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Tania Ismail, Mathumai Kanapathipillai
Tau protein aggregation is believed to be one of the key drivers of Alzheimer's disease. The two hexapeptide amino acid sequences 306 VQIVYK311 and 275 VQIINK280 of the tau protein are responsible for aggregation, and subsequent functional loss leading to Alzheimer's progression. Hence, it is important to understand the factors that promote the self-aggregation of this tau peptide fragments. Cellular microenvironmental polyanions are known to play a major role in tau protein aggregation and loss of function...
November 2018: Journal of Peptide Science: An Official Publication of the European Peptide Society
Justin R Welden, Jacob van Doorn, Peter T Nelson, Stefan Stamm
The microtubule-associated protein Tau, generated by the MAPT gene is involved in dozens of neurodegenerative conditions ("tauopathies"), including Alzheimer's disease (AD) and frontotemporal lobar degeneration/frontotemporal dementia (FTLD/FTD). The pre-mRNA of MAPT is well studied and its aberrant pre-mRNA splicing is associated with frontotemporal dementia. Using a PCR screen of RNA from human brain tissues, we found that the MAPT locus generates circular RNAs through a backsplicing mechanism from exon 12 to either exon 10 or 7...
September 2018: Biochimica et biophysica acta. Molecular basis of disease
Keerthi Nadimidla, Tania Ismail, Mathumai Kanapathipillai
Tau protein plays a major role in Alzheimer's disease. The tau protein loses its functionality by self-aggregation due to the two six-amino acid sequences VQIVYK and VQIINK of the protein. Hence it is imperative to find therapeutics that could inhibit the self-aggregation of this tau peptide fragments. Here, we study the inhibitory potential of a cationic polymer polyethyleneimine (PEI) and a cationic polypeptide arginine (Arg) on the aggregation of VQIVYK, and GKVQIINKLDL peptides, and tau mutant protein (P301L), found frequently in taupathy...
September 2017: Biopolymers
M A Faiq, T Dada
In the present analysis, we aim at probing into many important mechanisms that serve to bridge conceptual gaps to fill up the mosaic of a picture revealing that glaucoma indeed is brain specific diabetes and more appropriately "Diabetes Type 4". Based on this conceptual substance, we weave a novel idea of insulin being a potential remedy for glaucoma. This analysis synthesizes upon the published literature on brain changes in glaucoma, possibility of isolated brain diabetes, insulin signaling glitches in glaucoma pathology, mitochondrial dysfunction and insulin resistance in glaucomatous eyes, insulin mediated regulation of intraocular pressure and its dysregulation in mitochondrial dysfunction...
2017: Current Molecular Medicine
İrem Lütfiye Atasoy, Erdinç Dursun, Duygu Gezen-Ak, Derya Metin-Armağan, Melek Öztürk, Selma Yılmazer
Intracellular aggregation of hyperphosphorylated tau in neurofibrillary tangles (NFTs) is a major neuropathological hallmark of taupathies such as Alzheimer's disease. Okadaic acid (OKA) is a potent inhibitor of PP2A, leading to abnormal tau phosphorylation. Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is selectively downregulated in AD. In this study, we investigated the effects of OKA induced tau hyperphosphorylation on secreted and cellular levels of BDNF in primary cortical neurons that were treated with 25nM OKA...
March 2017: Journal of Chemical Neuroanatomy
Poul Jørgen Jennum, Lars Østergaard Pedersen, Justyna Maria Czarna Bahl, Signe Modvig, Karina Fog, Anja Holm, Birgitte Rahbek Kornum, Steen Gammeltoft
OBJECTIVES: To investigate whether cerebrospinal fluid (CSF) biomarkers of neurodegeneration are altered in narcolepsy in order to evaluate whether the hypocretin deficiency and abnormal sleep-wake pattern in narcolepsy leads to neurodegeneration. METHODS: Twenty-one patients with central hypersomnia (10 type 1 narcolepsy, 5 type 2 narcolepsy, and 6 idiopathic hypersomnia cases) aged 33 years on average, and with a disease duration of 2-29 years, and 12 healthy controls underwent CSF analyses of levels of β-amyloid, total tau protein (T-tau), phosphorylated tau protein (P-tau181), α-synuclein, neurofilament light chain (NF-L), and chitinase 3-like protein-1 (CHI3L1)...
September 9, 2016: Sleep
Mohammad Haddadi, Samaneh Reiszadeh Jahromi, Upendra Nongthomba, T Shivanandappa, S R Ramesh
Oxidative stress is one of the major etiological factors implicated in pathogenesis of neurodegenerative diseases. Since neurons are more sensitive to oxidative damage there is an increasing interest in developing novel antioxidant therapies, especially herbal preparations due to their safety profile and high efficiency. In this regard, the neuroprotective potential of a novel antioxidant compound, 4-hydroxyisophthalic acid (4-HIPA) isolated from aqueous extract of Decalepis hamiltonii roots was examined using transgenic Drosophila model of taupathy expressing wild-type and mutant forms of 2N4R isoform of human microtubule associated protein tau (MAPT)...
