bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPML1: A novel therapeutic target to remediate endolysosomal pathology in Alzheimer’s disease
Authors: Somogyi Aleksandra , Kirkham Emily D. , Lloyd‐Evans Emyr , Allen Nicholas D. , Anderson Karen E. , Hawkins Phillip T. , Sims Rebecca , Boland Barry , O'Neill Cora 
Published: December 2020

AbstractBackgroundTRPML1 (transient receptor potential channel mucolipin 1) is an essential endosomal‐lysosomal Ca2+ channel whose loss of function can cause neurodegeneration. Defects in the endosomal‐autophagic‐lysosomal (EAL) are a primary feature of Alzheimer’s disease (AD) pathogenesis, and many late‐onset AD (LOAD) risk genes, including APOE4, functionally converge on the EAL system, although the underlying mechanisms remain unclear. Dysfunctional TRPML1 activity has been reported in genetic models of AD involving cells deficient in presenilin 1. Here, we hypothesised that TRPML1 malfunction underlies EAL defects in LOAD, and can be therapeutically targeted to remediate EAL defects in LOAD.MethodCell and molecular approaches were employed to investigate the integrity of endolysosomes in LOAD (n = 10) and matched control (n = 10) post‐mortem brain, and in APOE isoform expressing human cortical neurons derived from induced pluripotent stems cells. TRPML1 activity was manipulated in primary neurons to determine whether blocking TRPML1 could recreate EAL defects evident in LOAD and whether TRPML1 could be targeted therapeutically to protect against EAL defects in LOAD.ResultWe identified perinuclear clustering of enlarged LAMP‐1‐positive endolysosomes in post‐mortem LOAD hippocampal neurons, indicative of TRMPL1 dysregulation. Our results reveal for the first time that TRPML1 activity was significantly reduced in APOE4 expressing human cortical neurons derived from induced pluripotent stems cells, resulting in elevated endolysosomal Ca2+ content. Furthermore, depletion of the TRPML1 agonist, PI(3,5)P2 in primary neurons using YM201636, recreated many features of AD endolysosomal neuropathology. This included endolysosomal swelling, accumulation of autophagic vacuoles (AVs), and increased endolysosomal Ca2+ accumulation. Strikingly, the re‐activation of TRPML1 in YM201636‐treated cultures, using the synthetic small molecule agonist ML‐SA1, restored endolysosomal Ca2+ pool to its normal size, mitigated endolysosomal swelling, prevented the accumulation of AVs, and increased levels of non‐pathogenic alpha‐secretase derived C‐terminal fragments of the amyloid precursor protein (APP).ConclusionTogether, these finding implicate defects in TRPML1 in LOAD and present TRPML1 as a novel potential therapeutic target to remediate endolysosomal pathology in AD.
Plasma neurofilament light chain (NFL) is differentially associated with neuropsychological test performance among non‐Hispanic whites and hispanic, Mexican Americans: A HABLE study
Authors: Petersen Melissa , Hall James R. , Mozdbar Sima , Johnson Leigh Ann , Yaffe Kristine , Braskie Meredith N , King Kevin , Toga Arthur W. , O'Bryant Sid ,   the HABLE Research Team
Published: December 2020

