bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial phenotypes in iPSC AD models
Authors: Flannagan Kaitlin , Stopperan Julia A. , Troutwine Benjamin M , Lysaker Colton R , Strope Taylor , Draper Julia , Shaddy‐Gouvion Cynthia , Vivian Jay , Haeri Mohammad , Wilkins Heather M 
Published: December 2021

AbstractBackgroundMitochondrial dysfunction is observed in Alzheimer’s disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. Postmortem brain tissue was used as a comparison.MethodiPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer’s Disease Research Center (KU ADRC) cohort or purchased from WiCell. Postmortem brain samples were from the KU ADRC cohort when available. A total of four non‐demented and four sporadic AD iPSC lines were examined. Postmortem brain tissue was derived from 9 ND and 12 AD subjects. iPSCs were differentiated into neurons, astrocytes, or cerebral organoids using StemCell Technologies protocols and reagents. iPSC derived models and postmortem brain tissue were subjected to mitochondrial respiration analysis using Seahorse XF technology and spectrophotometric COX Vmax assays. iPSC derived neurons and astrocytes underwent fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, and mitophagy levels.ResultiPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects. These results were not observed in astrocytes. Postmortem human brain samples showed reduced COX Vmax in AD subjects. iPSC derived neurons had reduced mitochondrial respiration parameters, mitochondrial mass, mitophagy, mitochondrial membrane potential, and mitochondrial superoxide production. iPSC derived astrocytes had reduced mitochondrial respiration parameters but increased mitochondrial membrane potential and no change in mitochondrial superoxide production.ConclusioniPSC derived models from AD subjects show mitochondrial dysfunction phenotypes like what is observed in postmortem brain. As iPSCs do not maintain their epigenetic signatures after reprogramming the observed phenotypes are likely due to other somatic factors.
Praxis deficits in patients with Parkinson’s disease
Authors: Rounis Elisabeth 
Published: December 2021

AbstractBackgroundLimb apraxia has been described in several neurological disorders including Parkinson’s disease (Leiguarda and Marsden, 2000) and may predict progression to Alzheimer’s dementia in patients with mild cognitive impairment. Our aim was to study presence of apraxia and subtypes of deficits in patients with idiopathic Parkinson’s Disease.Method20 patients with idiopathic Parkinson’s disease, recruited from the Oxford Parkinson’s Disease Centre, were tested for presence of limb apraxia, measured on a battery of tasks, comparing their performance to deficits measured using the UPDRS, and independent measures of cognition (MOCA), and dexterity. Results were analysed using Pearson’s correlations, with correction for multiple comparisonsResultDetailed neuropsychological testing revealed significant deficits in praxis with 9 out of 20 patients displaying significant ideomotor deficits on finger and hand imitation, 2 patients showing ideational deficits on pantomime of tool use. Most patients made errors in the praxis tasks even though they did not qualify as apraxic per se, with only one patient performing faultlessly at all the screening tasks.Both ideational and ideomotor deficits correlated with Part 3 of the UPDRS score. Similarly, Part 3 of the UPDRS correlated with cognitive performance on the MOCA. Ideomotor deficits also correlated with deficits in dexterity and response inhibition. Whereas deficits in dexterity correlated with PD severity; praxis and cognitive deficits did not.ConclusionThe study shows different deficits in limb praxis assessed using batteries of tasks in patients with Parkinson’s disease. We identified relationships between praxis deficits and cognitive as well as motor performance in PD patients. Testing for apraxia in PD patients might provide a useful way for stratifying patients’ impairments, progression to PD dementia and response to treatment.
Investigating auditory electrophysiological measures of participants with mild cognitive impairment and Alzheimer’s disease: A systematic review and meta‐analysis of event‐related potential studies
Authors: Tarawneh Hadeel Y. , Mulders Wilhelmina H.A.M , Sohrabi Hamid R , Martins Ralph N , Jayakody Dona M P 
Published: December 2021