November 2016: Neurochemistry International
A C Jiji, A Shine, Vinesh Vijayan
In tau proteins, the hexapeptides in the R2 and R3 repeats are known to initiate tau fibril formation, which causes a class of neurodegenerative diseases called the taupathies. We show that in R3, in addition to the presence of the hexapeptides, the correct turn conformation upstream to it is also essential for producing prion-like fibrils that are capable of propagation. A time-dependent NMR aggregation assay of a slow fibril forming R3-S316P peptide revealed a trans to cis equilibrium shift in the peptide-bond conformation preceding P316 during the growth phase of the aggregation process...
September 12, 2016: Angewandte Chemie
Mohamed Salama, Wael M Y Mohamed
There is a strong correlation between taupathies and the development and progression of neurodegenerative disorders. Abnormal tau becomes hyperphosphorylated and dissociated from microtubules with the aggregation of intracellular tau aggregates within the patient's brain. The current review is divided into two broad sections. In the first section we discuss the molecular biology and the clinicopathologic features of taupathies. While in the second section we discuss the relationship between mitochondrial complex-I and taupathies...
June 1, 2015: Applied & Translational Genomics
Edward Rockenstein, Kiren Ubhi, Michael Mante, Jazmin Florio, Anthony Adame, Stefan Winter, Hemma Brandstaetter, Dieter Meier, Eliezer Masliah
BACKGROUND: Tauopathies are a group of neurodegenerative disorders with accumulation of three-repeat (3R) or four-repeat (4R) Tau. While 3R tau is found in Pick's disease and Alzheimer's disease (AD), 4R tau is more abundant in corticobasal degeneration, progressive supranuclear palsy, and AD. We have previously shown that Cerebrolysin™ (CBL), a neuropeptide mixture with neurotrophic effects, ameliorates the pathology in amyloid precursor protein transgenic (tg) mouse model of AD and 4R tau, however it is unclear if CBL ameliorates the deficits and neuropathology in the mouse model of Pick's disease over expressing 3R tau...
November 26, 2015: BMC Neuroscience
José Joaquín Merino, Vilma Muñetón-Gómez, María-Isabel Alvárez, Adolfo Toledano-Díaz
Microglia and astrocytes are the major source of cytokines in Alzheimer,s disease (AD). CX3CR1 is a delta chemokine receptor found in microglia and its neuronal ligand, Fractalkine, has two isoforms: an anchored-membrane isoform, and a soluble isoform. The reduced soluble fractalkine levels found in the brain (cortex/hippocampus) of aged rats, may be a consequence of neuronal loss. This soluble fractalkine maintains microglia in an appropiate state by interacting with CX3CR1. The ablation of the CX3CR1 gene in mice overexpressing human amyloid precursor protein (APP/PS-1) increased cytokine levels, enhanced Tau pathology and worsened behavioural performance in these mice...
2016: Current Alzheimer Research
M S Bele, K A Gajare, A A Deshmukh
Typical form of neurons is crucially important for their functions. This is maintained by microtubules and associated proteins like tau. Hyperphosphorylation of tau is a major concern in neurodegenerative diseases. Glycogen synthase kinase3β (GSK3β) and cyclin-dependent protein kinase 5 (Cdk5) are the enzymes that govern tau phosphorylation. Currently, efforts are being made to target GSK3β and Cdk5 as possible therapeutic avenues to control tau phosphorylation and treat neurodegenerative diseases related to taupathies...
June 2015: In Vitro Cellular & Developmental Biology. Animal
Eloi Magnin, Claire Paquet, Maité Formaglio, Bernard Croisile, Ludivine Chamard, Carole Miguet-Alfonsi, Gregory Tio, Julien Dumurgier, Isabelle Roullet-Solignac, Mathilde Sauvée, Catherine Thomas-Antérion, Alain Vighetto, Jacques Hugon, Pierre Vandel
BACKGROUND: Patients with logopenic variant of primary progressive aphasia (lvPPA) display neuropathological differences from typical amnestic Alzheimer's disease (AD). OBJECTIVE: The aim of the study was to compare cerebrospinal fluid (CSF) biomarker levels between patients with lvPPA due to AD (lvPPA-AD), non-logopenic forms of AD (nlAD), and amnestic mild cognitive impairment due to AD (aMCI-AD). METHODS: CSF biomarker concentrations were assessed in 124 patients divided into three groups matched for age, level of education, center, and disease duration: lvPPA-AD (n = 30), nlAD (n = 67)...