AbstractBackgroundNeurofilament light chain (NfL) has been examined as a biomarker of Alzheimer’s disease (AD) due to its link with neurodegeneration. Among a community sample of Mexican Americans, NfL was found to be inversely related to processing speed, attention, executive functioning, and memory among those with normal cognition (NC) as well as those with mild cognitive impairment (MCI). This study aimed to validate prior work and examine if the relationship between NfL and cognition differed by ethnicity when split by diagnostic status.MethodData were analyzed on n= 503 non‐Hispanic white (n=363 NC; n= 140 impaired cognition [MCI +dementia]) and n=357 Mexican American (n=187 NC; n=169 impaired cognition [MCI +dementia]) participants enrolled in a study of health disparities. Plasma NfL were assayed using Simoa. Neuropsychological test battery included Trail Making Test Part A and B, FAS, Animal Naming, Spanish and English Verbal Learning Test (Immediate and Delayed Recall), and Digit Symbol Substitution. Linear regression models analyzed cognitive test performance as the dependent variable while NfL was included as the independent variable. Covariates included age, gender, and education. Regression models were run separately for each cognitive test. Analyses were split by both ethnicity and diagnosis.ResultAmong non‐Hispanic whites with normal cognition, NfL was related to poorer neuropsychological test performance across measures of attention, processing speed, verbal fluency (FAS), and immediate memory. Among those with impaired cognition, NfL was associated with poorer performance across neuropsychological measures of attention, processing speed, executive functioning, and verbal fluency (animal naming). Among Hispanic, Mexican Americans with normal cognition, NfL was only found to be associated with poorer neuropsychological test performance on a measure of verbal fluency (animal naming). NfL was not found to be associated with any cognitive domain examined for Hispanic, Mexican Americans with impaired cognition.ConclusionThese findings highlight that biomarkers associated with AD, such as NfL, likely differ by ethnicity. This corresponds with our prior work that has shown lower rates of APOEe4 and amyloid among Hispanic, Mexican Americans. This further supports the need to examine more closely underlying biological mechanisms of neurodegenerative conditions among minority populations such as Hispanic, Mexican Americans.
Influence of amyloid‐beta isoforms in different in vitro models
Authors: Van Bulck Michiel , Gräler Markus , Castillo Ana Maria Pérez , Braeuer Anja 
Published: December 2020

AbstractBackgroundAlzheimer disease (AD) is a complex multifactorial neurodegenerative disorder, characterized by mild cognitive impairment and late dementia. Understanding and treatment of AD is one of the greatest challenges in modern medicine. The pathological brain features includes formation of extracellular amyloid plaques, intracellular neurofibrillary tangles, leading to neuronal cell death. The underlying process, onset and progression are not yet elucidated, although impaired neurogenesis, synaptic dysfunction, and dysregulation of lipid metabolism are known to be involved. Homeostatic balance of Amyloid‐beta (Aβ) peptide during normal brain development and function, are depending on soluble or insoluble isoforms, aggregation state, developmental stage of the brain and concentration of Aβ peptide. Physiological and pathophysiological features of Aβ peptide remain controversial due to complexity, inconsistency and contradictory results. Investigating the effect of low concentration of human synthetic Aβ isoforms on adult neurogenesis, synaptic plasticity, and alteration of lipid metabolism might help better understanding the biochemical pathways in AD.MethodWe performed immunofluorescence, high performance thin layer chromatography, and mass spectrometry analyses on hippocampal neurons, glial cells and neurospheres treated with and without low concentration (1µM) of human synthetic Aβ40 and Aβ42 for 3‐12 hours.ResultPreliminary results of neurospheres treated with Aβ40 and Aβ42 showed altered levels in stem cell differentiation towards neuronal phenotype. The hippocampal neurons showed synaptic loss after 3‐12 hours. Lipid analysis showed altered levels of phospholipids (e.g. Phosphatidylcholine, Phosphatidylserine) and sphingolipids in hippocampal neurons after 3‐12 hours of Aβ40 and Aβ42 treatment compared to glial cells. Glial cells showed altering lipid levels after 3 hours of Aβ42 treatment and 12 hours for both Aβ40 and Aβ42 treatment.ConclusionPreliminary results showed that treatment with low concentration of Aβ40 and Aβ42 might have neurotrophic effect on stem cell differentiation and synaptic loss on hippocampal neurons. Lipid profiles showed altering levels in phospholipids and sphingolipids in both glial cells and hippocampal neurons. These results will have potential impact in a better understanding, finding of new biomarkers for diagnostics, and developing new therapeutics for AD.
Development of an ultrasensitive multiplex assay for simultaneous detection of Aβ1‐42, Aβ1‐40, GFAP and NF‐L in blood
Authors: Shan Dandan , Holdridge Marcella , Chang Lei , Stoops Erik , Verberk Inge M.W. , van Der Flier Wiesje , Teunissen Charlotte E. , Ball Andrew J. 
Published: December 2020

