bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tactics, teaching and transitioning: Response to the COVID‐19 pandemic in the nursing home sector
Authors: Reda Lillian 
Published: December 2021

AbstractFrom leadership to the front‐line our skilled nursing organization leveraged the expertise of all professionals in our various disciplines. A cohesive aligned approach was implemented to provide support, create and standardize guidance, develop systems, education and policies to conquer challenges being posed by COVID‐19 in our settings. In addition to keeping residents safe from the virus, we as operators needed to establish creative ways to respond to the delivery of quality care, caring for residents, families and staff all while adhering to regulatory compliance and the ongoing pandemic and new challenges posed as we venture into a post pandemic world.
DNA damage in brain may lead to cognitive dysfunctions and reduced longevity in WNIN/Ob obese rats
Authors: Sinha Jitendra Kumar , Ghosh Shampa , Raghunath Manchala 
Published: December 2021

AbstractBackgroundOne of the most common neurodegenerative diseases is Alzheimer’s disease where complex etiological alterations have been observed along with the typical pathology. Specifically, it has been proposed that epigenetic activation of specific genes due to other physiological conditions may also contribute to its pathology.MethodAgeing being one of the strongest risk factor where accumulation of DNA damage is rampant, we evaluated the extent in the brain of 15 months old WNIN/Ob obese rats. Early accumulation of DNA damage in brain can result in devastating genetic instability and wide array of physiological problems. WNIN obese rats have significantly reduced longevity (average lifespan of 15‐18 months). The extent of DNA damage in brain was studied as a hallmark of senescence in order to establish this rat as a model of aging related studies. DNA damage was assessed at the single cell level in neocortex and hippocampus of WNIN obese rats, WNIN lean littermates and normal WNIN controls at 3 and 15 months of age by Comet Assay. The samples were processed for neutral and alkaline electrophoresis, followed by fluorescent staining and analysis.ResultThe extent of DNA damage in the form of single‐strand breaks (SSBs) as well as double‐strand breaks (DSBs) in cells of neocortex and hippocampus of young WNIN obese rats was comparable with those seen in the 15 months old normal WNIN rats. Interestingly the extent of SSBs and DSBs in young WNIN lean littermates and WNIN controls were comparable.ConclusionOnset of significant DNA damage in different brain regions of obese rats at a much younger age is a plausible cause of reduced longevity observed in this novel obese rat model.
TDP‐43 promotes pathological tau phosphorylation and selective neurotoxicity in C. elegans
Authors: Latimer Caitlin S. , Keene C. Dirk , Kraemer Brian C , Liachko Nicole F 
Published: December 2021

AbstractBackgroundTDP‐43‐positive inclusions are present in disease‐affected neurons in over half of patients with Alzheimer’s disease (AD). AD patients with TDP‐43 pathology have worsened clinical outcomes and increased neurodegeneration, but the molecular mechanisms underlying this are unknown.MethodsWe have developed new models of multi‐pathology AD by combining tau and TDP‐43 or tau and Aβ in C. elegans neurons. To characterize these transgenic animals, we measured changes in behavioral outcomes, pathological protein accumulation, and neuron loss. We further tested whether the potent tau modifier sut‐2 influences synergistic neurotoxicity exhibited by tau and TDP‐43 co‐expression.ResultsTDP‐43 promotes tau but not Aβ neurotoxicity, resulting in enhanced uncoordinated locomotion, neuronal dysfunction, pathological protein accumulation, and selective neurodegeneration through aging. Synergism between tau and TDP‐43 is rescued by sut‐2 loss‐of‐function.ConclusionsCharacterizing the relationship between TDP‐43 and tau in vivo is critical to understand and ultimately treat mixed pathology AD. Studies of this novel model of tau and TDP‐43 combined proteotoxicity provide insights into mechanisms underlying tau and TDP‐43 synergistic neurotoxicity. The identification of sut‐2 as a robust modifier of co‐expressed tau and TDP‐43 implicates TDP‐43 as an enhancer of tau toxicity.
Assessing therapeutic potential of PLD1 inhibition in dementia: Systematic assessment of behavior, electrophysiology & mechanisms of synaptic dysfunction using different parameters including sex‐specific differences
Authors: Natarajan Chandramouli , Bourne Krystyn Z , Ramaswamy Karthik , Cook Charles M , Krishnan Balaji 
Published: December 2021

