. The understanding of these structures can be greatly enhanced by the use of techniques for the visualization and quantitative analysis of three-dimensional structure. Three projects from current research activities will be presented in order to illustrate both the present capabilities of computer aided techniques as well as their limitations and future possibilities.The first project concerns the three-dimensional reconstruction of the neuritic plaques found in the brains of patients with Alzheimer's disease. We have developed a software package “Synu” for investigation of 3D data sets which has been used in conjunction with laser confocal light microscopy to study the structure of the neuritic plaque. Tissue sections of autopsy samples from patients with Alzheimer's disease were double-labeled for tau, a cytoskeletal marker for abnormal neurites, and synaptophysin, a marker of presynaptic terminals.

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 ALZHEIMER’S DISEASE THERAPEUTIC APPROACHES

2018 ◽  
Vol 11 (7) ◽  
pp. 17
Author(s):  
Sandhya A ◽  
Gomathi Kannayiram
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Protein Misfolding ◽  
Amyloid Fibrils ◽  
Adult Population ◽  
Three Dimensional ◽  
Lewy Bodies ◽  
Cerebral Hypoperfusion ◽  
Dimensional Structure ◽  
Islet Amyloid

A protein is a large biomolecule which consists of one or more chains of amino acid residues. Proteins exhibit a biological phenomenon in which, they are misfolded as aggregates (i.e., accumulate and clump together) either intra- or extracellularly. This process plays a central role in the pathogenesis of Alzheimer’s disease (AD) and diabetes mellitus (DM) - 2 and common for many degenerative diseases. In this case, the histopathological consequences of protein misfolding such as sensile plaques and neurofibrillary tangles in AD and lewy bodies in Parkinson’s disease occur. 8–10% of adult population shares risk factors with AD. Amyloid fibrils which build up in tissue as an abnormal protein form Amyloidosis. Conformational change in three-dimensional structure forms amyloid fibrils. Type 2 DM is characterized by the deposition of islet amyloid polypeptide within beta cells of the pancreas which leads to chronic cerebral hypoperfusion that result in degeneration of neuroglial cells.

Design, Synthesis and Biological Evaluation of New Cycloalkyl Fused Quinolines Tethered to Isatin Schiff Bases as Cholinesterase Inhibitors

2020 ◽  
Vol 23 ◽  
Author(s):  
Baswaraju Macha ◽  
Ravindra Kulkarni ◽  
Anil Kumar Garige ◽  
Rambabu Palabindala ◽  
Raghuramrao Akkinepally ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Schiff Bases ◽  
Active Site ◽  
Inhibitory Activity ◽  
Docking Studies ◽  
Behavioral Studies ◽  
Cholinesterase Inhibitory Activity ◽  
Butyryl Cholinesterase

Aims and Objective: Alzheimer’s disease is now a most prevalent neuro degenerative disease of central nervous system leading to dementia in elderly aged population. Numerous pathological changes have been associated in the progression of Alzheimer’s disease. One of such pathological hypothesis is declined cholinergic activity which eventually affects cognitive and memory deficits. Inhibition cholinesterases will apparently elevate acetyl choline levels which is benefactor on cognitive symptoms of the disease. This manuscript describes the new tacrine derivatives tethered to isatin Schiff bases through alkanoyl linker and screened for cholinesterase inhibitory activity. Materials and Methods: Tacrine and two more cycloalkyl ring fused quinolones were synthesized and converted to Ncycloalkyl fused quinoline chloroamides. Isatin Schiff bases were also synthesized by the reaction between isatin and substituted aromatic anilines and in subsequent reaction, isatin Schiff bases were reacted with cycloalkyl fused quinolones to afford anticipated compounds 10a-i, 11a-i and 12a-i. All the compounds have been screened for acetyl and butyryl cholinesterase inhibitory activity and in vivo behavioral studies. Binding interactions of the desired compounds have also been studied by docking them in active site of both cholinesterases. Results: Three compounds 12d, 12e and 12h with propionyl and butyroyl linker between amine and isatin Schiff base scaffold have shown potent acetyl and butyryl cholinesterase inhibitory activity. However most potent cholinesterase inhibitor was 13d with IC50 value of 0.71±0.004 and 1.08±0.02 μM against acetyl and butyryl cholinesterases respectively. The hepatotoxicity of potent compounds revealed that the tested compounds were less hepatotoxic than tacrine and also exhibited encouraging in vivo behavioral studies in test animals. Docking studies of all the molecules disclosed close hydrogen bond interactions within the binding site of both cholinesterases. Conclusion: New cycloalkyl fused quinolones tethered with alkoyl linker to isatin Schiff bases endowed significant and potent cholinesterase inhibitory activities. Few of the compounds have also exhibited lesser hepatotoxicity and all the synthesized compounds were good in behavioral studies. Molecular docking studies also indicated close interactions in active site of cholinesterases.

scholarly journals Microglia in Alzheimer’s Disease in the Context of Tau Pathology

Biomolecules ◽  
2020 ◽  
Vol 10 (10) ◽  
pp. 1439 ◽  
Author(s):  
Juan Ramón Perea ◽  
Marta Bolós ◽  
Jesús Avila
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tau Protein ◽  
Molecular Mechanisms ◽  
Senile Plaques ◽  
Protein A ◽  
Amyloid Β ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
The Impact

Microglia are the cells that comprise the innate immune system in the brain. First described more than a century ago, these cells were initially assigned a secondary role in the central nervous system (CNS) with respect to the protagonists, neurons. However, the latest advances have revealed the complexity and importance of microglia in neurodegenerative conditions such as Alzheimer’s disease (AD), the most common form of dementia associated with aging. This pathology is characterized by the accumulation of amyloid-β peptide (Aβ), which forms senile plaques in the neocortex, as well as by the aggregation of hyperphosphorylated tau protein, a process that leads to the development of neurofibrillary tangles (NFTs). Over the past few years, efforts have been focused on studying the interaction between Aβ and microglia, together with the ability of the latter to decrease the levels of this peptide. Given that most clinical trials following this strategy have failed, current endeavors focus on deciphering the molecular mechanisms that trigger the tau-induced inflammatory response of microglia. In this review, we summarize the most recent studies on the physiological and pathological functions of tau protein and microglia. In addition, we analyze the impact of microglial AD-risk genes (APOE, TREM2, and CD33) in tau pathology, and we discuss the role of extracellular soluble tau in neuroinflammation.

Proteolytic processing of the amyloid-beta protein precursor of Alzheimer's disease

2002 ◽  
Vol 38 ◽  
pp. 37-49 ◽  
Author(s):  
Janelle Nunan ◽  
David H Small
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Beta ◽  
Alternative Pathway ◽  
Protein A ◽  
Proteolytic Processing ◽  
Gamma Secretase ◽  
Amyloid Beta Protein ◽  
Protein Precursor ◽  
Amyloid Beta Protein Precursor

The proteolytic processing of the amyloid-beta protein precursor plays a key role in the development of Alzheimer's disease. Cleavage of the amyloid-beta protein precursor may occur via two pathways, both of which involve the action of proteases called secretases. One pathway, involving beta- and gamma-secretase, liberates amyloid-beta protein, a protein associated with the neurodegeneration seen in Alzheimer's disease. The alternative pathway, involving alpha-secretase, precludes amyloid-beta protein formation. In this review, we describe the progress that has been made in identifying the secretases and their potential as therapeutic targets in the treatment or prevention of Alzheimer's disease.

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