AbstractBackgroundPrevious work (1) has described plasma amyloid, GFAP and NF‐L as predictors of Alzheimer’s pathology. Here we build on the Amyblood 1‐42/1‐40 Simoa assay (1,2) where GFAP and NF‐L, as indicators of astrogliosis and neurodegeneration, further added to the prediction for Aβ PET imaging or diagnosis. We report a Simoa multiplex assay that simultaneously measures Aβ1‐42, Aβ1‐40, GFAP and NF‐L in blood.MethodsA 4‐plex immunoassay was designed using Simoa technology. A monoclonal capture antibody specific for each analyte was attached to one of four different fluorescent dye‐encoded beads. Antibodies against Aβ1‐42 and Aβ1‐40 were from ADx (clones 21F12 and 2G3 as capture; 3D6 as detector), NF‐L and GFAP antibodies were as supplied in Quanterix commercial kits. The assay was further evaluated for its analytical performance, including analyte detectability in commercially‐sourced human plasma (n=20) and CSF (n=10) from healthy controls, and for discrimination between AD patient and control plasma (each n=10) from the Alzheimer Center Amsterdam.ResultsAssay calibration ranges were 0.041‐30pg/mL (Aβ1‐42), 0.016‐12pg/mL (Aβ1‐40), 6.86‐5000pg/mL (GFAP), and 0.686‐500pg/mL (NF‐L). Lower Limits of detection were 0.148pg/mL (Aβ1‐42), 0.084pg/mL (Aβ1‐40), 1.66pg/mL (GFAP), 0.157pg/mL (NF‐light). Limits of quantification for assay prototype were 0.381pg/mL (Aβ1‐42), 0.125pg/mL (Aβ1‐40), 4.99pg/mL (GFAP), 0.493pg/mL (NF‐light). In parallelism studies, mean recovery of serially diluted endogenous plasma and CSF (each n=4) was within 80‐120%. Grand mean recovery of expected spike concentration was within 70‐130% (n=4). The assay has 100% detectability for all four analytes in both plasma and CSF samples. NF‐L and GFAP concentrations increased in AD samples (respectively p<0.05 and 0.01) while the Aβ 42/40 ratio decreased (p<0.05) in AD samples versus healthy donors.ConclusionsThis multiplex Simoa assay accurately and specifically measure four biomarkers simultaneously in plasma and CSF, providing a new tool to quantify Aβ1‐42, Aβ1‐40, GFAP and NF‐L. Ongoing studies using a larger cohort of clinical samples will determine the potential clinical utility of this assay. References: (1)Verberk et al, Plasma amyloid, GFAP and NfL as predictors of Alzheimer’s pathology (AAIC 2019). (2)Stoops et al, Characterization and Transfer of a Novel Plasma Aβ1‐42/ Aβ1‐40 Simoa Assay for integration into the clinic (AAIC 2019).
An in silico target‐specific drug repurposing approach for autism
Authors: Marisse Lakshmi Prasanna , Sree G.N.S. Hema , Rajalekshmi Saraswathy Ganesan 
Published: December 2020

AbstractBackgroundAutism a most disabling heterogenous neuro‐developmental disorder with vast heritability is exemplified by impaired social interaction, communication, motor function, cognition, restricted and repetitive stereotyped behaviors. The inability to identify risk factors and genetic variants associated with the pathogenesis has attributed to its complexity. The current research of autism is only focused on symptomatic relief rather than cure. This dearth in research for specific drugs aids in unwinding druggable targets via drug repurposing.MethodThe GEO dataset GSE22507 from National Centre for Biotechnology Information (NCBI) comprising the microarray data of 67 autistic children and 47 controls was selected. Increasing paternal age, an established risk factor for the development of autism was later considered for computing the median age of fathers in to young fathers, old fathers and total age. This data was analyzed through Geo2 Enrichr for retrieving significant differential expressed genes (DEG’s) which were processed for functional enrichment analysis though Database for Annotation Visualization and Integrated Discovery tool. Subsequently, protein‐protein interactions were constructed between DEG’s and literature derived genes using Search Tool for Retrieval of Interacting Genes. The common genes amongst the groups were identified and considered as potential targets. Selected targets and their respective drugs acquired from FDA were subjected to molecular docking studies through Extra Precision (XP) mode in Glide tool of Schrodinger drug design suite (version 10.7). The shortlisted targets were ranked and evaluated to energy calculations via MM‐GBSA.ResultProtein‐protein interaction for all the groups revealed FOS a proto‐oncogene as the potential target. Drugs that are found to possess the best docking score and glide energy were further subjected to MM‐GBSA studies. Compounds exhibiting top binding free energies (∆G) i.e., ‐60 k.cal/mol are selected for literature survey. This survey revealed the affinity of 6 drugs namely, Pranlukast, Bemotrizinol, Ceforanid, Dasabuvir, Flavin Adenine Dinucleotide drugs. These drugs were not reported in literature for autism.ConclusionThe FOS target should be validated further along with the aforementioned drugs in in vitro and in vivo to identify potential targets for a devastating disease like autism.
Epigenomic features related to microglia are associated with attenuated effect of APOE ε4 on Alzheimer’s disease risk in humans
Authors: Ma Yiyi , Yu Lei , Olah Marta , Smith Rebecca G. , Pishva Ehsan , Menon Vilas , Lunnon Katie , Bennett David A. , Klein Hans‐Ulrich , De Jager Philip L. 
Published: December 2020