AbstractBackgroundPhosphatidyl choline phospholipase D (PC‐PLD), a lipolytic enzyme that breaks down membrane phospholipids via two isoforms ‐ a constitutively expressed PLD2 and an inducible PLD1 isoform ‐ are also involved in developmentally important signaling mechanisms that regulate synaptic function. We were the first to propose and present a systematic study that established PLD1 as the aberrantly elevated isoform in AD and related dementia using human clinical samples and provided functional proof using mouse models to demonstrate the underlying synaptic dysfunction and memory deficits.MethodsWe used different transgenic rodent models of AD‐like pathology and did a corroborative assessment of behavior, electrophysiology and biochemistry including western blots analysis, Golgi studies and immunofluorescence to assess the efficacy of treatment of the aberrantly elevated PLD1 levels using chronic regimen of a specific small molecule inhibitor.ResultChronic PLD1 inhibition is effective in ameliorating the synaptic dysfunction and associated memory deficits in the treated cohort compared to the age‐matched cohort. We also assessed and report sex‐specific changes in these responses that strengthen our understanding of the underlying mechanisms and brain regions that are targeted by the therapeutic approaches.ConclusionUsing chronic administration of a well‐tolerated halopemide derivative of the specific PLD1 isoform inhibitor in the preclinical mouse models of synaptic dysfunction and memory deficits associated with amyloidogenic effects of Aβ and tau, we demonstrated neuroprotective aspects involving changes in the dendritic spine integrity that contributes to the preservation of memory with an emphasis on the sex‐specific effects.
Autophagy and lysosomal defects in cells expressing disease‐associated tau
Authors: Pollack Saskia J , Dakkak Dina , Guo Tong , Gómez‐Suaga Patricia , Noble Wendy , Hanger Diane P 
Published: December 2021

AbstractBackgroundIntracellular accumulation of insoluble tau is an important hallmark of Alzheimer’s disease (AD) and related tauopathies. We have previously identified in human tauopathy brain a truncated tau species (Tau35), comprising the C‐terminal half with four microtubule‐binding repeats. Minimal Tau35 expression in transgenic mice results in a progressive tauopathy phenotype including tau phosphorylation and aggregation, cognitive and behavioural abnormalities and impaired protein clearance. The autophagy‐lysosomal pathway (ALP) plays a crucial role in the clearance of protein aggregates and defects in ALP are associated with the pathogenesis of AD. We sought to explore the effect of Tau35 expression on the ALP and whether autophagy is disrupted due to lysosomal dysfunction.MethodChinese hamster ovary (CHO) cells stably expressing Tau35 (CHO‐Tau35) or full‐length human 2N4R tau (CHO‐FL) were generated. Primary cortical neurons from Tau35 transgenic and wild‐type mice were cultured for 14 days in vitro(DIV) and brain homogenates were prepared from mice aged 4 and 12 months. The effect of Tau35 on the ALP was examined using immunofluorescence and western blots.ResultNuclear translocation of transcription factor EB (TFEB), a key mediator of lysosomal biogenesis, was significantly reduced in both CHO‐FL and CHO‐Tau35 cells. However, only CHO‐Tau35 cells exhibited disrupted mammalian target of rapamycin complex 1 (mTORC1) activity and autophagic flux. Expression of ALP markers, including LC3‐I/II, LAMP1, LAMP2 and cathepsin D, were also reduced in CHO‐Tau35 cells.ConclusionOur findings suggest that N‐terminally cleaved tau damages both lysosomal clearance of cellular proteins and lysosomal biogenesis. The Tau35‐expressing cultured neurons will provide a useful tool to explore molecular mechanisms underlying tau‐induced lysosomal dysfunction, which may lead to the identification of novel therapeutic targets for dementia.
Therapeutic investigation of alpha napthoflavone in the intracerebroventricular injection of L‐cysteine induced vascular dementia in rats
Authors: Rishitha Narahari , Muthuraman Arunachalam 
Published: December 2021

