bluuebunny/crossref_metadata_2025_split huggingface dataset:
Gelsolin Amyloidosis: aggregation propensities of wild and mutant peptides and their inhibition
Authors: Arias Carlos Quintero , Martic Sanela 
Published: December 2021

AbstractBackgroundGelsolin is an actin‐binding protein responsible for the remodeling of the actin cytoskeleton. Gelsolin Amyloidosis, the formation of misassembled protein into insoluble amyloid fibril aggregates, is the result of point mutations that promote aberrant proteolytic cleavage. Amyloidosis can be instigated and spread by existing amyloid fibrils through the process of seeding, where existing fibrils promote the formation of new fibrils. Gelsolin fragments are prone to aggregation and systematic deposition into organs including peripheral/cranial nerves, skin, eyes, and kidneys. The D187Y mutation has been identified to promote cleavage of Gelsolin, although studies have demonstrated the mutant’s elusive aggregation propensity.MethodMutant Gelsolin peptide aggregation was monitored and characterized in vitro using various spectroscopic methods, Thioflavin T (ThT), turbidity, and Dynamic Light Scattering (DLS). Transmission electron microscopy (TEM) allowed for the identification and visualization of β‐sheet formation within aggregatesResultWe reported that CFILDL‐containing peptides were prone to aggregation, which may be inhibited by using small molecules. Of note is the unique behaviour of peptide mutants with respect to their aggregation propensities pointing to their biological relevance. Preliminary results suggest that seeding may induce peptide aggregationConclusionSince other neurodegenerative proteinopathies (Alzheimer’s & Parkinson’s) exhibit similar prion‐like mechanisms of seeding that initiate aggregation, understanding the fundamentals of seeding may expose potential therapeutic targets for preventing the progression of amyloidosis.References 1) Ahmad, M., Esposto, J., Golec, C., Wu, C., & Martic‐Milne, S. (2021). Aggregation of gelsolin wild‐type and G167K/R, N184K, and D187N/Y mutant peptides and inhibition. Molecular and Cellular Biochemistry, 476, 2393–2408. https://doi.org/10.1007/s11010‐021‐04085‐62) Walker, L. C., Diamond, M. I., Duff, K. E., & Hyman, B. T. (2013). Mechanisms of protein seeding in neurodegenerative diseases. JAMA Neurology, 70, 304‐310. https://doi.org/10.1001/jamaneurol.2013.14533) Solomon, J. P., Page, L. J., Balch, W. E., & Kelly, J. W. (2012). Gelsolin amyloidosis: genetics, biochemistry, pathology and possible strategies for therapeutic intervention. Critical Reviews in Biochemistry and Molecular Biology, 47, 282–296. https://doi.org/10.3109/10409238.2012.6614014) Ihne, S., Morbach, C., Sommer, C., Geier, A., Knop, S., & Störk, S. (2020). Amyloidosis‐the diagnosis and treatment of an underdiagnosed disease. Deutsches Ärzteblatt International, 117, 159–166. https://doi.org/10.3238/arztebl.2020.0159
Remote cognitive rehabilitation in patients post‐cerebrovascular accident: an experience report
Authors: Alves Larissa Scoralich , Dutra Letícia Silva , Santos Lucas Neves , Gonzaga Franciele Aparecida , Shigaeff Nadia 
Published: December 2021

AbstractBackgroundAiming to contribute to the reduction of cognitive impairment, as well as to improve the quality of life of patients affected by stroke, it was proposed to carry out a cognitive rehabilitation focused on attentional aspects (sustained, alternate, selective and divided attention). Due to the new Coronavirus pandemic and the need for social isolation, the rehabilitation was adapted to the remote model.MethodsThe rehabilitation was designed and carried out with six patients, coming from a public neurology outpatient service, who had suffered a stroke within a period of up to one year before the start of rehabilitation. Fifteen sessions of cognitive rehabilitation were carried out, lasting approximately 50 minutes, once a week, for four months. In all functions, the four types of attention were worked on. In addition, there were also unassisted activities performed by the patients after each session.ResultsThe protocol was carried out by Psychology and Medicine students, who elaborated and adapted all activities to be performed by video call. The adaptations were made based on the knowledge and effectiveness of face‐to‐face rehabilitation for this population. Patients and family members collaborated in the activities, but the emergency adaptation to the remote model also had limitations, such as the withdrawal of some patients due to difficulty access or unstable internet connection. However, there were also positive results, such as the possibility of participation by people from other cities and people with mobility difficulties. This experience allowed students to develop skills in interacting with patients, as well as strategies to deal with the challenges of remote care. Thus, it was not necessary to interrupt the students´ education, moreover, the skills developed are important for the e‐health context, which is an increasingly present demand in today's world.ConclusionRemote cognitive rehabilitation is a possibility for patients who have suffered cognitive impairment due to stroke. Despite the difficulties arising from the pandemic, it was an important experience, with significant value for academic training, which stimulated the skills needed to care for patients, in addition to creativity and adaptation in the face of adversity.
The Role of PKR as a Potential Target for Treating Systemic Inflammation Triggered Neuroinflammation, Tau Phosphorylation and Cognitive Dysfunctions
Authors: Cheng Wai‐Yin , Ho Yuen‐Shan , Chang Raymond Chuen‐Chung 
Published: December 2021

