bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of MAPT mutations on transcriptomic signatures of FTLD brains and patient‐derived pluripotent cell models
Authors: Minaya Miguel , Martinez Rita , Eteleeb Abdallah , Cruchaga Carlos , Harari Oscar , Karch Celeste M. 
Published: December 2021

AbstractBackgroundMutations in the microtubule‐associated protein tau (MAPT) cause heterogeneous forms of frontotemporal lobar dementia with tau inclusions (FTLD‐tau). Yet the pathogenic events linked to disease remain poorly understood. This study aimed to identify genes and pathways that lead to FTLD‐tau.MethodTo identify the earliest genes and pathways that are dysregulated in FTLD‐tau, we identified differentially expressed genes in RNA‐seq data generated from induced pluripotent stem cell (iPSC)–derived cortical neurons carrying MAPT R406W, MAPT P301L, and MAPT IVS10+16 and isogenic, controls and brain tissue samples from progressive supranuclear palsy (PSP) and control brains. We then identified pathological pathways and drug targets that were enriched among the differentially expressed genes.ResultsWe identified 275 genes that were differentially expressed in iPSC–derived cortical neurons from MAPT R406W carriers compared to isogenic controls, MAPT IVS10+16 carriers compared to isogenic controls, and MAPT P301L carriers compared with isogenic controls. These commonly dysregulated genes were enriched for pathways involving synaptic function, neuronal development, and endolysosomal function. A subset of these genes were also changed in brains from human subjects with PSP compared to normal control brains. Finally, a subset of genes, enriched in glutamate receptor signaling, were altered across the mutant neurons and significantly changed with tau accumulation in a mouse model of tauopathy (Tau‐P301L mice).ConclusionThe results from this study demonstrate that iPSC‐derived neurons capture molecular processes that occur in human brains and can be used to model disease and point to common molecular pathways driven by 3 distinct MAPT mutations
Investigating inflammatory responses in a corticosterone‐induced model of depression
Authors: Dunnett Sophie Louise , Chang Raymond Chuen‐Chung 
Published: December 2021

AbstractBackgroundMajor depressive disorder (MDD) is a prevalent neuropsychiatric condition, affecting approximately 264 million people worldwide. While various hypotheses have been proposed for MDD, the full extent of the neuropathology underlying depression has not yet been elucidated. Nonetheless, evidence suggests that inflammation is a key pathological feature underlying depression, and that inflammation can predispose individuals to developing depression. In this study, we utilised a corticosterone (CORT)‐induced model of depression in rats, since elevated glucocorticoids are an important feature of MDD. Using this model, we investigated the inflammatory changes that occur both systemically and in various brain regions, focusing on inflammatory cytokines and various markers of innate immune pathways. Additionally, we administered CORT for different durations to assess how the inflammatory status changes depending on the length of elevated CORT levels.MethodsCORT or vehicle (sesame oil) is administered daily via subcutaneous injections to Sprague‐Dawley (SD) rats for 14, 21 or 28 days. Afterwards, various tissues samples including liver, kidney, frontal cortex, hippocampus, striatum, thalamus and hypothalamus are collected and processed for qPCR analysis. Additionally, tissue samples from the brain are collected and processed for immunofluorescence staining of GFAP and Iba1.ResultsFollowing 14 days of CORT administration, there are alterations to some of the inflammatory cytokines and markers of the innate immune system assessed in the liver, with no alterations to inflammatory markers in the brain. However, at 21 days there are increases in many of the inflammatory cytokines and innate immune markers assessed in both the liver and the kidney. Additionally, in the brain there are elevated levels of cytokines TNFa and Il1b in the striatum, IL1b in the thalamus and TNFa in the hypothalamus. At 28 days, many of the markers that were altered at 21 days return to baseline in the liver and kidney, though TNFa and IL1b in the kidney and IL1b in the liver remain elevated. Additionally, TNFa is elevated in the frontal cortex and striatum following CORT administration.ConclusionCORT administration impacts inflammation both in the periphery and in the brain. However, the alterations that occur depend on the duration of CORT administration and the tissue.
Evaluation of the effect of Donepezil hydrochloride on Ethanol‐induced hippocampal damage
Authors: Okhuevbie Daniel Ohiokhai , Awolaja Simbiat , Balogun Zainab 
Published: December 2021