AbstractBackgroundNot all APOE ε4 carriers who survive to advanced age develop Alzheimer’s disease (AD); factors attenuating the ε4 risk on AD may exist.MethodGuided by the top ε4‐attenuating signals from methylome‐wide association analyses (N = 572, ε4+ and ε4‐) of neurofibrillary tangles and neuritic plaques, we conducted a meta‐analysis for pathological AD within the ε4+ subgroups (N = 235) across four independent collections of brains. Cortical RNA‐seq and microglial morphology measurements were used in functional analyses.ResultThree out of the four significant CpG sites were captured by one principle component (PC1), which interacts with ε4 on AD, and is associated with expressions of innate immune genes and activated microglia. In ε4 carriers, reduction in each unit of PC1 attenuated the odds of AD by 59% (OR = 2.41, 95%CI = [1.64,3.52], P = 7.40 × 10−6).ConclusionAn epigenomic factor associated with a reduced proportion of activated microglia appears to attenuate the risk of ε4 on AD.
Brain amyloid accumulation and glucose hypometabolism in Chinese Alzheimer’s disease population
Authors: Ren Shuhua , Huang Qi , Jiang Donglang , Huang Lin , Wang Ying , Guan Yihui , Guo Qihao , Xie Fang 
Published: December 2020

AbstractBackgroundAmyloid is the main pathology for Alzheimer’s disease (AD), amyloid and glucose metabolism alternation are very important to investigate the progress of Alzheimer’s disease. However, not so many results were reported in Chinese population. In this study, we try to figure out the brain structure, function alternation and brain network alternation in Chinese subjective cognitive decline (SCD), mild cognition impairment (MCI) and Alzheimer’s disease (AD) from the data of Chinese preclinical Alzheimer’s disease (C‐PAS), which is initiated by us.Method200 participants were enrolled in this study, including 93 normal cognition (NC) healthy volunteers, 37 SCD, 34 MCI and 36 AD patients.6 types of neuropsychological tests from 3 cognitive domains and MMSE, Moca B were performed. FDG and amyloid PET (18F‐Flortabetapir) were conducted in these participants. 18F‐FDG and 18F‐Flortabetapir PET images were coregistered to the individual structural MRI images and then spatially normalized into MNI space. To assess the regional pattern of the 4 group, one‐way ANOVA followed by two sample t test for post hoc analysis were performed, The statistical level was set at p<0.05 with FDR correction and a minimum cluster extent Ke>20 voxels.ResultsIn Chinese population, changed glucosemetabolism were present in Superior temporalcortex, inferior temporal cortex, superior occipital cortex, precuneus, frontal cortex, supra‐marginal gyrus, anterior cingulate cortex, insula in a multiple comparison of AD MCI, SCD, and NC. And amyloid plaque were found in temporal cortex, frontal cortex, middle occipital cortex, inferior parietal cortex, insular, lingual gyrus, calcarine fissure and surrounding cortex, cingulate gyrus, fusiform gyrus, gyrus rectus, angular gyrus in these participants. Most of these changes were from AD patients, but slight hypometabolism, and amyloid accumulation were found among NC, SCD, MCI.ConclusionCortex and cingulate gyrus were the main regions for amyloid accumulation and glucose hypometabolism for Chinese AD patients. However, slight change was observed in NC, SCD, MCI participants.
Undulating changes in human plasma proteome profiles across the lifespan are linked to disease
Authors: Lehallier Benoit , Gate David , Schaum Nicholas , Nanasi Tibor , Lee Song Eun , Yousef Hanadie , Losada Patricia Moran , Berdnik Daniela , Keller Andreas , Verghese Joe , Sathyan Sanish , Franceschi Claudio , Milman Sofiya , Barzilai Nir , Wyss‐Coray Tony 
Published: December 2020