AbstractBackgroundSystemic inflammation has been linked to neuroinflammation and the progression of neurodegenerative diseases. Double‐stranded RNA‐dependent protein kinase (PKR) is a key signaling molecules that regulates immune responses by regulating macrophage activation, various inflammatory pathways, and formation of inflammasomes. This study aims at investigating whether PKR can be a pharmacological target to prevent both systemic inflammation‐triggered neuroinflammation, tau phosphorylation and cognitive dysfunctions.MethodLaparotomy, a non‐bacterial endotoxin mouse model, is adopted to address the systemic inflammation triggered by surgery. Male wild‐type C57BL/6J and PKR‐KO mice were randomly divided into two groups: control group under sevoflurane anesthesia and laparotomy group under sevoflurane anesthesia. Expression of mRNA for cytokines and tau protein phosphorylation in different tissues was examined after laparotomy by quantitative RT‐PCR and western blot analysis respectively. Behavioral tests were also performed to examine the effects of laparotomy on cognitive functions.ResultWe have shown that laparotomy induced peripheral inflammation and neuroinflammation in male C57BL/6J mice. By genetic knockout of PKR in mice, it potently downregulated the increased IL‐1 expression induced by laparotomy in both the liver and frontal cortex at 4 h and day 1 after laparotomy. Meanwhile, knockout of PKR significantly reduced the laparotomy induced tau protein phosphorylation (AT8 and pS416) in the frontal cortex. Furthermore, in wild type mice, cognitive impairment was observed following laparotomy in terms of the decline in problem‐solving abilities, impaired short‐term and long term memory in the puzzle box test; reduced recognition memory with lower discrimination index in the novel object recognition test; and impaired spatial working memory with the reduced percentage of alteration in the spontaneous Y‐maze; while for PKR‐KO mice, cognitive flexibility, short‐term and long term memory recognition memory remained intact after laparotomy.ConclusionThis study reveals that genetic knockout of PKR in mice could attenuate laparotomy induced systemic inflammation, neuroinflammation, abnormal tau phosphorylation and cognitive impairment.Further studies will be performed to examine the effect of knockout of PKR in macrophages and cholinergic neurons on systemic inflammation, neuroinflammation and cognitive functions.Acknowledgement: The study is supported by General Research Fund (17123217) to RCCC.
Adaptive x‐ray techniques for coherent scattering from distributed amyloid targets in the brain
Authors: Breedlove Sophya , Badano Aldo 
Published: December 2021

AbstractBackgroundRecently, spectral small‐angle x‐ray scattering (SAXS) techniques have been proposed for interrogating deep targets including amyloid plaques and other protein aggregates in the brain, which could aid in the early diagnosis of neurodegenerative diseases such as Alzheimer's disease.MethodA model was developed to predict the main features of SAXS profiles from targets with varying shape, size and location corresponding to brain regions of interest. An optimization approach was devised adapting the beam orientation for improving deep target characterization. We calculate a figure of merit based on relative scattering intensity, scattering vector smearing , and path length.ResultIncreasing target size introduced additional signal smearing due to location uncertainty. Beam incidence angle and target shape affected the scattering profile by altering the path length or effective target size. For temporal and frontal lobe targets, beam effectiveness varied by up to 2 orders of magnitude.ConclusionBeam orientation optimization for coherent x‐ray scattering could allow a clinical implementation to target regions of interest while minimizing the radiation does to other radiosensitive areas of the head.
Type 2 Diabetes and association with neuropathological changes and domain specific cognitive decline
Authors: Karanth Shama D , Abner Erin L , Braithwaite Dejana , Fardo David W. , Nelson Peter T. , Katsumata Yuriko 
Published: December 2021