AbstractBackgroundAlcohol consumption has long been associated with brain damage. In particular, ethanol has direct effect on nerve cells and has been implicated in the progression of neurodegenerative diseases such as Alzheimer’s disease. Due to its high level of plasticity, the hippocampus is one of the most susceptible sites to neurotoxicity. The aim of this study was to evaluate the effect of a named cholinesterase inhibitor on ethanol‐induced brain damageMethodTwenty‐one Wistar rats were placed into seven groups and housed in cages. They were fed with standard rat chow and water ad libitum. Six groups (groups A, B, C, D, E and F) were treatment groups and received ethanol while group G served as the control. Groups D, E and F received Donepezil hydrochloride after a week of ethanol administration while the first three groups continue to receive ethanol. After three weeks, the rats were dissected and the brain tissue were preserved in 10% formol saline. Histological examination was carried out on the hippocampus section using Haematoxylin and Eosin (H & E) staining procedure.ResultThe hippocampus was cut into sections and placed in a cassette. Findings revealed general degenerative changes in the treatment groups while the capillaries of the control group appeared without any form of congestion and microangiopathy. Group A specifically experienced autolysis while group F underwent glial cell vacuolation in response to neuronal cell injury induced by ethanol.ConclusionThis study shows it is possible to ameliorate and probably reverse the neurotoxic effect of ethanol on the brain.
Auditory processing in AD: An EEG study
Authors: Georgalli Christina 
Published: December 2021

AbstractBackgroundAlzheimer's disease is a progressive neurodegenerative disorder, which is associated with cognitive impairment, behavioral disorders and memory loss, among others (Andrade, Cortes, Guzman‐Martinez and Maccioni, 2017; Cortés, Andrade and Maccioni, 2018; Tarawneh and Holtzman, 2012). By 2050, nearly 14 million (13.8 million) Americans over age 65 could be living with the disease (Hebert, Weuve, Scherr and Evans, 2013), a fact that highlights the importance of identifying and discriminating biomarkers; the reason why the study is mainly conducted: to indicate whether or not auditory deficits occur in patients with Alzheimer's disease (AD) and memory deficits and hence to identify potential biomarkers.MethodThe study aims to compare measurements of amplitude for three different latencies which are between 0 and 50 ms, between 50 and 100ms and between 100 and 200ms for three different events such as new event, old event and difference between new and old event, using EEG data gathered from a specific memory task. Data have been collected from 136 participants based on two groups such as 73 participants belonged to the control group while 63 belonged to the patient group. The data were reliable and normal therefore analyzed with the help of t‐test.ResultThe results indicate that there is no significant difference between the control and patient groups at 0 to 50 amplitude latency. However, the study concluded a statistically significant difference between control and patient group at 50 to 100 and 100 to 200 ms amplitude latency.ConclusionEEGs with reduced levels of maladaptation reveal the presence of hidden neurodegenerative disorders and resistance to memory or psychiatric complaints such as depression and Alzheimer’s disease. The importance of EEG in diagnosing differences in common causes of dementia depends on specific clinical issues. The results of this study allow us to claim that such differences in amplitude latencies might contribute to our knowledge about auditory processing in AD and such knowledge could be beneficial as a diagnostic criterion of the disease in the future.
Targeted and untargeted mass spectrometry reveals impact of high fat diet on peripheral amino acid regulation in a mouse model of Alzheimer's disease
Authors: Taylor Amelia L , Davis Don E , Codreanu Simona G , Harrison Fiona E. , Sherrod Stacy D , McLean John A 
Published: December 2021

