bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational Inhibition of Multiple Neurotoxic Proteins Leads to Improved Motor Function in Parkinson’s Disease
Authors: Fang Cheng , Hernandez Priscilla , Liow Kore , Chen Michael , Zetterberg Henrik , Blennow Kaj , Maccecchini Maria L. 
Published: December 2022

AbstractBackgroundParkinson’s disease (PD) is a neurodegenerative disorder that affects predominately dopaminergic neurons in substantia nigra. Although alpha‐synuclein (αSYN) is the main component of Lewy bodies, TDP‐43, Aβ and tau are also detected in PD. Buntanetap has been shown to inhibit the translation of multiple neurotoxic proteins such as amyloid precursor protein, tau and alpha‐synuclein. It been shown in animal models to restore axonal transport, lower inflammation and protect nerve cells from dying. By reversing the toxic cascade leading to nerve cell death, Buntanetap preserves and restores full function in 7 different animal models of neurodegenerative diseases including PD.MethodIn our double‐blind, placebo‐controlled, dose‐finding Phase 2a trial, 5 different doses of Buntanetap (5mg, 10mg, 20mg, 40mg and 80mg QD) were tested compared to control after25±2 days treatment. Buntanetap’s safety, pharmacokinetics, biomarkers and efficacy were evaluated.ResultIn clinical trials, Buntanetap was safe in over 200 subjects, both in healthy volunteers and in AD/PD patient. In PD patients, Buntanetap lowers neurotoxic proteins, improves axonal integrity and synaptic function, and lowers inflammation. Buntanetap improves PD patients’ mobility shown by MDS‐UPDRS and WAIS coding test after 25±2 days treatment. Of the 5 different doses, 10 & 20mg Buntanetap QD showed the best clinical outcomes.ConclusionThese data supported us getting regulatory approval to develop next stage pivotal studies in larger population and for longer durations. The FDA consented us to move the development into two phase 3 clinical studies – one in early and one in advanced PD. Our first pivotal trial intends to treat 450 early PD patients at 1:1:1 ration for 10mg, 20mg Buntanetap QD or placebo for 6 months duration.
Depletion of the AD risk gene SORL1 causes endo‐lysosomal dysfunction in human microglia
Authors: Mishra Swati , Knupp Allison , Young Jessica E. , Jayadev Suman 
Published: December 2022

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder which is currently incurable. Prior to well‐established neuropathological changes in AD, enlarged early endosomes are cytopathological hallmark of AD and strong genetic evidence links genes involved in intra‐cellular trafficking, mediated by endo‐lysosomal pathway, to increased AD risk, suggesting that this pathway is integral to the pathogenesis of AD. We recently identified SORL1, an intracellular sorting receptor as a potential regulator of this pathway. Using CRISPR/Cas9 to deplete SORL1 in human induced pluripotent stem cells (hiPSCs), we showed that loss of SORL1 results in enlarged early endosomes in (hiPSCs)‐derived neurons, but not microglia. This model replicates the earliest AD cytopathology and our data underscores important cell‐type specific differences in response to loss of SORL1. Building on this study, we further examined alterations in lysosomal function, with altered expression of SORL1 in hiPSC‐derived microglia.MethodIsogenic hiPSC lines that are deficient in SORL1 were generated and differentiated into microglia using previous published protocols. Lysosome function was assayed by examining lysosome morphology, lysosomal trafficking of fibrillar Aβ, lysosomal degradation, lysosome enzyme activity and lysosomal exocytosis. Lysosome morphology and number were measured using immunocytochemistry, confocal microscopy and Cell Profiler and Image J software. To assess Aβ transport into lysosomes, pH sensitive fluorescent dye, Phrodo, conjugated to Aβ, was used. Lysosomal degradation was measured using a proteolysis sensitive fluorogenic substrate, DQ‐BSA. Fluorescence intensity of both Phrodo and DQ‐BSA was measured using flow cytometry. Lysosome enzyme activity and exocytosis assays were performed using previously published protocols.ResultLoss of SORL1 results in increased lysosome size and decreased lysosome number in SORL1 KO microglia indicating altered lysosome function. In support of this idea, we observed decreased lysosomal degradation, trafficking of Aβ to lysosomes and lysosomal enzyme activity and also decreased lysosomal exocytosis in SORL1 KO microglia.ConclusionOverall, our results have unraveled a previously unexplored function of the AD risk gene SORL1 in human microglia and our work indicates that maintaining homeostatic balance in the endo‐lysosomal network impacts diverse CNS cell types. Our study will define the endo‐lysosomal network in general, and SORL1 in particular, as a novel therapeutic target for AD.
Inhibiting tyrosine kinase c‐KIT as a therapeutic strategy for Alzheimer’s Disease
Authors: Stevenson Max E , Hebron Michaeline , Liu Xiaoguang , Kavulu Balaraman , Wolf Christian , Moussa Charbel E‐H 
Published: December 2022