AbstractBackgroundAlpha napthoflavone (ANF) is a flavonoid compound it is also know as Alpha‐ 7,8‐benzoflavone, it is a natural flavone available in Russian knapweed in larger quantity. Pharmacologically, it is also reported to produce the cardioprotection, neuroprotection including anti‐Alzheimer actions. It possesses multiple cellular actions like anti‐oxidant, anti‐inflammatory, and anti‐apoptotic actions. However, the role of ANF in vascular dementia (VaD) not explored yet.MethodVaD was induced by i.c.v. injection of L‐Cys in rats. The test compounds i.e., ANF (40 and 80 mg/kg; p.o.) and reference drug i.e., donepezil (10 mg/kg; p.o.) were administered for 5 consecutive days. The behavioral assessment i.e., learning and memory functions were evaluated by Morris water maze (MWM) test. In addition, the biochemical markers i.e., acetylcholinesterase (AChE) activity; lipid peroxidation (LPO) and homocysteine (HCy) levels were estimated in hippocampal tissue samplesResultANF shown ameliorative effect against i.c.v. injection of L‐Cys induced VaD in rats via reduction of AChE activity, LPO and HCy levelsConclusionANF may be a newer candidate from herbal origin for the management of cerebrovascular disorders like stroke and vascular dementia.
Regional abdominal adiposity and related factors are associated with brain volumes and cognitive functioning in middle‐aged adults at high AD‐risk
Authors: Golan Sapir , Boccara Ethel , Ravona‐Springer Ramit , Inbar Yael , Livny Abigail , Yore Iscka , Heymann Anthony , Beeri Michal Schnaider 
Published: December 2021

AbstractBackgroundAlzheimer’s dementia (AD) is one of the most challenging diseases, affecting individuals, their families, and society. There is evidence for the involvement of midlife obesity (measured by BMI) in mild cognitive impairment (MCI), dementia, and AD risk in late life. Regional abdominal adiposity has been related to metabolic syndrome and inflammation, both consistently linked to cognitive impairment and neuropathology of AD. The accelerating prevalence of obesity and dementia in our aging population further amplifies the potential public health impact of the proposed investigation.MethodThe Israel Registry for Alzheimer’s Prevention (IRAP) (N=500), which aims to examine the connection between longevity and dementia, was capitalized. Newly collected data ‐ regional abdominal adiposity (abdominal (AAT) visceral (VAT), subcutaneous (SAT), pancreatic, and hepatic adipose tissue) by MRI (N=92), and adiposity‐related factors of visceral fat (TNF‐α, Leptin), pancreases (PP, PYY), and liver (PAI‐1, Fetuin) via serum (N=26).ResultHigh pancreatic fat percentage was associated with lower hippocampal and IFG volumes, and lower executive memory function. High hepatic fat percentage was associated with lower hippocampal volume and lower executive memory function. High VAT percentage was associated with lower amygdalar and hippocampal volumes, while high VAT volume was associated with lower cognitive functioning (executive and working memory, language, and global cognition). Serum levels of PP, PAI‐1, and Fetuin were negatively associated with para‐hippocampal and IFG volumes. Serum levels of Leptin were associated with amygdala and hippocampal volumes. High levels of PYY, PAI‐1, and TNF‐α were associated with lower executive memory function.ConclusionGreater regional abdominal adiposity and related secreted factors are associated with poorer cognitive functions and lower volumes of cognition and BMI‐related brain regions, already in midlife in asymptomatic individuals enriched for AD risk, regardless of global body adiposity measured by BMI. These results strongly support our overall hypothesis that specific fat deposits in specific tissues and organs are differentially associated with cerebrovascular and AD‐related neuropathology and cognition, advancing the field to new potential mechanistic pathways underlying the adipose tissue‐brain link.
Learning deficits occurs prior to memory retrieval impairment in female Senescence Accelerated Mouse (SAMP8)
Authors: Sun Jiaqi , Mamo John CL , Takechi Ryu , Owada Yuji , Nicolazzo Joseph , Pan Yijun 
Published: December 2021

AbstractBackgroundThe most regularly used mouse models of Alzheimer's disease in drug development include APP/PS1, 3xTg, and 5xFAD mice. This is a limitation as all these mice represent familial AD. Given sporadic AD accounts for the majority of the AD cases in human, there is an unmet need to validate potential rodent models to better represent sporadic AD. SAMP8 is a naturally‐occurring mouse line that displays many characteristics identified in Alzheimer’s disease (AD) patients, such as learning and memory deficits, and accumulation of beta‐amyloid. In people with preclinical AD, deficits in learning manifest faster than decline in memory retrieval. It is unclear if SAMP8 mice also exhibit this feature, and therefore the current study aims to determine if this feature can be observed in SAMP8, to support the use of SAMP8 as a mouse model of sporadic AD for drug development.MethodThe cognitive function of SAMP8 mice and their age‐matched non‐AD control SAMR1 mice (at various ages) were assessed using Y maze spatial memory test, with 3‐10 min training duration and 1.5‐3 h interval between training and testing session.ResultAt 3‐4 months old, SAMP8 but not SAMR1 failed to differentiate the novel arm from familiar arm in a standard Y maze test (3 min training, 3 h interval). When training time was increased to 10 min, SAMP8 passed the test, while increased training time did not affect the performance of SAMR1 mice. These data indicated that longer training time is required by SAMP8 than SAMR1 to achieve the expected performance, suggesting the presence of learning deficits in SAMP8. Interestingly, at 6‐7 months old, though both SAMP8 and SAMR1 received 10‐min training, only SAMR1 passed the test. The performance of SAMP8 mice was successfully improved by shortening the interval between training and testing (from 3 h to 1.5 hr). These data indicate a deteriorated memory retention capability and a possible impairment in memory retrieval in SAMP8.ConclusionOverall, this study has provided supportive evidence that learning deficits occurs prior to memory retrieval impairment in SAMP8, and the use of SAMP8 as mouse model for AD.
In silico screening of existing FDA approved drugs for spermine synthase inhibition as a therapeutic approach in Alzheimer’s disease
Authors: Wilson Joel , Nampoothiri Madhavan , Satarker Sairaj 
Published: December 2021