AbstractBackgroundMass spectrometry‐based metabolomics analyses were performed to examine metabolic changes under diet‐induced obesity in Alzheimer's Disease (AD) and assess whether these changes are reversible with diet modification. Specifically, amino acid metabolism was investigated because amino acid levels are related to obesity/diabetes and elevated levels have been shown to induce many of the pathophysiological hallmarks of AD.MethodTargeted hydrophilic interaction liquid chromatography‐triple quadrupole mass spectrometry (HILIC‐MS/MS) and untargeted reversed‐phase liquid chromatography‐high resolution tandem mass spectrometry (RPLC‐HRMS/MS) assays were developed to analyze the metabolic changes that occur in AD and obesity. Frozen liver samples were obtained from a previously defined study, in which APPSwe/PS1ΔE9 (APP/PSEN1) transgenic mice (to represent familial or early‐onset AD) and wild‐type litter mater controls were fed either a high‐fat diet (HFD, 60% kcal from lard), low‐fat diet (LFD, 10% kcal from lard), or reversal diet (REV, high‐fat for 7.5 months followed by low‐fat for 2.5 months). Liver samples were collected after sacrifice and were prepared through homogenization and an established protein precipitation protocol.ResultMultiple amino acids (including alanine, glutamic acid, leucine, isoleucine, and phenylalanine), carnitines, and members of the fatty acid oxidation pathway were significantly increased in APP/PSEN1 mice on HFD compared to LFD. More substantial effects and changes were observed in the APP/PSEN1 mice than WT mice, suggesting that they were more sensitive to a HFD. These dysregulated peripheral pathways include numerous amino acid pathways and fatty acid beta oxidation and suggest that obesity combined with AD further enhances cognitive impairment. These dysregulated peripheral pathways include pathways directly linked to the TCA cycle and mitochondrial dysfunction, which suggest that the HFD may contribute to AD pathogenesis by further contributing to this mitochondrial dysfunction. Furthermore, partial reversibility of many altered pathways was observed, which highlights that diet change can mitigate metabolic effects of AD. The same trends in individual amino acids were observed in both strategies, highlighting the biological validity of the results.ConclusionOur targeted and untargeted metabolomics results suggest that numerous peripheral pathways, specifically amino acid metabolism and fatty acid metabolism, were significantly affected in a combinatorial fashion by AD genotype and diet.
Role of tau protein on the photophysical properties of fluorescent carbon dots
Authors: Camilus Nayomi S , Lucas Sarah , Wu Colin , Naccache Rafik , Martic Sanela 
Published: December 2021

AbstractBackgroundGlobally, a number of individuals who live with Alzheimer’s disease (AD), an incurable and debilitating disease, is increasing. Tau protein has a structural role, maintains integrity of microtubules and is one of the underlying causes of the tauopathies [1]. It is unfolded and highly soluble under physiological conditions. However, tau protein undergoes post‐translational modifications like phosphorylation and aggregates causing cell death and spreading. In vitro, tau aggregation is typically evaluated using spectroscopic and microscopic methods.MethodsHerein, we propose to evaluate the use of carbon dots, an important type of fluorescent nanoparticles, as potential probes for tau protein aggregation. Dual fluorescent carbon dots were used in combination with tau protein, prior and post aggregation. Aggregation of the longest isoform of tau441 was induced using heparin. The fluorescence spectroscopy was used to analyze photophysical properties of carbon dots as a function of monomeric and aggregated tau.ResultsThe fluorescence quenching was observed for all protein containing samples, and was dependent on the aging time used for aggregation. The performance of carbon dots was compared to the standard Thioflavin T assay.ConclusionData indicate that nanomaterials may be useful platforms for sensing application targeting biomarkers of neurodegenerative diseases.References:[1] a. Andronesi, O. C., Bergen, M. V., Biernat, J., Seidel, K., Griesinger, C., Mandelkow, E., & Baldus, M. (2008). Characterization of Alzheimer’s‐like paired helical filaments from the core domain of tau protein using solid‐state NMR spectroscopy. Journal of the American Chemical Society, 130(18), 5922‐5928.; b. Jeganathan, S., Hascher, A., Chinnathambi, S., Biernat, J., Mandelkow, E. M., & Mandelkow, E. (2008). Proline‐directed pseudo‐phosphorylation at AT8 and PHF1 epitopes induces a compaction of the paperclip folding of Tau and generates a pathological (MC‐1) conformation. Journal of Biological Chemistry, 283(46), 32066‐32076.
Association of pulmonary function with mild cognitive impairment and brain pathologies: a community‐based cohort study
Authors: Wang Jiao , Dove Abigail , Song Ruixue , Qi Xiuying , Ma Jun , Bennett David A. , Xu Weili 
Published: December 2021

AbstractBackgroundThe association of pulmonary function (PF) with mild cognitive impairment (MCI) and its underlying mechanisms remain unclear. We examined the association of PF with MCI and brain pathologies.MethodWithin the Rush Memory and Aging Project, the 1025 no cognitive impairment (NCI) participants (mean age: 79.41±7.77 years) were followed for up to 21 years to detect incident MCI. PF was assessed with a composite score based on forced vital capacity, forced expiratory volume in 1s, and peak expiratory flow measured at baseline, and further divided into tertiles (i.e., lowest, middle, and highest). MCI was diagnosed following standard criteria. During the follow‐up, 396 participants died and underwent autopsies for neuropathological assessment (including Alzheimer’s disease [AD], and vascular brain pathologies). Data were analyzed using Cox regression, Laplace regression, and Logistic regression.ResultDuring the follow‐up (median 7 years, interquartile range 4‐10 years), 461 participants developed MCI. Compared to the highest PF, the multi‐adjusted HR (95% CI) was 2.07 (1.55‐2.78) for MCI. The median time from NCI to MCI development was 4.05 (95% CI: 2.78‐5.31) years shorter in people with the lowest PF than those with the highest PF. In the pathological data analysis, the lowest PF was significantly related to higher AD pathology (odds ratio [OR]: 1.45, 95% CI: 1.29‐1.62) and vascular brain pathologies (OR: 3.47, 95% CI: 1.50‐8.03) compared to the highest PF.ConclusionThe lowest PF is associated with a 2‐fold risk of MCI and accelerates progression from NCI to MCI by more than 4 years. Both neurodegenerative and vascular mechanisms may underlie this association.
Preclinical modelling in the mouse of altered neuroinflammation in Alzheimer’s disease – Down syndrome
Authors: Mumford Paige , Noy Suzanna , Tybulewicz Victor L , Fisher Elizabeth , Hong Soyon , Wiseman Frances K 
Published: December 2021