AbstractBackgroundObjectively measuring auditory functions has been proposed as an avenue in differentiating normal age‐related cognitive dysfunction from Alzheimer’s disease (AD) and its prodromal states. Previous research has suggested auditory event‐related potentials (AERPs) to be non‐invasive, cost‐ effective and efficient biomarkers for the diagnosis of AD. The objective of this paper is to review the published literature on AERPs measures in older adults diagnosed with AD and those at higher risk of developing AD, i.e., mild cognitive impairment (MCI) and subjective cognitive decline (SCD).MethodThe search was performed on six major electronic databases (Ovid MEDLINE, OVID EMBASE, PsycINFO, PubMed, Scopus and CINAHL Plus). Articles identified prior to 7th May 2019 were considered for this review. A random effects meta‐analysis and analysis of between study heterogeneity was conducted using the Comprehensive Meta‐Analysis software.ResultThe search identified 1076 articles; 74 articles met the full inclusion criteria and were included in the systematic review, and 47 articles were included into the analyses. Pooled analysis suggests that AD participants can be differentiated from controls due to significant delays in ABR, N100, P200, N200 and P300 latencies. P300 amplitude was significantly smaller in AD participants compared to controls. P300 latencies differed significantly between MCI participants and controls based on the pooled analysis.ConclusionThe findings of this review indicate that some AERPs may be valuable biomarkers of AD. In conjunction with currently available clinical and neuropsychological assessments, AERPs can aid in screening and diagnosis of prodromal AD.
Drug repurposing strategy for treating Alzheimer’s disease
Authors: Das Anik Kumar Kumar , Sharma Divya , Sharma Lalit 
Published: December 2021

AbstractBackgroundAlzheimer’s disease with a long preclinical period of ∼20 years is a chronic, insidious, and progressive neurodegenerative disease of old age. Neuropathologically AD is characterized by the presence of accumulated Amyloid‐beta in plaques (in extracellular spaces, and walls of blood vessels) and aggregated tau protein in neurofibrillary tangles. Drug repurposing is the search for new indications or molecular targets distinct from a drug’s acknowledged activity, pharmacological effect or binding specificities. With the ever‐increasing rates of termination of drugs in clinical trials, drug repositioning has risen as one of the effective solutions against the risk of drug failures.MethodA comprehensive literature search was performed in the Pub Med/Science direct/Google scholar/Plos one databases and connected papers to review relevant articles in English, using keywords ‘‘Drug repurposing and neurological disorder, drug repurposing and dementia, drug repurposing and Alzheimer 'disease. The research papers were scrutinized and studied thoroughly.ResultAccording to literature it has been found that some repurposed drugs i.e, Allopurinol, Bromocriptine, Bupropion, Raloxifene, Thalidomide, Zidovudine may have a potential to treat Alzheimer’s disease.ConclusionThe repurposing drug approach may be used to treat Alzheimer’s and these drugs are needed to studied further.
Exploring NSAIDs as anti‐amyloidal agents: A drug repurposing approach to treat Alzheimer’s disease
Authors: Sharma Palvi , Sharma Divya , Sharma Lalit 
Published: December 2021

AbstractBackgroundAlzheimer is a severe, stealthy and progressive neurodegenerative disease. Maximum number of cases are arises after the age of 65 ie. called Late Onset of Alzheimer Disease. AD is characterised by the neuronal cell dysfunctioning / death, shrinkage of brain tissue and progressive cognitive, motor, behavioural impairment. Literature suggest that NSAIDs are able to alter the conformation of Aβ peptides exerting anti‐aggregation activity and induce the expression of amyloid‐binding proteins, e.g., transthyretin, that play an important role in sequestering Aβ peptides and preventing their aggregation.MethodIn‐silico studies are totally based on the computational work, leads to counting receptor and ligand preparation, docking simulations, grid formation and its analysis followed with in‐vitro investigation via Thioflavin T‐amyloid binding assay and protease (Trypsin) digestion assay.ResultThe computational approach provided us naproxen with higher estimated free energy of binding. The drug has the property to traverse the blood brain barrier and hence, it might have the possibility of curing or treating the Alzheimer’s through altering the conformation of Aβ peptides and exerting anti‐aggregation activity.ConclusionNASAIDs may alter the conformation of amyloid beta and exerts anti‐aggregation activity by inducing the expression of amyloid binding proteins.
7T imaging in progressive supranuclear palsy and behavioural variant frontotemporal dementia
Authors: Naessens Michelle , Cope Thomas E , Murley Alexander G , Malpetti Maura , Rua Catarina , Hughes Laura E , Perry Alistair , Ye Rong , Rodgers Chris T , Jones P Simon , Rowe James B 
Published: December 2021