AbstractBackgroundAging is a predominant risk factor for numerous chronic diseases that limit healthspan. Mechanisms of aging are thus increasingly recognized as potential therapeutic targets. Blood from young mice reverses aspects of aging and disease across multiple tissues, which supports a hypothesis that age‐related molecular changes in blood could provide novel insights into age‐related disease biology.MethodWe measured 2,925 plasma proteins from 4,263 young adults to nonagenarians (18‐95 years old) using an aptamer‐based platform.ResultWe identified a proteomic clock that can be used to predict chronological age. Deviations from this plasma proteomic clock are correlated with changes in clinical and functional parameters in healthy subjects and AD patients from the Addneuromed cohort have an older proteomic age than their chronologic age (n=641). We are currently expanding this analysis to 881 healthy controls, MCI and AD subjects of the EMIF‐AD consortium. Thus, this panel of proteins can be used to assess the relative health of an individual and to measure healthspan, analogous to epigenetic clocks based on DNA methylation patterns. In addition, we describe a 46‐protein aging signature that is conserved in humans and mice, allowing deeper investigation of translational aging interventions in mice. Finally, we developed a novel bioinformatics approach, which uncovered marked non‐linear alterations in the human plasma proteome with age. Waves of changes in the proteome in the fourth, seventh, and eighth decades of life reflected distinct biological pathways and revealed differential associations with the genome and proteome of age‐related diseases and phenotypic traits.ConclusionThis new approach to the study of aging led to the identification of unexpected signatures and pathways, which might offer potential targets for age‐related diseases. Our results also have strong implications for the development of diagnostic and prognostic tests. Indeed, the undulating nature of the aging plasma proteome and its interactions with diseases has to be considered when developing proteomic signatures for diagnostic purposes. Such reliable tests are still urgently needed for Alzheimer’s disease.
Effects of magnetic nanoparticle hyperthermia on the disruption of beta‐amyloid and microglia‐mediated inflammation
Authors: Dyne Eric , Li Junfeng , Cawood Meghan , Yu Bing , Huang Songping , Kim Min‐Ho 
Published: December 2020

AbstractBackgroundInsoluble and aggregated forms of beta‐amyloid peptides (Aβ) were shown to contribute to chronic inflammation in Alzheimer’s disease, in large part due to an impaired ability of microglial cells to clear Aβ when they form insoluble large aggregates. The objective of this study is to validate whether the application of mild magnetic nanoparticle (MNP) hyperthermia, which can generate heat on the surface of MNPs selectively attached to the Aβ aggregates to a remotely applied alternating magnetic field (AMF), is sufficient to disaggregate Aβ plaques and if then, can this alter the phagocytic and inflammatory responses of microglial cells towards the clearance of Aβ plaques.MethodsAggregated Aβ peptides were prepared by incubating beta‐amyloid1‐42 peptides for 16 h, which resulted in 2‐10 um size of Aβ. Varying concentrations (1‐3 mg/mL) of MNPs (20 nm, paramagnetic nanoparticles) were added to the wells containing Aβ fibrils and incubated for 2 h, The samples were then treated with an AMF for 10 min duration at a field strength of 30 kA/m. The extent of Aβ disruption was assessed by using dynamic light scattering particle analysis and ultrastructure microscopy. The fragmented Aβ samples received with MNP/AMF were subsequently treated to the culture of human microglial cells (C20 cell line and HMC3 cell line (CRL‐3304™)), and changes in expression of pro‐ and anti‐inflammatory genes as well as phagocytic activity were quantified.ResultsThe application of MNP/AMF for 10 min resulted in disaggregation of Aβ into smaller fragments, which was positively related to MNP concentration. The expression of pro‐inflammatory genes, IL‐1β and TNF‐α, in microglial cells were increased in the presence of large aggregate of Aβ plaques compared to an untreated control. However, the responses were significantly attenuated when cells were treated with Aβ plaques treated with MNP/AMF, which was associated with an increase in the uptake of Ab by microglia.ConclusionsOur results demonstrate that a localized heating of magnetic nanoparticles localized around Aβ plaques is enough to disrupt the chemical bonds between beta‐amyloid plaques by destabilizing the aggregates, which could promote the functional activity of microglial cells towards clearance of beta‐amyloid debris, eliciting the attenuation of pro‐inflammatory signaling.