AbstractBackgroundPeople with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology, amyloid plaques and neurofibrillary tangles, by age 40 and the majority will develop dementia, due to having three copies of the chromosome 21 (Hsa21) gene APP leading to raised Aβ. How trisomy of the other Hsa21 protein‐encoding genes affects AD is unclear (1). People with DS have a perturbed immune system, with elevated pro‐inflammatory cytokines and an over‐activated interferon response (2,3). Several genes on Hsa21 have been implicated in inflammation differences in DS but how these genes modify neuroinflammation, an important aspect of AD, in AD‐DS is unknown. We are investigating how an extra copy of five Hsa21 candidate genes (RUNX1, IFNAR1, IFNAR2, IFNGR2, and IL10RB) modify neuroinflammation.MethodMouse models used had three copies of Hsa21 orthologous genes in the mouse, including our five candidate genes; the Dp2Tyb strain (three copies of ∼33 genes) and Dp1Tyb strain (three copies of ∼148 genes). Techniques used were qPCR, immunohistochemistry, and MSD immunoassay.ResultThe Dp1Tyb and Dp2Tyb brain has increased expression of Hsa21 candidate genes. The Dp1Tyb model has increased microglia number in the hippocampus, elevated levels of IL‐1β, and elevated Oas2, C3, and C1qa expression (n=11 wild‐type, n=10 Dp1Tyb). The Dp2Tyb model has elevated levels of interferon‐γ in the cortex but few changes to interferon‐stimulated genes (n=12 wild‐type, n=12 Dp2Tyb).ConclusionThe Dp1Tyb and Dp2Tyb models have neuroinflammatory changes that reflect those seen in people with DS, though the phenotypes of the Dp1Tyb are more pronounced. The increased microglial number, IL‐1β levels, and neuroinflammatory genes found in the Dp1Tyb were not seen in the Dp2Tyb, suggesting these changes are due to gene(s) which are in three‐copies in the Dp1Tyb but not the Dp2Tyb. One such candidate gene is USP25, which was recently found to exacerbate neuroinflammation in a mouse model of amyloid pathology (4).References: 1. Wiseman FK et al. Nat Rev Neurosci. 2015;16(9):564‐574. doi:10.1038/nrn3983 2. Sullivan KD et al. Elife. 2016;5:e16220. doi:10.7554/eLife.16220 3. Sullivan KD et al. Sci Rep. 2017;7(1):14818. doi:10.1038/s41598‐017‐13858‐3 4. Zheng Q et al. Sci Adv. 2021;7(1):eabe1340. doi:10.1126/sciadv.abe1340
Characterisation of the biophysical and cellular properties of Tau35, a disease‐associated tau fragment
Authors: Lyu Chen 
Published: December 2021

