Tau and Amyloid- Conformational Change to  -Sheet Structures as Effectors in the Development of Alzheimer's Disease

Anda-Hernández, Martha A. De; León, Karla I. Lira-De; Mena, Raúl; Campos-Peña, Victoria; Meraz-Ríos, Marco Antonio

doi:10.5772/37909

Cited by 4 publications

(3 citation statements)

References 135 publications

(158 reference statements)

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“…These conformational changes in proteins can both define and differentiate various diseases [83]. As described for AD, growing evidence points towards monomeric Aβ peptides as building blocks for amyloid fibers via a range of intermediate structures [62, 84]. A conformational shift from α-helix to β-sheet within the protein structure has been reported during the aggregation of amyloid fibrils associated with AD [85].…”

Section: Role Of Aβ Structure In Admentioning

confidence: 99%

Protein Misfolding and Aggregation in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Ashraf¹,

Greig²,

Khan³

et al. 2014

CNSNDDT

151

103

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In general, proteins can only execute their various biological functions when they are appropriately folded. Their amino acid sequence encodes the relevant information required for correct three-dimensional folding, with or without the assistance of chaperones. The challenge associated with understanding protein folding is currently one of the most important aspects of the biological sciences. Misfolded protein intermediates form large polymers of unwanted aggregates and are involved in the pathogenesis of many human diseases, including Alzheimer’s disease (AD) and Type 2 diabetes mellitus (T2DM). AD is one of the most prevalent neurological disorders and has worldwide impact; whereas T2DM is considered a metabolic disease that detrementally influences numerous organs, afflicts some 8% of the adult population, and shares many risk factors with AD. Research data indicates that there is a widespread conformational change in the proteins involved in AD and T2DM that form β-sheets like motifs. Although conformation of these β-sheets is common to many functional proteins, the transition from α-helix to β-sheet is a typical characteristic of amyloid deposits. Any abnormality in this transition results in protein aggregation and generation of insoluble fibrils. The abnormal and toxic proteins can interact with other native proteins and consequently catalyze their transition into the toxic state. Both AD and T2DM are prevalent in the aged population. AD is characterized by the accumulation of amyloid-β (Aβ) in brain, while T2DM is characterized by the deposition of islet amyloid polypeptide (IAPP, also known as amylin) within beta-cells of the pancreas. T2DM increases pathological angiogenesis and immature vascularisation. This also leads to chronic cerebral hypoperfusion, which results in dysfunction and degeneration of neuroglial cells. With an abundance of common mechanisms underpinning both disorders, a significant question that can be posed is whether T2DM leads to AD in aged individuals and the associations between other protein misfolding diseases.

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Section: Role Of Aβ Structure In Admentioning

confidence: 99%

Protein Misfolding and Aggregation in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Ashraf¹,

Greig²,

Khan³

et al. 2014

CNSNDDT

151

103

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show abstract

“…Tauopathies are also a group of neurodegenerative diseases characterized by the aggregation of Tau protein into filamentous lesions such as NFTs. Tau protein, which is main component of NFTs, belongs to the family of microtubule-associated protein (MAP) is an essential factor of the neuronal cytoskeleton and is involved in kinesin-dependent axonal transport, microtubule stabilization and neurite outgrowth [5,6] and exists as six alternatively spliced isoforms, arising from a single gene located on chromosome 17 [7]. This intrinsically disordered protein (IDP), rich in charged amino acid residues, characterized by its low content of secondary structure (see Fig.…”

Section: Introductionmentioning

confidence: 99%

Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study

Jangholi

Ashrafi-Kooshk

Arab

et al. 2016

Archives of Biochemistry and Biophysics

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In many neurodegenerative diseases, formation of protein fibrillar aggregates has been observed as a major pathological change. Neurofibrillary tangles, mainly composed of fibrils formed by the microtubule-associated protein; Tau, are a hallmark of a group of neurodegenerative diseases such as Alzheimer's disease. Tau belongs to the class of natively unfolded proteins and partially folds into an ordered β-structure during aggregation. Polyanionic cofactors such as heparin are commonly used as inducer of Tau aggregation in vitro. The role of heparin in nucleation and elongation steps during Tau fibril formation is not fully understood. In the current study, aggregation kinetics as well as structure of Tau amyloid fibrils, by using the 1N4R isoform, have been reproducibly determined in the presence of heparin and the shorter molecule; enoxaparin. The kinetic studies demonstrated that heparin (not enoxaparin) efficiently accelerates Tau amyloid formation and revealed, mechanistically, that the molecular weight of the inducer is important in accelerating amyloidogenesis. The kinetic parameter values of Tau amyloid aggregation, especially, the amyloid aggregation extent, were relatively different in the presence of heparin and enoxaparin, at various stoichiometries of the inducers binding. Also, based on the results, obtained from CD, FTIR, AFM and XRD studies, it may be suggested that the inducer length plays a critical role mainly in the nucleation process, so that it determines that oligomers lie on or off the pathway of Tau fibrillization. The biochemical results herein suggest that the chemical environment of the extracellular matrix as well as localization of distinct glycosaminoglycans may influence deposition behavior of Tau amyloidosis.

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“…In NFTs, polymerization, stability, and organization of microtubules are regulated by the microtubule-associated proteins (MAPs) family. Tau, a member of the MAPs family, is mostly found in the axons of neurons in the central nervous system whose functions are involved in stability and assembly modulation of microtubules, neurite growth, and kinesin-dependent axonal transportation [ 3 , 4 ].…”

Section: Introductionmentioning

confidence: 99%

Cannabidiol Inhibits Tau Aggregation In Vitro

Alali

Riazi

Ashrafi-Kooshk

et al. 2021

Cells

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A hallmark of Alzheimer’s disease (AD) is the accumulation of tau protein in the brain. Compelling evidence indicates that the presence of tau aggregates causes irreversible neuronal destruction, eventually leading to synaptic loss. So far, the inhibition of tau aggregation has been recognized as one of the most effective therapeutic strategies. Cannabidiol (CBD), a major component found in Cannabis sativa L., has antioxidant activities as well as numerous neuroprotective features. Therefore, we hypothesize that CBD may serve as a potent substance to hamper tau aggregation in AD. In this study, we aim to investigate the CBD effect on the aggregation of recombinant human tau protein 1N/4R isoform using biochemical methods in vitro and in silico. Using Thioflavin T (ThT) assay, circular dichroism (CD), atomic force microscopy (AFM), we demonstrated that CBD can suppress tau fibrils formation. Moreover, by quenching assay, docking and job’s plot, we further demonstrate that one molecule of CBD interacts with one molecule of tau protein through a spontaneous binding. Experiments performed by quenching assay, docking and Thioflavin T assay further established that the main forces are hydrogenvan der Waals and some non-negligible hydrophobic forces, affecting the lag phase of tau protein kinetics. Taken together, this study provides new insights about a natural substance, CBD, for tau therapy which may offer new hope for the treatment of AD.

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Tau and Amyloid- Conformational Change to  -Sheet Structures as Effectors in the Development of Alzheimer's Disease

Cited by 4 publications

References 135 publications

Protein Misfolding and Aggregation in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Protein Misfolding and Aggregation in Alzheimer’s Disease and Type 2 Diabetes Mellitus

Appraisal of role of the polyanionic inducer length on amyloid formation by 412-residue 1N4R Tau protein: A comparative study

Cannabidiol Inhibits Tau Aggregation In Vitro

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