AbstractBackgroundImpaired autophagy and neuroinflammation, two primary features of Alzheimer’s Disease, were examined as potential pharmacological targets for alleviating amyloid‐beta and tau burden using novel tyrosine kinase inhibitors.MethodTransgenic APP mice were treated for 6 weeks with either one of two novel tyrosine kinase inhibitors or DMSO (n = 10) before having their behavior tested on the novel object recognition test, the Morris water maze, and the elevated plus maze. Brain samples were then extracted and probed for levels of amyloid‐beta, tau, and autophagic machinery, as well as numbers of mast cells and microglia using ELISA, immunohistochemistry, and flow cytometry.ResultMice treated with our novel tyrosine kinase inhibitors exhibited robust improvements on behavioral measures. These treated mice displayed concurrent decreases in levels of amyloid‐beta and tau, as well as increased levels of autophagic machinery and decreased numbers of microglia and mast cells.ConclusionTyrosine kinase inhibition represents a valid mechanism for improving autophagic clearance of neurotoxic protein and mitigating mast cell and microglial‐mediated inflammation, identifying this method as a potential target for therapeutic intervention for treating Alzheimer’s Disease.
Camouflaged regions conceal critical regions in ATAC‐Seq and Hi‐C sequencing assays, hiding potential contributing factors in Alzheimer’s disease
Authors: Wadsworth Mark E , Page Madeline L , Heberle Bernardo Aguzzoli , Miller Justin B , Ebbert Mark T.W. 
Published: December 2022

AbstractBackgroundFor many regions of the genome, genetic variants are completely overlooked when using standard short‐read sequencing approaches because of either; (1) lack of coverage (i.e., ‘dark‐by‐depth'), or (2) reads aligning to multiple regions (i.e., ‘dark‐by‐MAPQ', a.k.a. ‘camouflaged’ genes). Multiple alignments occur because of genomic duplication events that contribute to molecular evolution, but present major analytical challenges for aligning short‐read sequencing data to the genome. We previously presented a method to identify and differentiate dark and camouflaged regions by analyzing the read depth and reads with multiple alignments. Here we present data demonstrating that not only do camouflaged regions conceal essential genetic variants, but they further conceal results from other short‐read sequencing assays, including ATAC‐Seq and Hi‐C. Our results have important implications for all disease research, including Alzheimer’s disease.MethodsWe identified and validated genome‐wide camouflaged regions using an updated version of our algorithm to identify camouflaged genomic regions, and then applied it to publicly available ATAC‐Seq and Hi‐C sequencing data sets.ResultsWe identified 148,197 camouflaged regions of greater than 20 bases. Of these regions 23.23% overlap at least one Ensembl transcript. Additionally, we found that results for camouflaged regions, including CR1 (a top Alzheimer’s disease gene), are also non‐existent in ATAC‐Seq and Hi‐C data. As previously described, we can rescue variants that fall within these regions such as the frameshift we described in CR1. Thereby, we show that including a rescuing step in your alignment pipeline may provide important insights into disease etiology.ConclusionWhile short‐read sequencing has been a major boon to research, there are many systematic flaws to using short‐read sequencing, including camouflaged regions. Rescuing variants or peaks in these camouflaged regions could elucidate important findings related to Alzheimer’s Disease etiology that are missed by standard short‐read sequencing methods.
Applying novel EMBRACE technological solutions to measure and optimize brain response to exercise.
Authors: de Frutos Jaisalmer , Doval Sandra , Fernández Ricardo Bruña , Cabrera Jesús , de Fano Antonio , Fiedler Patrique , Tamburro Gabriella , Haueisen Jens , Zanow Frank , Ros Bruno , Pusil Sandra Angelica , Vaquero Lucia , Comani Silvia 
Published: December 2022