AbstractBackgroundType 2 Diabetes (T2DM) and Alzheimer’s disease (AD) are common diseases in aging populations in the US. Multiple large epidemiological studies suggest that T2DM is strongly associated with cognitive impairment. However, the association between T2DM and AD is still controversial. The current study was conducted to investigate the association of diabetes history with neuropathological and cognitive features.MethodParticipant data were drawn from the National Alzheimer’s Coordinating Center (NACC). Diabetes status was determined based on any reported diabetes diagnosis or diabetic treatment during annual assessments. Standardized z scores in memory, attention, language, and executive function were derived from neuropsychological test scores assessed at each annual visit. Multivariable linear mixed‐effects models assessed associations between cognitive domain scores and diabetes and APOE ε4 interaction adjusting for sex, age at each visit, education, hypertension, time and center. In a subset of 5190, autopsied participants, logistic regression was used to examine the association of diabetes and specific neuropathology changes adjusting for sex, age at death, education, hypertension, years of follow‐up and center.ResultAfter excluding participants who reported any other type of diabetes, whose age at baseline were < 60 years, and who had missing APOE genotype data, diabetes was present in 4,899 participants (13.5%) with a mean age at last visit of 77.2 ±8.5 (Table 1). Participants with diabetes history had lower odds for AD neuropathology changes (ADNC), OR=0.77 (95% CI=0.63‐0.94). Diabetes history was associated with increased odds of brain infarcts/lacunes (OR=1.47 and 95% CI=1.21‐1.78) and moderate arteriosclerosis (OR=1.37 and 95%CI=1.05‐1.79). Diabetes history plus APOE ε4 allele was associated with lower attention domain scores (Figure 1).ConclusionDiabetes was positively associated with cerebrovascular pathology and negatively associated with ADNC. APOE ε4 genotype modified the association between diabetes and cognitive features.
Combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy
Authors: Gnoth Kathrin , Geissler Stefanie , Ilse Victoria , Rahfeld Jens‐Ulrich , Cynis Holger , Schilling Stephan 
Published: December 2021

AbstractBackgroundPassive immunotherapy is a very promising approach for the treatment of Alzheimer’s disease (AD). We recently demonstrated that the antibody‐mediated targeting of isoD7‐modified Aβ peptides leads to the attenuation of AD‐like amyloid pathology in 5xFAD mice (Gnoth et al., 2020). Targeting post‐translationally modified Aβ peptides is a promising approach for reduction of effective therapeutic antibody amount and thereby decreasing treatment‐related side effects. Nevertheless, high dosing of monoclonal antibodies and appearance of side effects such as amyloid‐related imaging abnormalities (ARIAs) provide room for approaches such as combination therapies.MethodWe investigated the role of CD33 for Aβ phagocytosis in transgenic mice treated with an isoD7‐Aβ antibody. CD33 or sialic‐acid‐binding immunoglobulin‐like lectin 3 (Siglec‐3) is an inhibitory receptor molecule on the surface of brain microglia. We generated a new mouse line by crossing 5xFAD mice (Oakley et al., 2006) with CD33 knock out mice (Brinkman‐Van der Linden et al., 2003). This mouse line was then used for treatment studies with our anti‐isoD7‐Aβ antibody K11_IgG2a. Therefore, 3month‐old female 5xFAD and 5xFAD/CD33 mice were treated with 4 mg/kg K11_IgG2a and IgG2a isotype control. After 38 weeks treatment an Elevated Plus Maze (EPM) test have been performed, followed by the preparation of mouse brain and the read out by ELISA and Immunohistochemistry.ResultWe could demonstrate that CD33 knock out leads to the reduction of Aβ plaque load as well as the rescue of behavioral deficits in 5xFAD mice. Above that, we detected elevated amounts of plaque surrounding microglia in 5xFAD/CD33KO mice receiving antibody treatment, followed by an even more decrease of Aβ plaque load.ConclusionIn summary, a combinational therapy, concomitantly targeting post‐translational modified Aβ peptides and CD33, leads to an add‐on effect in passive immunotherapy.
Investigating circular RNA‐mediated neurotoxicity in tauopathies
Authors: Atrian Farzaneh , Ramirez Paulino , Frost Bess 
Published: December 2021