AbstractBackgroundProgressive supranuclear palsy (PSP) and behavioural variant frontotemporal dementia (bvFTD) are clinical syndromes associated with frontotemporal lobar degeneration (FTLD). Although distinct diseases, they have in common cognitive and behavioural changes, including personality, motivation and executive function. This phenotypic overlap between bvFTD and PSP is reflected in the MDS‐2017 criteria for the PSP‐F subtype (Höglinger et al., 2017), and frequent parkinsonism seen in bvFTD (Rowe, 2019). This study uses ultra‐high field MRI to identify the atrophy patterns in bvFTD and PSP, complementing neurochemical insights from spectroscopy (Murley, 2020).Method23 Healthy controls, 23 people with probable PSP, and 16 people with bvFTD underwent structural imaging with MP2RAGE sequence (0.7mm isotropic resolution) at ultra‐high field (7T) on a MAGNETOM Siemens TERRA scanner. Clinical and cognitive assessment was undertaken contemporary with imaging. Grey and white matter volumes were compared between groups using independent two‐sample t‐tests, including age and total intracranial volume as covariates of no interest. Significant effects were identified using cluster‐level statistics (p<0.05, family‐wise error corrected for multiple comparisons) above a height threshold of p<0.001 (uncorrected).ResultCompared to controls, both patients with PSP and bvFTD show significant atrophy of the cingulate gyrus, frontal gyri, and the supplementary motor cortex with the parietal and especially occipital lobe being spared (p <0.05, FWE). Patients with PSP show additional white matter atrophy of the brainstem and basal ganglia (p <0.05, FWE). Compared to PSP, patients with bvFTD show more grey matter atrophy in the inferior frontal gyrus, inferior temporal gyrus, temporal pole, as well as the right insula. Patients with PSP show more white matter atrophy of the basal ganglia, brain stem, and superior cerebellum compared to those with bvFTD (p<0.001, uncorrected).ConclusionThis is the first voxel‐based morphometry study comparing bvFTD and PSP at ultra‐high field, with higher resolution imaging than previous studies at 1.5T or 3.T. Although both classified as syndromes associated with FTLD, patients with bvFTD and PSP show both specific and complementary patterns of atrophy compared to those of healthy controls and each other.
Memory impairments and synaptic deficits in Tg19959 and APP/PS1 AD model mice are alleviated by eEF2K inhibitor A‐484954
Authors: Kasica Nicole P , Zhou Xueyan , Yang Wenzhong , Ma Tao 
Published: December 2021