AbstractBackgroundExtensive evidence supports the notion that physical activity (PA) promotes healthy aging and contributes to the prevention of brain damage and dementia. However, there are relevant differences in individual response to exercise that could mediate the extent of the PA‐induced benefits. Here, we propose the application of the novel technology that is currently being developed by the EMBRACE project researchers to the characterization of the individual physiological response to exercise in older adults.MethodEMBRACE is an intersectoral and international consortium that brings together experts in biomedical engineering, material science, signal processing, neuroscience and social psychology from 3 academic and 3 industrial partners across 3 EU countries to develop: 1) a new mobile and wireless dry electrode EEG system suitable for monitoring brain activity during full body movements; 2) novel body network sensors and a multimodal alignment system for simultaneously recording of neural, physiological and kinematic signals from two interacting subjects; 3) novel analytical solutions for motion artefact removal and multi‐level analysis of multimodal data; and 4) a new research dyadic paradigm to exploit the technological advances.ResultThe novel technological solutions that are being currently developed by the EMBRACE consortium will enable the study of joint action at the neural, cognitive, behavioral and social levels while the participant engages in PA (individually or in social interaction), wearing a comfortable and long‐lasting acquisition system.ConclusionA detailed characterization of the individual response to exercise will help in the optimization of exercise routines with the aim to elicit the desired physiological response to enhance brain health and prevent dementia.
Effect of calcineurin inhibitors on cognition in a canine model of Alzheimer’s disease
Authors: Sordo Lorena , Ubele Margo F. , Boaz Kathy , Mefford Jennifer L. , Jones Erin Denhart , Smiley Jeffrey , Bresch Fred , Phelan Michael J. , Puskas Laszlo G. , Norris Christopher M. , Head Elizabeth 
Published: December 2022

AbstractBackgroundCalcineurin (CN) is a Ca2+/calmodulin‐dependent phosphatase that regulates diverse cellular phenotypes through activation of NFAT transcription factor1. CN/NFAT signaling increases in Alzheimer’s disease (AD)2,3 and is associated with synaptic loss, neuron degeneration, neuroinflammation, amyloid‐β production, and cognitive decline4,5. Thus, calcineurin inhibitors (CNI) are attractive potential therapeutic to improve cognitive impairments associated with AD.Tacrolimus is an FDA‐approved CNI commonly prescribed for the prophylaxis of solid organ transplant rejection6. In mouse models of AD, tacrolimus ameliorates cognitive deficits7. Moreover, epidemiological studies suggest that tacrolimus reduced the incidence of dementia in kidney transplant patients, when compared to age‐matched controls8.Q134R, a hydroxyquinoline derivative with cytoprotective properties9, inhibits NFAT activity without suppressing CN activity. Q134R improves synapse function and reduce neuroinflammation in AD mouse models10.We hypothesized that chronic low dose tacrolimus and Q134R treatment will prevent cognitive decline over time in middle‐aged beagles, a natural model of human brain aging, amyloid‐β accumulation, and amyloid‐related cognitive impairment.MethodsCognitive outcomes were evaluated in 37 middle‐aged dogs at baseline and during follow‐up (years 1, 2 and 3). Spatial learning and working memory were evaluated using the landmark‐discrimination (1, 2 and 4cm) task and a delayed non‐matching to position (20‐, 70‐, and 110‐second delays) test. Dogs were ranked for cognition at baseline and randomized into one of three treatment groups: Control (n = 12; placebo), Q134R (n = 12; 8mg/day PO), and tacrolimus (n = 13; 0.075mg/kg/day PO).ResultsAccuracy at each landmark‐discrimination distance declined significantly among controls faster per year than both treatment groups. Control dogs declined 20% faster than tacrolimus dogs at all distances, and 15% faster than Q134R dogs, at the most difficult distance (4cm).Accuracy on the spatial working memory task declined in each year among controls faster than dogs in the active treatment groups. This effect tended to increase with treatment duration in tacrolimus dogs, whereas it attenuated in Q134R dogs.ConclusionOur findings suggest that both tacrolimus and Q134R have beneficial effects on cognitive outcomes in a canine model of AD, as dogs treated with these compounds showed improved learning, memory, attention, and working memory. Hence, inhibition of the CN pathway may reduce/delay cognitive impairment in AD.
Microglia with fatty acid‐binding protein 5 deficiency exhibit proinflammatory phenotype contributing to neuroinflammation
Authors: Kagawa Yoshiteru , Jin Liang , Sun Jiaqi , Nicolazzo Joseph , Owada Yuji , Pan Yijun 
Published: December 2022