AbstractBackgroundCircular RNAs (circRNA) are a subclass of non‐coding RNAs with a covalently closed loop structure that are formed via non‐canonical splicing1. CircRNAs are specifically enriched in the brain among different species and further accumulate in the brain as a function of physiological aging2. CircRNA biogenesis is regulated by N6‐methyladenosine (m6A), a post transcriptional RNA modification3. Elevated levels of circRNAs and abnormal m6A modification significantly correlate with clinical diagnosis and development of Alzheimer’s disease, respectively4, 5. Alzheimer’s disease and related “tauopathies” are pathologically defined by various forms of tau aggregates in the brains of affected individuals. We have previously reported that tau‐induced dysfunction of lamin, a nuclear scaffold protein, causes nuclear polymorphisms including invaginations and blebs 6, 7. We have also found that polyadenylated RNA accumulates within nuclear invaginations in the context of tauopathy and that genetic and pharmacologic reduction of RNA export reduce RNA accumulation within invaginations and suppresses tau neurotoxicity8. While dysfunction of the nuclear envelope and consequent aberrant RNA export mediate tau‐induced neurotoxicity, the identity of RNAs that accumulate within nuclear blebs, the role of m6A in circRNA accumulation, and their relationship with aging and tauopathy are currently unknown. Based on the association between nuclear polymorphism and RNA export, alongside the global enrichment of circRNAs and disrupted RNA methylation in Alzheimer’s disease brains, I hypothesize that m6A‐dependent accumulation of circRNAs in tauopathies sequester complementary RNAs and RNA binding proteins into large inclusions that trigger RNA export via nuclear blebbing.MethodsRNA‐seq, digital PCR, TUNEL, electron microscopy and immunofluorescence.ResultsI find that circRNAs accumulate in brains of a Drosophila model of tauopathy and that RNAi‐mediated reduction of mbl, which is particularly enriched in its circular form in the brain, significantly suppresses tau‐induced neurotoxicity. RNAi‐mediated reduction of an m6A writer and reader significantly reduces circMbl biogenesis and neuronal death in tau transgenic Drosophila. I find that circMbl lines the nuclear blebs that contain large inclusions in brains of tau transgenic Drosophila.ConclusionsTau‐induced accumulation of circRNA is mediated by aberrant m6A modification. Presence of circMbl‐lined nuclear buds suggests a potential role of nuclear blebs in circRNA nuclear export.
The Effects of Melatonin on Cognition and Αβ load in an Alzheimer’s Disease Mouse Model
Authors: Miliotou Eleni , Riley‐DiPaolo Lexi , Stavnezer Amy Jo 
Published: December 2021

AbstractBackgroundThe neurohormone melatonin is released from the pineal gland and is an endogenous antioxidant and free radical scavenger that regulates sleep/wake cycle and circadian rhythm. Decline of nocturnal melatonin secretion with severe sleep disturbance has been consistently reported in Alzheimer’s Disease (AD), a neurodegenerative disease characterized by cognitive deficits and neuronal loss. However, exogenous melatonin supplementation can reduce Αβ neurotoxicity and formation while improving cognitive performance and sleep quality.MethodIn this study, the long‐term influence of melatonin on behavioral and neuropathological changes were evaluated in the 5xFAD mouse model, when treatment was started in adolescence. After ∼20 weeks of orally administered melatonin (10 mg/kg), Morris water maze behaviour was assessed in 54 mice, followed by Aβ42 quantification in hippocampal tissue.ResultOverall, transgenic mice showed impaired learning, and a significant increase in Aβ42 plaque load, replicating previous results with this strain. Melatonin marginally improved learning by decreasing distance travelled in the Morris water maze and slightly decreasing Aβ42 concentration in the hippocampus. These results support the hypothesis that long‐term melatonin supplementation may be beneficial at early stages of the disease process and should be explored more fully.ConclusionAbnormal accumulation of neurotoxic forms of Αβ occur in brain regions involved in the regulation of sleep in AD patients and the disturbed regulation of sleep that occurs early in the disease may contribute to cognitive decline by decreasing Αβ clearance. In contrast to conventional antioxidants, melatonin crosses the blood‐brain barrier, is relatively devoid of toxicity, and constitutes a straight‐forward potential therapeutic candidate in AD treatment.
Identification of Akt activators for the treatment of Alzheimer’s disease: An In‐silico approach
Authors: Kumar B Harish , Prasada K Shama , Pai Sreedhar Ranganth 
Published: December 2021