2014: Journal of Alzheimer's Disease: JAD
Syed Waseem Bihaqi, Nasser H Zawia
Late Onset Alzheimer Disease (LOAD) constitutes the majority of AD cases (∼90%). Amyloidosis and tau pathology, which are present in AD brains, appear to be sporadic in nature. We have previously shown that infantile lead (Pb) exposure is associated with a change in the expression and regulation of the amyloid precursor protein (APP) and its beta amyloid (Aβ) products in old age. Here we report that infantile Pb exposure elevated the mRNA and protein levels of tau as well as its transcriptional regulators namely specificity protein 1 and 3 (Sp1 and Sp3) in aged primates...
December 2013: Neurotoxicology
Lili-Naz Hazrati, Maria C Tartaglia, Phedias Diamandis, Karen D Davis, Robin E Green, Richard Wennberg, Janice C Wong, Leo Ezerins, Charles H Tator
BACKGROUND: Chronic traumatic encephalopathy (CTE) is the term coined for the neurodegenerative disease often suspected in athletes with histories of repeated concussion and progressive dementia. Histologically, CTE is defined as a tauopathy with a distribution of tau-positive neurofibrillary tangles (NFTs) that is distinct from other tauopathies, and usually shows an absence of beta-amyloid deposits, in contrast to Alzheimer's disease (AD). Although the connection between repeated concussions and CTE-type neurodegeneration has been recently proposed, this causal relationship has not yet been firmly established...
2013: Frontiers in Human Neuroscience
K R Mridula, S Alladi, D R Varma, J R Chaudhuri, Y Jyotsna, R Borgohain, S Kaul
Corticobasal syndrome (CBS) is characterised by asymmetric apraxia, cortical sensory loss, extrapyramidal features and cognitive decline. Although CBS is classically described as a taupathy, heterogeneity of its aetiology is increasingly recognised. Clinical presentation of CBS appears to reflect areas of the brain involved and not necessarily the nature of the underlying pathology. We report a patient in whom resolution of a thalamic tuberculoma was associated with progressive atrophy of the parietotemporal cortex, resulting in an unusual presentation of CBS...
2009: BMJ Case Reports
Bennet I Omalu, Ronald L Hamilton, M Ilyas Kamboh, Steven T DeKosky, Julian Bailes
UNLABELLED: We present a case of chronic traumatic encephalopathy (CTE) in a retired National Football League (NFL) Player with autopsy findings, apolipoprotein E genotype, and brain tissue evidence of chronic brain damage. This 44-year-old retired NFL player manifested a premortem history of cognitive and neuropsychiatric impairment, which included in part, chronic depression, suicide attempts, insomnia, paranoia, and impaired memory before he finally committed suicide. A full autopsy was performed with Polymerase Chain Reaction-based analyses of his blood to determine the apolipoprotein genotype...
2010: Journal of Forensic Nursing
Bennet I Omalu, Julian Bailes, Jennifer Lynn Hammers, Robert P Fitzsimmons
We present 5 cases of professional American contact sport athletes who committed parasuicides and suicides aged 50, 45, 44, 36, and 40 years old. Full forensic autopsies and immunohistochemical analyses of the brains revealed chronic traumatic encephalopathy (CTE). The brains appeared grossly normal at autopsy without gross evidence of remote traumatic injuries or neurodegenerative disease. Brain immunohistochemical analyses revealed widespread cerebral taupathy in the form of neurofibrillary tangles and neuritic threads without neuritic amyloid plaques...
June 2010: American Journal of Forensic Medicine and Pathology
Anna Pavlova, Evan R McCarney, Dylan W Peterson, Frederick W Dahlquist, John Lew, Songi Han
We present a generally applicable approach for monitoring protein aggregation by detecting changes in surface hydration water dynamics and the changes in solvent accessibility of specific protein sites, as protein aggregation proceeds in solution state. This is made possible through the Overhauser dynamic nuclear polarization (DNP) of water interacting with stable nitroxide spin labels tethered to specific proteins sites. This effect is highly localized due to the magnetic dipolar nature of the electron-proton spin interaction, with >80% of their interaction occurring within 5 A between the unpaired electron of the spin label and the proton of water...
August 21, 2009: Physical Chemistry Chemical Physics: PCCP
Alla B Salmina
Accumulating evidence suggests that alterations of neuron-glia interactions are associated with development of neurodegenerative diseases referred to as taupathies. Astrocytes contribute to a variety of functions of neurons, including synapse formation and plasticity, energetic and redox metabolism, and synaptic homeostasis of neurotransmitters and ions. Microglia represent the immune system of the brain and therefore are critically involved in various injuries and diseases. Oligodendrocytes have a role in regulation of steroid synthesis which is important for neuroprotection against degeneration...
2009: Journal of Alzheimer's Disease: JAD
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