AbstractBackgroundMicroglia are the resident immune cells in the brain, which show a broad spectrum of phenotypes ranging from the pro‐inflammatory, potentially cytotoxic to the anti‐inflammatory, scavenging, and regenerative. Fatty‐acid binding protein 5, an intracellular protein that are important for cellular metabolism, have been identified in human and mouse microglia; however, its role in microglia is yet to be defined. Studies from our laboratory and others have shown that FABP5 is downregulated in the brain of Alzheimer’s disease patients and APP/PS1 mice. This study is to explore the impact of FABP5‐deficiency on microglia phenotype.MethodTotal protein from FABP5‐knockout mouse brains (4‐5 months old) was extracted to assess cytokine levels (TNFα, IL‐1ß). Microglia abundance in the hippocampus of FABP5‐knockout mice and their wildtype control mice was quantified immunohistochemically. FABP5 in the immortalized mouse microglia BV2 was downregulated using siRNA, and the metabolism of the treated microglia was assessed via [3H]‐2‐deoxy‐D‐glucose (2dg) uptake and oleic acid oxidation assay.ResultA significant increased levels of TNFα (1.4‐fold) and IL‐1ß (1.25‐fold) was detected in the brain homogenates of FABP5‐knockout mice (vs wildtype control mice). Interestingly, a higher abundance (8%) of microglia was observed in the hippocampus of the FABP5‐knockout mice. The downregulated FABP5 in BV2 using siRNA and achieved a 76.4% reduction in FABP5 protein expression. We subsequently observed a 1.5‐fold elevation of 3H‐2dg uptake in FABP5‐downregulated BV2 cells, suggesting a possible increase in glycolysis. This shift was in agreement with the metabolism requirement of the proinflammatory microglia.ConclusionFurther studies need to be performed to confirm the role of FABP5 in microglia. Our data supports that FABP5 deficiency possibly leads to microglia proinflammatory activation and contribute to neuroinflammation in mice.
Investigating Distinct Alpha Synuclein Oligomer‐Mediated Cellular Toxicity
Authors: Moore Kenya 
Published: December 2022

AbstractBackgroundAlpha Synuclein (ASyn), an amyloidogenic protein observed in Parkinson’s (PD) and Alzheimer’s (AD) disease, oligomers are toxic and polymorphic protein aggregates that with further investigation could be essential to improving potential neurodegenerative therapeutics.MethodUsing monoclonal antibodies (SynTCs) that bind toxic conformations of ASyn, we utilize cellular models such as primary cortical neurons and primary astrocytes isolated from C57/BL6 mice to investigate differences in the neurotoxic effects of ASyn oligomeric strains. These differences were evaluated by both immunocytochemistry and cell‐based assays. In addition, we analyzed the thermodynamic binding occurring between SynTCs and ASyn oligomeric strains.ResultUtilizing isothermal titration calorimetry (ITC), we confirm the thermodynamic binding between SynTCs and ASyn oligomers in contrast to ASyn monomers and fibrils. Asyn oligomeric strains exhibit differential toxicity in both primary neuron and astrocyte cells. When immunodepleted by SynTCs, cytotoxicity and endogenous ASyn aggregation decreased.ConclusionInvestigating mechanisms of neurotoxicity mediated by Asyn oligomeric strains is valuable in determining biological effects and the therapeutic potential of targeting and reducing toxic ASyn oligomers that contribute to the neurotoxicity observed in multiple neurodegenerative diseases.
A Systemic Review of depressive intervention for the older adults
Authors: Choi Junsu , Choi Sungjoo , Jung Minye 
Published: December 2022