AbstractBackgroundIn Alzheimer’s disease (AD), Aβ directly downregulates the activity of the Akt pathway by decreasing insulin receptor, IGF, IGFR and PI3K levels leading to reduced phosphorylation of Akt. The diminished inhibitory influence of Akt results in the deranged activity of GSK‐3β, Forkhead, BAD, mTOR pathways, which leads to increased tau phosphorylation, oxidative stress, and cell death. Many researchers have proven that activating the Akt pathway can ameliorate cognitive defects like learning and memory in AD and protect neurons from cell death.MethodMaestro platform from Schrodinger Inc. was used for shape‐based screening by using already know activators like SC79, inositol‐(1,3,4,5)‐tetrakisphosphate, Baicalin, Puerarin, and Chlorogenic acid as a template to screen Asinex and enamine CNS databases. Later, pharmacophore models like receptor‐ligand complex (1UNQ PBD) pharmacophore, Receptor cavity‐based pharmacophore, and multiple ligand‐based pharmacophores were built and used to screen the same databases. Lastly, the Fingerprint‐based 2D QSAR model was built using known active ligands and inactive ligands. Seventeen QSAR models which predicted the activity without error were used to screen databases. Ligands that came out positive in a maximum number of all models were selected and then docked with PH domain of the Akt1, which is the only PDB(1UNQ) with PH domain in an active conformation.ResultDue to the lack of crystal structure of Akt1 protein in active conformation, ligand‐based approach was used. After all the approaches mentioned in the methodology, we selected Asinex CNS ‐275 and Enamine CNS‐76 lead molecules and docked them with PH domain of Akt1. After docking, each molecule pose was analyzed and molecules that interact with the critical residues like Arg 23, Arg 25, Lys 14, Arg 86, Asn 53 essential for activation were selected. Using all these approaches from the library of 2,00,000 compounds, we have narrowed it down to 13 lead molecules.ConclusionUsing an in silico‐based approach, we identified lead molecules that may act as Akt activators and help alleviate the harmful effect of tau hyperphosphorylation. However, an in vivo experiment is needed for supporting this claim.
Event‐Related Delta Oscillations are Diminished in Parkinson’s Disease with Different Cognitive Status: A Longitudinal EEG Study
Authors: Gündüz Duygu Hünerli , Çolakoğlu Beril Dönmez , Güntekin Bahar , Yener Gorsev 
Published: December 2021

AbstractBackgroundThe neurophysiological differences between Parkinson’s disease mild cognitive impairment (PD‐MCI) and cognitively normal Parkinson’s disease (PD‐CN) have been poorly understood, covering limited electrophysiological interpretation. Delta event‐related oscillations (ERO) are recognized as a useful electrophysiological indicator of cognitive decline (Güntekin et al., 2018; Yener et al., 2019). The aim of the present study was to investigate baseline and follow‐up delta EROs of individuals with PD‐CN and PD‐MCI in comparison with healthy controls (HC).MethodsThirty one PD‐CN, 23 PD‐MCI, and 30 demographically‐matched HC were included. All examinations were applied to participants in a time period of 12.50±0.80 months. A comprehensive neuropsychological test battery was used for the PD‐MCI classification (Litvan et al., 2012). EEGs were recorded during visual oddball paradigm. The maximum peak‐to‐peak event‐related delta (0.5‐3.5 Hz) responses of the groups to the target stimulus were measured. Repeated measures ANOVA included Group (3 levels: HC, PD‐CN, PD‐MCI) as a between‐subject factor, Time (2 levels: baseline, follow‐up), and Anterior‐Posterior Electrode Location [AP (6 levels: frontal, central, temporal, temporoparietal, parietal, occipital)] as a within‐subject factor.ResultsThere was an interaction effect for Group x Time on event‐related delta responses [F(2,81)=3.650, p=0.030], indicating follow‐up delta EROs were reduced only in PD‐CN group (Figure 1). Further analyses revealed that there was an interaction effect for AP x Group on baseline delta responses [F(10,405)=11.629, p<0.001], and follow‐up delta [F(10,405)=9.569, p<0.001] responses. At baseline, PD‐MCI had reduced delta EROs in all electrode locations except occipital than both PD‐CN and HC, while PD‐CN had reduced delta responses than HC over frontal and central areas (for all; p<0.030) (Figure 2). At follow‐up, higher delta responses were detected in HC compared to both PD‐CN and PD‐MCI over all locations except occipital area (for all; p<0.001) (Figure3).ConclusionsThe current study revealed that longitudinal delta ERO reduction was apparent only in PD‐CN group. Individuals with PD‐MCI demonstrated decline at both baseline and follow‐up assessments. These findings may be interpreted as diminished delta EROs can be a successful indicator of subtle cognitive alterations in PD‐CN before neuropsychological assessments.