AbstractBackgroundTauopathies are characterised by the accumulation of intracellular tau aggregates in the brain. Tau inclusions contain various of truncated tau species, but the potential detrimental effects of these tau fragments are not well established. Tau35 is a C‐terminal fragment of wild‐type human tau, identified in tauopathy brain. We showed that minimal expression of Tau35 in transgenic mice recapitulates key features of tauopathy, including cognitive and motor dysfunction.MethodWe used small angle X‐ray scattering (SAXS), circular dichroism (CD), and transmission electron microscopy (TEM) to characterise the conformations of recombinant or aggregated Tau35 and full‐length (2N4R) tau. Tau assembly kinetics was monitored using Thioflavin T (ThT) and quantified. To assess cellular effects of tau, differentiated SH‐SY5Y cells (dSH) and mouse primary cortical neurons were exposed to Cy5‐labelled oligomeric tau and examined by immunofluorescence, western blots and live dead assay.ResultSAXS analysis showed that both Tau35 and 2N4R tau display characteristics of intrinsically disordered monomeric proteins, with Tau35 exhibiting more restricted motions. ThT kinetics indicated that Tau35 is more prone to beta‐sheet formation and this was confirmed by CD and TEM analysis. Rapid uptake of aggregated Tau35 and 2N4R tau was observed by both dSH and mouse neurons. Internalised tau accumulates with time. However no significant cell death were observed with dSH.ConclusionOur results demonstrate that Tau35, a fragment associated with human tauopathy, exhibits increased aggregation and rapid uptake into neuronal cells, which likely impacts on tau propagation.
An investigative study to demonstrate the link between combined intake of marijuana and codeine in Alzheimer’s disease pathology
Authors: Memudu Adejoke Elizabeth , Waziri Ruth Joan 
Published: December 2021

AbstractBackgroundAssessment of the contributory role of combined ingestion of codeine and Marijuana to the pathogenesis of Alzheimer’s disease which is the most common cause of dementia among older adults; by studying changes in spatial memory, astrocytic proliferation, Nissl bodies, lipid peroxidation and antioxidant enzyme status.MethodTwenty (20) adult male Wistar rats used for this study were divided into four groups (n=5): the control, codeine, marijuana and a group given both codeine and marijuana. The animals were exposed to the drug treatment for ten (10) days. Behavioral tests for memory using Y maze was conducted. The animals were euthanized and brain tissues fixed in 4% PFA and processed for Cresyl fast Violet stain for Nissl bodies, glial fibrillary acidic protein (GFAP) immunohistochemistry for astrocytes with focus on prefronto‐hippocampus cortex. Serum antioxidant activity of superoxide dismutase (SOD), glucose‐6‐phosphodehydrogenase (G6PDH), Lactate dehydrogenase (LDH) activity and lipid peroxidation enzyme marker –Malondialdehyde (MDA) were accessed.ResultThe prefronto‐hippocampal cortex of rats exposed to Codeine, Marijuana (B and C) and those give both drugs (D) were characterized with loss of neurons, necrosis, chromatolysis and proliferation of astrocytes as compared with the control. However, combined drug use has more severity in the loss of loss of spatial memory, reduced number of arm entries and increased immobility time as compared with the control, codeine and Marijuana only groups. Group D, had severe decline in SOD and G6PDH serum activity and an elevation in lipid peroxidation as compared with B and C.Conclusionthe combine use of codeine and marijuana has more deleterious effects on neuron cell integrity, memory, cognition and antioxidant enzymes because it induces severe oxidative stress that predisposes to the development of Alzheimer’s disease in an individual.
Openness and age influence the progression of mild cognitive impairment
Authors: Merlin Silvia Stahl , de Oliveira Maira Okada , Cassimiro Luciana , Avolio Isabella B , Brucki Sonia Maria Dozzi 
Published: December 2021

AbstractBackgroundThe characterization of risk factors for dementia and protective factors for the maintenance of healthy aging remains a relevant area for research. For this reason, the way people interact with the world around them and, therefore, some psychological and personality characteristics of individuals, seem to determine behavioral patterns that are associated with better health throughout life and, consequently, prevent the progression of early cognitive changes to dementia.MethodOne hundred and two volunteers were evaluated clinically and for personality characteristics and neuropsychological testing. Of these, 25 subjects were classified as cognitively normal (CN), 25 as subjective cognitive decline (SCD), 28 as non‐amnestic mild cognitive impairment (naMCI), and 24 as amnestic mild cognitive impairment (amMCI). Follow‐up occurred over two years from the initial assessment, and participants' cognitive categories were re‐analyzed every six months to observe variation in the same.ResultOf the 102 subjects, 65 remained at follow‐up. The sample followed up longitudinally was composed predominantly of women (65%), white (74%), with a mean age of 78 (±7.5) years and 12 (±4.8) years of education. Throughout the process, 23% of CN, 15% of DCS, and 27% of CCLNA individuals worsened cognitively. In the same period, 15% of the CCLAM and 31% of the CCLNA improved in cognitive ratings. Using the contingency table to study associations of variables, it was observed that older ages present greater cognitive worsening (p=0.05), and that very low or high indices of the personality trait Openness present associations with cognitive worsening (p=0.005). Probably because the Open extremes are a product of the improper functioning of the Standard Mode Network.ConclusionThe factors most associated with cognitive change in this group of elderly were age and the intensity of the Openness aspects of the personality.