AbstractBackgroundAutophagy dysfunction may lead to amyloid‐β (Aβ) secretion and directly influence the accumulation of intracellular Aβ and generation of extracellular Aβ plaque. Natural polyamine, spermidine present in all living organisms, is critically involved in cellular homeostasis maintenance and influences many biological processes, namely cell growth and proliferation, DNA and RNA stabilization, tissue regeneration, regulation of translation, and enzymatic modulation. Brain spermidine/polyamine levels decrease during aging and various neurodegenerative disorders leading to impairment in autophagy. Spermine synthase is an enzyme involved in biosynthesis of polyamines. It catalyzes the formation of spermine from spermidine. Thus, we focused to repurpose USFDA approved drugs to inhibit spermine synthase which may increase the spermidine levels in the brain.MethodSchrodinger Suite's Maestro graphical user interface was used to carry out computational simulation experiments. Spermidine structure and US‐FDA licensed molecules compounds were downloaded. The molecules were configured using LigPrep tool in maestro software of Schrodinger. Spermine synthase structure (3C6K) bound to 5‐methylthioadenosine (MTA) was downloaded from Protein Data Bank (PDB). After the protein was minimized, the 2D interaction of the ligand‐protein interaction was conducted to observe the amino acid interactions. Spermidine and USFDA licensed molecules were docked using the Schrodinger Glide module. In the present study, the MMGBSA tool is utilized to calculate the prediction of the top compounds. The MD simulation was performed on Schrodinger's Desmond module.ResultFor increasing spermidine pool in the brain by inhibiting spermine synthase, Ribavirin, Sapropterin and Theobromine were found to cross the BBB and have good inhibitory interactions with the enzyme in an in‐silico system. RMSD values for all these three drugs were not satisfactory, but other parameters like protein‐ligand contact‐interaction fraction, 2D interaction diagram and protein‐Ligand contacts through different amino acids present in 3C6K showed satisfactory results.ConclusionOur study showed that ribavirin, sapropterin and theobromine were able to show inhibitory interactions with the spermine synthase. Further, in vitro and in vivo studies may be done to search for the ability of these molecules in the treatment of cognitive dysfunction.
Functional study in the young rTg4510 mouse model of tauopathy
Authors: Mondragón‐Rodríguez Siddhartha , Cueva‐Xolalpa Lorena , García‐Carlos Carlos , Villaseñor‐Zepeda Rocío , Orta‐Salazar Erika , Díaz‐Cintra Sofia , Peña‐Ortega Fernando , Perry George 
Published: December 2021

AbstractBackgroundTau hyperphosphorylation (pTau) is considered a key pathogenic event in the development of tauopathies. Nevertheless, we recently demonstrated that at the very early disease stage, pTau promotes neuroprotection by preventing seizure‐like activity.MethodTo further support the notion that very early pTau is not detrimental, the present work evaluated the young rTg4510 mouse model of tauopathy as a case study. Thus, in mice at one month of age (p30‐35), we studied the increase of pTau within the hippocampal area as well as hippocampal and locomotor function.ResultOur results showed that the very young rTg4510 model has no detectable changes in hippocampal dependent tasks, such as spontaneous alternation and nesting, or in locomotor activity. However, at this very early stage the hippocampal neurons from p30‐35 rTg4510 mice accumulate pTau protein and exhibit changes in hippocampal oscillatory activity. Moreover, we found an increased number of dendrites per cell in granule neurons.ConclusionAltogether, this study provides new insights into the early pathogenesis of tauopathies and provides further evidence that pTau remodels hippocampal function and morphology.
Role of endothelial TRPA1 expression in blood‐brain barrier dysfunction
Authors: Yang Euitaek , Kaddoumi Amal 
Published: December 2021

