Beta Amyloid Peptide: Research Paper : Category-specific verb-semantic deficits in Alzheimer's disease: Evidence from static and dynamic action naming

Category-specific verb-semantic deficits in Alzheimer's disease: Evidence from static and dynamic action naming

Abstract

We investigated the representation and breakdown of verb knowledge employing different syntactic and semantic classes of verbs in a group of individuals with probable Alzheimer's Disease (pAD). In an action naming task with coloured photographs (Fiez & Tranel, 1997. Standardized stimuli and procedures for investigating the retrieval of lexical and conceptual knowledge for action. Memory and Cognition, 25(4), 543-569. https://doi.org/10.3758/BF03201129), pAD individuals were impaired for naming actions compared to objects. Verb tense was also affected, with simple-past (e.g., chopped) being more difficult to name than the gerundial form (e.g., chopping). Employing action-naming with short movies depicting events and states, we contrasted three verb classes based on their hypothetical structural and semantic/conceptual properties: argument structure, thematic structure, and conceptual templates. The three classes were: causatives (peel), verbs of perception (hear), and verbs of motion (run) Overall, results suggest that individuals with pAD are selectively impaired for verb tense and thematic assignment, but not conceptual-template complexity. Methodologically, we also show that dynamic scenes are more ecologically valid than static scenes to probe verb knowledge in AD.

Keywords: Alzheimer's disease; Verb-semantic deficits; action naming; category-specific deficits; concepts; dynamic scenes; semantic templates; thematic hierarchy; thematic roles; verb meaning.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33455543/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins

Systematic Differences between Current Molecular Dynamics Force Fields To Represent Local Properties of Intrinsically Disordered Proteins

Abstract

The prevalence of intrinsically disordered proteins (IDPs) and protein regions in structural biology has prompted the recent development of molecular dynamics (MD) force fields for the more realistic representations of such systems. Using experimental nuclear magnetic resonance backbone scalar 3J-coupling constants of the intrinsically disordered proteins α-synuclein and amyloid-β in their native aqueous environment as a metric, we compare the performance of four recent MD force fields, namely, AMBER ff14SB, CHARMM C36m, AMBER ff99SB-disp, and AMBER ff99SBnmr2, by partitioning the polypeptides into an overlapping series of heptapeptides for which a cumulative total of 276 μs MD simulations were performed. The results show substantial differences between the different force fields at the individual residue level. Except for ff99SBnmr2, the force fields systematically underestimate the scalar 3J(HN,Hα)-couplings due to an underrepresentation of β-conformations and an overrepresentation of either α- or PPII conformations. The study demonstrates that the incorporation of coil library information in modern MD force fields, as shown here for ff99SBnmr2, provides substantially improved performance and more realistic sampling of the local backbone dihedral angles of IDPs as reflected by the good accuracy of the computed scalar 3J(HN,Hα)-couplings with less than 0.5 Hz error. Such force fields will enable a better understanding of how structural dynamics and thermodynamics influence the IDP function. Although the methodology based on heptapeptides used here does not allow the assessment of potential intramolecular long-range interactions, its computational affordability permits well-converged simulations that can be easily parallelized. This should make the quantitative validation of intrinsic disorder observed in MD simulations of polypeptides with experimental scalar J-couplings widely applicable.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33444020/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Discovery of the First Druggable GPR52 Antagonist to Treat Huntington's Disease

Discovery of the First Druggable GPR52 Antagonist to Treat Huntington's Disease

Abstract

GPR52 is an orphan G protein-coupled receptor (GPCR) highly expressed in the brain, especially in the striatum, and represents an emerging therapeutic target for Huntington's disease (HD), an incurable monogenic neurodegenerative disorder caused by the mutation of the huntingtin (mHTT) gene. This Viewpoint discusses the discovery, published in this journal, that a highly potent and specific GPR52 antagonist was identified through high-throughput screening and structure-activity relationship study, which diminishes not only mHTT protein levels, but also ameliorates HD-like phenotypes in the animal disease models. This strategy offers intriguing promise as a surprising approach for HD therapy, where nucleic acid medicine approaches such as small interference RNAs have been the main focus and encounter obstacles such as delivery efficiency.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33443413/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Going From Zero to 100 in Remote Dementia Research: A Practical Guide