AbstractBackgroundMounting evidence indicates synaptic failure as an early and key event in Alzheimer’s Disease (AD) pathophysiology. Maintenance of long‐term memory and synaptic plasticity requires de novo protein synthesis. Phosphorylation of mRNA translation factor eukaryotic elongation factor 2 (eEF2) by its kinase eEF2K results in inhibition of general protein synthesis. Previous studies have shown elevated levels of eEF2 phosphorylation in post mortem AD human brain tissue and in AD mouse models. Here, we investigated whether suppression of eEF2 phosphorylation via eEF2K inhibitor A‐484954 can alleviate AD‐associated synaptic failure and memory impairments.MethodAged Tg19959 mice (6‐9 months), APP/PS1 (12‐16 months) and age‐matched controls were treated with a subcutaneous pellet containing A‐484954 or vehicle. The pellet continuously releases treatment over 30 days. Starting two weeks after pellet placement, the mice underwent cognitive assessment via the Novel Object Recognition (NOR) and Morris Water Maze (MWM) tasks. Golgi‐Cox Stain, Amyloid Beta immunohistochemistry, Western blots, SUnSET Assays, mass spectrometry (MS) proteomic analysis, and transmission electron microscopy (TEM) were also performed.ResultWe found that cognitive impairments displayed in aged Tg19959 and APP/PS1 mice were alleviated with treatment of A‐484954. Brain tissue from these mice also underwent high performance liquid chromatography (HPLC) to assess drug concentration in the brain. In addition, Golgi‐Cox stain was done to assess dendritic spine density and morphology. Spine analysis indicates a rescue in levels of mature spines in the CA1 region of the hippocampus in APP/PS1 mice treated with A‐484954. TEM analysis indicated a rescue in dendritic polyribosome assembly, post‐synaptic density (PSD) formation, and PSD length. Additionally, SUnSET assays revealed a rescue in translational capacity in the hippocampi of AD mice treated with A‐484954.ConclusionTaken together, our results suggest that treatment with a eEF2K inhibitor, A‐484954, alleviates cognitive impairments, restores synaptic morphology, and rescues translational capacity in mouse models of AD.
Alzheimer’s disease: A potential diabetes type 3
Authors: González Andrea , Camila Calfio , Maccioni Ricardo Benjamin 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly. Neuronal death and synaptic dysfunctions are considered the main hallmarks of this disease. The latter could be directly associated to an impaired metabolism. In particular, glucose metabolism dysregulation has demonstrated to be a key regulatory element in the onset and progression of AD, which is why nowadays AD is considered the type 3 diabetes.MethodsWithin this revised topic, we provide an analysis regarding the influence of glucose metabolism in AD from three different perspectives: i) As a regulator of the energy source, ii) through several metabolic alterations, such as insulin resistance, that modify peripheral signaling pathways that influence the activation of the immune system (e.g., insulin resistance, diabetes, etc.) and iii) as modulators of various key post‐translational modifications for protein aggregation.ResultsDuring our research, it was demonstrated the relationship between glucose metabolism dysregulation and the onset and Alzheimer’s disease: The latter is mediated by several metabolic alterations. Among those, included in our research, are metabolic dysregulation events (e.g insulin resistance), which in turn alters the proper ATP generation, and finally, post‐translational modifications, e.g., glycosylation and phosphorylation that mediates protein aggregation (i.e tau hyperphosphorylation that leads to misfolding and pathological self‐assembly).ConclusionsAlzheimer’s disease onset and development is related to a glucose metabolism impairment that affects energy source (ATP) regulation, several metabolic alterations such as insulin resistance, and mediator of post‐translational modifications in key proteins (i.e tau) that promotes its self‐assembly and aggregation. Thus, considering all the above mentioned, is it seems plausible to consider Alzheimer as the diabetes type 3.
Characterization of novel neuropeptide proteolytic processing involved in dementia pathophysiology
Authors: Ethier Elizabeth C. , Quinn James P. , Kandigian Savannah E. , Trombetta Bianca A. , Arnold Steven E. , Carlyle Becky C. 
Published: December 2021

AbstractBackgroundNeuropeptides are neurotransmitter‐like molecules with multiple roles in neuronal activity that are processed into functional peptides (aka proteoforms) by prohormone convertases and other currently unidentified proteases. Both neuropeptides and their proteoforms are implicated in the pathogenesis of different forms of dementia. The neuropeptide VGF is decreased in the cerebrospinal fluid (CSF) and brain of patients with Alzheimer’s disease (AD) and other forms of dementia. VGF356‐375 and VGF1‐40 decrease in the CSF of patients with AD and frontotemporal dementia (FTD), respectively, compared to healthy age‐matched controls. Although many such neuropeptide proteoforms are thought to be involved in dementia, current research has focused on the neuropeptides themselves, leaving the proteoforms and their physiological processing pathways understudied and their contribution to dementia pathogenesis unclear.MethodUsing recombinant proteolysis assays, we aimed to investigate the proteolytic processing of several neuropeptides involved in dementia. Neuropeptides of interest were identified by mass spectrometry analysis of pooled CSF samples obtained from five AD patients and five healthy controls. Proteasix, the MEROPS, and the human protein atlas databases were used to identify novel neuronally‐expressed proteases that may cleave these identified neuropeptides; proteases of interest were selected based on the predicted probability of cleavage. Recombinant protein assays and immunoblots with neuropeptide‐specific antibodies were used to investigate the ability of these proteases to cleave the neuropeptides, and banding patterns were confirmed in triplicate.ResultTwenty‐two neuronally expressed proteases previously linked to dementia were identified that may cleave the neuropeptides chromogranin A (CHGA), secretogranin‐1 (SCG1), secretogranin‐2 (SCG2), secretogranin‐3 (SCG3), and VGF. The proteases a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS4), calpain‐1 (CAPN1), cathepsin S (CTSS), granzyme A (GZMA), and matrix metalloprotease‐3 (MMP‐3) displayed high probability for neuropeptide proteolysis. These proteases cleaved the neuropeptides into N‐terminal, mid‐region, or C‐terminal neuropeptide proteoforms, and all neuropeptide‐protease combinations except the SCG3‐CAPN1 pair demonstrated cleavage.ConclusionOverall, this work provides mechanistic insight into neuropeptide processing and expands our understanding of neuropeptide proteoform involvement in dementia. Future projects aim to confirm and expand upon these results using mass‐spectrometry, cell culture systems, and CSF and brain protein analysis.
Hypothiocyanous acid oxidizes collapsin response mediator protein 2 in brain pericytes
Authors: van Leeuwen Eveline 
Published: December 2021