AbstractBackgroundThis study systematically review and analyze the types and effects of depressive intervention for the older adults.MethodIn the last 10 years, a total of 4,478 documents were searched and reviewed using databases of Pubmed, CINAHL, EMBASE, MEDLINE, SCOPUS, and Web of Science, and 8 studies that met the selection criteria were derived. The selected studies were systematically organized using the Cochrane’s Risk of Bias [RoB] and then the interventions were aggregated to derive content.ResultThe age criteria of the eight selected papers were 1 over 50 years old, 1 over 55 years old, 3 over 60 years old, and 3 over 65 years old. The five types of occupational therapy depressive intervention, 3(37.5%) of the studies were conducted on Problem solving therapy, 2(25%) of the studies were conducted on Cognitive behavioral therapy, 1(12.5%) of the study was conducted Behavioral activation, 1(12.5%) of the study was conducted Yoga and 1(12.5%) of the study was conducted Story sharing. In intervention other than Story sharing, depression symptoms in intervention groups were significantly reduced compared to the control groups.ConclusionThe study investigated the effects of depressive interventions for the older in preparation for problems caused by the aging population of mankind. As a result of this study, it is thought that research on how to manage depression in the older in the clinical sector will be necessary.
Behavioral reaction to amyloid beta status disclosure
Authors: Lesman‐Segev Orit H. , Golan Sapir , Zadok Maya , Kishenevsky Sarah , Ben‐Meir Mery , Bem‐Moshe Ariela , Heymann Anthony , Azuri Joseph , Ravona‐Springer Ramit , Hoffmann Chen , Domachevsky Liran , Beeri Michal Schnaider 
Published: December 2022

AbstractBackgroundLimited information exist regarding the reaction of cognitively unimpaired research participants to amyloid status disclosure and even more so in observational studies. We aimed to assess the associations of amyloid status disclosure with reported subjective memory concern, motivation to change lifestyle, anxiety, and depression.MethodResearch participants that take part in two observational studies and two clinical trials that incorporate amyloid‐PET where included. Participants received information regarding amyloid‐PET testing, results, and interpretation. They then performed an interview prior to PET scan and four‐to‐six‐month following result disclosure assessing their subjective memory concern, motivation to change lifestyle, anxiety, and depression from the possibility of a positive amyloid‐PET result.Result130 cognitively normal adults completed both the pre‐PET and post‐PET questionnaires. Only 11 had a positive amyloid‐PET result and thus were excluded from the analyses. Of the 119 subjects with a negative PET scan, 70 (59%) were females, mean age = 62Y (rang 44‐88Y), mean education = 16Y (4‐25), mean MMSE = 29 (24‐30); most (64%) reported no memory concerns or mild memory concerns (1/2 on a scale of 5). This increased to 94% at 4‐6 month following amyloid‐PET disclosure (Figure 1). Most (84%) had high or very high motivation to change lifestyle (4/5 in a scale of 5) in the pre‐PET assessment. This decreased to 30% in the post‐PET assessment. High and very high (4/5 in a scale of 5) anxiety and depression from a positive amyloid scan rates decreased from 25% to 0% and from 10% to 0%, respectively following a negative PET result disclosure (Figure 1). Although most individuals reported favorable post‐PET changes, a few subjects experienced increase in memory decline (N = 8), anxiety (N = 6) or depression (N = 1) following disclosure (Figure 2).ConclusionIn cognitively normal adults, the disclosure of a negative amyloid‐PET scan result was associated with a general “comforting” effect as reflected by less subjective memory concerns, anxiety, and depression, and lower motivation to perform lifestyle changes. By AAIC 2022, we anticipate more participants who are amyloid‐PET positive allowing to compare their behavioral changes after disclosure of amyloid results to the changes of those who are amyloid‐PET negative.