Going From Zero to 100 in Remote Dementia Research: A Practical Guide

Abstract

Remote approaches for dementia research are required in the era of COVID-19, but moving a research program from in person to remote involves additional considerations. We recommend using outcome measures that have psychometric properties for remote delivery, and we recommend against adapting in-person scales for remote delivery without evidence for psychometric equivalency. We suggest remote research designs that maximize benefit for participants, which could have implications for control groups. Researchers should plan for flexibility in their methods for remote research and must not assume all participants will be able to videoconference; telephone-only research is possible. We recommend performing an assessment of information communication technology infrastructure and prior exposure to this technology with each participant before making a final choice on remote methods for research. In general, researchers should adapt their methods for remote research to each participant rather than requesting participants to adapt to the researchers. Screening for sensory loss should be conducted, and the impact of this on the use of technology for remote research should be considered. In this viewpoint, we detail how individualized training is required prior to engaging in remote research, how training plans interact with cognitive impairments and, finally, the steps involved in facilitating technology-based remote data collection.

Keywords: COVID-19; dementia; information communications technology; telehealth; videoconferencing.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33468448/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease

PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease

Abstract

DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease.

Keywords: DNA damage repair; Huntington's disease; PIAS; PNKP; SUMO.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33468657/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Hydration Thermodynamics of the N-Terminal FAD Mutants of Amyloid-β

Hydration Thermodynamics of the N-Terminal FAD Mutants of Amyloid-β

Abstract

The hydration thermodynamics of amyloid-β (Aβ) and its pathogenic familial Alzheimer's disease (FAD) mutants such as A2V, Taiwan (D7H), Tottori (D7N), and English (H6R) and the protective A2T mutant is investigated by a combination of all-atom, explicit water molecular dynamics (MD) simulations and the three-dimensional reference interaction site model (3D-RISM) theory. The change in the hydration free energy on mutation is decomposed into the energetic and entropic components, which comprise electrostatic and nonelectrostatic contributions. An increase in the hydration free energy is observed for A2V, D7H, D7N, and H6R mutations that increase the aggregation propensity of Aβ and lead to an early onset of Alzheimer's disease, while a reverse trend is noted for the protective A2T mutation. An antiphase correlation is found between the change in the hydration energy and the internal energy of Aβ upon mutation. A residue-wise decomposition analysis shows that the change in the hydration free energy of Aβ on mutation is primarily due to the hydration/dehydration of the side-chain atoms of the negatively charged residues. The decrease in the hydration of the negatively charged residues on mutation may decrease the solubility of the mutant, which increases the observed aggregation propensity of the FAD mutants. Results obtained from the theory show an excellent match with the experimentally reported data.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33440932/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress

Decrease of neuronal FKBP4/FKBP52 modulates perinuclear lysosomal positioning and MAPT/Tau behavior during MAPT/Tau-induced proteotoxic stress

Abstract

Defects of autophagy-lysosomal protein degradation are thought to contribute to the pathogenesis of several neurodegenerative diseases, and the accumulation of aggregation prone proteins such as MAPT/Tau in Alzheimer disease (AD). We previously showed the localization of the immunophilin FKBP4/FKBP52 in the lysosomal system of healthy human neurons suggesting its possible role in lysosome function. We also showed that decreased FKBP4 levels in AD brain neurons correlate with abnormal MAPT accumulation and aggregation. In this study, we demonstrate that FKBP4 decrease in a human neuronal cell line (SH-SY5Y) and in dorsal root ganglion (DRG) neurons from human MAPTP301S transgenic mice affected the function of the autophagy-lysosomal system under MAPT induced proteotoxic stress conditions. We show that acute MAPT accumulation in SH-SY5Y cells induced perinuclear clustering of lysosomes, triggered FKBP4 localization around the clusters and its colocalization with MAPT and MAP1LC3/LC3-positive autophagic vesicles; a similar FKBP4 localization was detected in some AD brain neurons. We demonstrate that FKBP4 decrease altered lysosomal clustering along with MAPT and MAP1LC3 secretion increase. Although ectopic FKBP4 expression could not induce autophagy under our experimental conditions, it prevented MAPT secretion after MAPT accumulation in SH-SY5Y cells implying a regulatory role of FKBP4 on MAPT secretion. Finally, we observe that FKBP4 deficiency decreased MAP1LC3-II expression and provoked MAPT accumulation during long-term stress in mouse DRG neurons. We hypothesize that the abnormal FKBP4 decrease observed in AD brain neurons might hinder autophagy efficiency and contribute to the progression of the tauopathy by modulating MAPT secretion and accumulation during MAPT pathogenesis. Abbreviations: AD: Alzheimer disease; AKT/protein kinase B: AKT serine/threonine kinase; ALP: Autophagy-lysosomal pathway; ATG: autophagy-related; BafA1: bafilomycin A1; CQ: chloroquine; CTSD: cathepsin D; DIV: days in vitro; DRG: dorsal root ganglion neurons; Dox: doxycycline; DNAJC5: DnaJ heat shock protein family (Hsp40) member C5; EL: empty lentiviral vectors; ENO2/NSE: enolase 2, gamma neuronal; FKBP4/FKBP52: FKBP prolyl isomerase 4; FTLD-Tau: frontotemporal lobar degeneration with Tau pathology; GFP: green fluorescent protein; LAMP1: lysosomal associated membrane protein 1; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPT/Tau: microtubule associated protein tau; MTT: tetrazolium salt; NFTs: neurofibrillary tangles; RPE-1: retinal pigment epithelial cells; shRNA: small-hairpin ribonucleic acid; SQSTM1/p62: sequestosome 1; SD: standard deviation; SEM: standard error of the mean; SH-SY5Y: human neuroblastoma cells; Sh1 or Sh2: Lentiviral shRNA vectors inducing FKBP4 decrease; SH-52GFP: MAPT/Tau-inducible SH-SY5Y cell line constitutively expressing FKBP4-GFP; TUBB3/βIII tubulin: tubulin beta 3 class III; UPS: ubiquitin-proteasome system.