AbstractBackgroundPericytes cover brain endothelium to enable maintenance of the blood‐brain barrier (BBB). Decreasing pericyte numbers are reported in Alzheimer’s disease and could lead to BBB dysfunction, triggering vascular inflammation and the recruitment of immune cells. Neutrophils contain high contents of myeloperoxidase, a heme enzyme that produces several oxidising species, including hypothiocyanous acid (HOSCN). HOSCN specifically targets cysteine residues in proteins and low molecular weight thiols, and is more stable than other oxidants in biological systems. A microtubule stabilising protein, collapsin response mediator protein 2 (CRMP2), is oxidised by hydrogen peroxide (H2O2) in some cell types, purportedly through a peroxiredoxin (Prx) relay mechanism. Here, we have tested whether HOSCN can oxidise CRMP2 and lead to disruption of microtubules (MT) in pericytes.MethodMurine pericytes were harvested and cultured, then treated with sub‐lethal concentrations of HOSCN and H2O2. Western blotting was used to observe CRMP2 and Prx oxidation, along with CRMP2 phosphorylation at sites important for MT binding. Fluorescent staining, live‐cell imaging and in vitro scratch assays were used to view cytoskeleton alterations and pericyte migration. Immunoprecipitation and proximity ligation assays were used to investigate physical associations between CRMP2 and Prxs.ResultTreatment of pericytes with HOSCN led to maximal CRMP2 oxidation after 60 min, whereas H2O2 reaches this in 5 min. Oxidation was closely associated with pericyte shrinkage, less growing microtubules and lower pericyte cell migration. CRMP2 oxidation occurred at the same time as Prx2 oxidation, and there was a physical association between these proteins, but it is not possible to conclude a redox relay occurs.ConclusionWe hypothesized that the longer‐lived oxidant HOSCN could oxidize CRMP2 and impair pericyte function at sub‐lethal doses. Indeed, HOSCN led to less dynamic MTs and subsequent lower migration of pericytes, likely lowering their ability to cover empty area on the inflamed vasculature to protect endothelial function. This effect is reversible upon HOSCN removal, nevertheless HOSCN could be a cause of BBB disruption during neuroinflammation. The mechanisms of CRMP2 oxidation are currently being investigated. Strategies that protect this MT regulatory protein from oxidation could have therapeutic benefit in neurological disease.
Alterations in dendritic GABAB receptor expression in an Alzheimer’s disease mouse model
Authors: McArdle Colin J , Niere Farr , Uneri Ayse , Raab‐Graham Kimberly F 
Published: December 2021

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by memory deficits and cognitive decline. Major hallmarks that occur during early stages of disease progression include amyloid beta plaque, neurofibrillary tangles, and synaptic loss. The mechanisms that particularly govern synaptic loss, however, remain under investigation. Local, dendritic mRNA translation is critical in maintaining proper synaptic architecture as well as engagement with presynaptic terminals. A master regulator of this process is controlled by mammalian target of rapamycin complex 1 (mTORC1), whose activity has shown to be significantly increased in AD patients as well as respective animal models. Increases in mTORC1 activity have consequently shown to upregulate the translation of various downstream synaptic proteins, one of those being GABAB receptors (Niere, 2016). Metabotropic, GABAB receptors are critical in maintaining slow, sustained inhibition throughout the central nervous system. However, their significance towards synaptic function is understudied in the context of AD.MethodsOur study utilized immunocytochemistry and microscopy to determine changes in GABAB1 receptor subunit expression in hippocampal dissociated neurons. Additionally, APP/PS1 transgenic mice were used as our model for AD.ResultsImmunocytochemical results indicate approximately a 22% increase in dendritic GABAB1 subunit expression in AD mice as compared to wildtypes (p<0.01).ConclusionsThe data indicates increases in GABAB1 receptor subunits in AD while highlighting a potential avenue in which transsynaptic signaling is disrupted in early stages of AD.