AbstractBackgroundTransient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel receptor that regulate calcium homeostasis among other cations. Calcium dyshomeostasis known to disrupt the blood‐brain barrier (BBB). In the brains of Alzheimer's disease (AD) transgenic mice, increased levels of TRPA1 was associated with increased levels of amyloid‐β (Aβ) and neuroinflammation. TRPA1 expressed in the endothelial cells of the BBB. The objective of this work is to investigate the effect of BBB‐endothelium TRPA1 activation on the BBB tightness and function.MethodWe performed in vitro and in vivo studies, Western blot, calcium assay, immunostaining.ResultWe performed in vitro studies using the mouse brain endothelial cell line bEnd3. First, we determined the expression of TRPA1 in bEnd3 by western blot and immunocytochemistry. Results confirmed TRPA1 expression in bEnd3. In addition, TRPA1 function was evaluated by monitoring calcium influx; the addition of the TRPA1 antagonist A‐967079 significantly reduced calcium influx in bEnd3, while the addition of Aβ42 oligomers to the cells increased intracellular calcium levels, which was blocked by the co‐addition of the TRPA1 antagonist suggesting that Aβ induces calcium influx via TRPA1. When tested in vivo in 5XFAD mouse model for AD by western blot, we found that TRPA1 levels were significantly higher in brain homogenates when compared to wild‐type (WT) mouse brains. Furthermore, the cerebrovascular levels of TRPA1 were significantly higher in 5XFAD compared to WT, which were also associated with BBB disruption as determined by increased IgG extravasation.ConclusionOur data suggests that endothelium‐TRPA1 could contribute to BBB disruption by increasing calcium influx.
Dynamics between Neuropsychiatric Symptoms and Biomarkers: A Pilot Study
Authors: Chiu Wei‐Hsuan , Goh Anita M Y , Velakoulis Dennis , Loi Samantha M 
Published: December 2021

AbstractBackgroundThe aetiology of neuropsychiatric symptoms (NPS) in dementia remains unclear, and currently, it is challenging to distinguish neuropsychiatric manifestations related to younger‐onset neurodegenerative diseases from those of primary psychiatric disorders. Neurofilament light chain (NfL) is a promising biomarker for axonal injury and has been found to differentiate between neurodegenerative diseases and primary psychiatric disorders. The aim was to investigate cerebrospinal fluid (CSF) NfL and its relationship with NPS and compare it with traditional biomarkers, namely Aβ and tau.MethodsRetrospective data for 54 patients with younger‐onset dementia was collated (mean age ± SD, 57.9 ± 7.1, females n = 15 [28%], co‐morbid psychiatric diagnoses n = 17 [31%]). Of these, 23 had Alzheimer’s disease (AD), 14 had frontotemporal dementia (FTD), 9 had mild cognitive impairment (MCI), and 8 were diagnosed with other types of dementia. Neuropsychiatric measures were extracted from the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), the Depression Anxiety and Stress Scale 21 (DASS‐21), and the revised Cambridge Behavioural Inventory (CBI‐R). CSF biomarkers included NfL, Ab‐42, p‐tau and t‐tau.ResultsNo significant associations between NPS and NfL was seen in patients with AD, FTD, MCI or other diagnoses. In the combined cohort, a positive correlation was found between the overall cognitive functioning and Ab‐42 levels (r = 0.47, p = 0.01), and visuoconstruction, a specific domain of cognitive functioning, was found to be positively correlated with Ab‐42 levels (r = 0.44, p = 0.03) and negatively correlated with t‐tau levels (r = ‐0.43, p = 0.03). In FTD, a positive correlation was found between stress and p‐tau levels (n = 8, r = 0.89, p = 0.04), and this correlation was stronger in patients without co‐morbid psychiatric diagnoses (n = 7, r = 0.93, p = 0.03).ConclusionThe results suggest that levels of CSF biomarkers, especially Ab‐42, are linked to deficits in cognitive functioning in patients with younger‐onset dementia, and levels of p‐tau are strongly related to stress particularly in the absence of co‐morbid psychiatric diagnoses. Therefore, these biomarkers may assist in the identification of patients who are at an increased risk of developing cognitive impairment and stress.