Keywords: Alzheimer disease; FKBP52; Tau; autophagy; lysosomes; proteotoxic stress.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33459145/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Telomeres: history, health, and hallmarks of aging

Telomeres: history, health, and hallmarks of aging

Abstract

The escalating social and economic burden of an aging world population has placed aging research at center stage. The hallmarks of aging comprise diverse molecular mechanisms and cellular systems that are interrelated and act in concert to drive the aging process. Here, through the lens of telomere biology, we examine how telomere dysfunction may amplify or drive molecular biological processes underlying each hallmark of aging and contribute to development of age-related diseases such as neurodegeneration and cancer. The intimate link of telomeres to aging hallmarks informs preventive and therapeutic interventions designed to attenuate aging itself and reduce the incidence of age-associated diseases.

Copyright © 2020 Elsevier Inc. All rights reserved.

Conflict of interest statement

Declaration of interests R.A.D. is a co-founder, director, and advisor of Tvardi Therapeutics and co-founder and advisor of Asylia Therapeutics, Nirogy Therapeutics, and Stellanova Therapeutics.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33450206/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : Multitasking guardian of mitochondrial quality: Parkin function and Parkinson's disease

Multitasking guardian of mitochondrial quality: Parkin function and Parkinson's disease

Abstract

The familial form of Parkinson's disease (PD) is linked to mutations in specific genes. The mutations in parkin are one of the most common causes of early-onset PD. Mitochondrial dysfunction is an emerging active player in the pathology of neurodegenerative diseases, because mitochondria are highly dynamic structures integrated with many cellular functions. Herein, we overview and discuss the role of the parkin protein product, Parkin E3 ubiquitin ligase, in the cellular processes related to mitochondrial function, and how parkin mutations can result in pathology in vitro and in vivo.

Keywords: Mitochondria; Mitophagy; PINK1; Parkin; Parkin mutations; Parkinson's disease.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33468256/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.  

Beta Amyloid Peptide: Research Paper : The role of innate immunity and inflammation in Parkinson´s disease

The role of innate immunity and inflammation in Parkinson's disease

Abstract

For many years, it was postulated that the brain is the organ behind the barrier with an autonomous need for its maintenance. This view has been changed by the concept that the central nervous system is sensitive to the immune processes occurring in the periphery as well as to the infiltration of peripheral immune cells. However, how the immune system might contribute to the development of neurodegenerative diseases, such as Parkinson's disease (PD), remains unclear. PD is a chronic neurodegenerative disorder that affects motor and cognitive functions. Although the precise cause of PD is unknown, studies in both mice and human suggest that alterations in the innate immunity may play a critical role in modulating PD progression. Here we review recent advancements in our understanding of inflammation and the innate immune mechanisms in PD pathology.

This article originally appeared in the "https://pubmed.ncbi.nlm.nih.gov/33471378/" and has their copyrights. We do not claim copyright on the content. This information is for research purposes only. This Blog is made available by publishers for educational purposes only as well as to give you general information and a general understanding , not to provide specific advice. By using this blog site you understand that there is no client relationship between you and the Blog publisher. The Blog should not be used as a substitute for competent research advice.