bluuebunny/crossref_metadata_2025_split huggingface dataset:
Lipid rafts act as a common platform for Aβ oligomer‐induced Alzheimer’s pathology
Authors: Kawarabayashi Takeshi , Nakamura Takumi , Sato Kaoru , Seino Yusuke , Ichii Sadanobu , Nakahata Naoko , Takatama Masamitsu , Shoji Mikio 
Published: June 2023

AbstractBackgroundAmyloid‐β (Aβ) oligomers induce the overproduction of phosphorylated tau and neurodegeneration. These cascades gradually cause cognitive impairment in Alzheimer’s disease (AD). While each pathological event in AD has been studied in detail separately, the spatial and temporal relationships between pathological events in AD remain unclear. We demonstrated that lipid rafts function as a common platform for the pathological cascades of AD.MethodCellular and synaptosomal lipid rafts were prepared from the brains of Aβ amyloid model mice (Tg2576 mice) and double transgenic mice (Tg2576 x TgTauP301L mice) and longitudinally analyzed.ResultAβ oligomers, the cellular prion protein (PrPc), and Aβ oligomer/PrPc complexes were detected in the lipid rafts. The levels of Fyn, the phosphorylated NR2B subunit of the N‐methyl‐D‐aspartate receptor, glycogen synthase kinase 3β, total tau, phosphorylated tau, and tau oligomers increased with Aβ oligomer accumulation in both the cellular and synaptosomal lipid rafts. Increases in the levels of these molecules were first seen at 6 months of age and corresponded with the early stages of Aβ accumulation in the amyloid model mice.ConclusionLipid rafts act as a common platform for the progression of Alzheimer’s pathology. The findings of this study suggest a novel therapeutic approach to AD, involving the modification of lipid raft components and the inhibition of their roles in the sequential pathological events of AD.
The combined effect of β ‐amyloid and white matter hyperintensities on present and future executive function performance in cognitively normal older adults
Authors: Ali Doaa , Khouli Riham H El , Abner Erin L , Bahrani Ahmed A , Gold Brian T. , Jiang Yang , Wilcock Donna M. , Jicha Gregory A 
Published: June 2023

AbstractBackgroundβ‐amyloid (Aβ) and White matter hyperintensities (WMH) are key drivers of cognitive decline in healthy older adults and both are considered biomarkers of preclinical dementia. Deficit in executive function (EF) linked to WMHs and Aβ burden, have been shown to predict the development of dementia. The present study aimed to explore the interactions of regional and global Aβ with WMH on baseline and longitudinal performance in EF in cognitively normal (CN) older adults.MethodGlobal and regional Standard Uptake Value ratios (SUVr) from Aβ‐PET, WMH volumes from MRI FLAIR images, and composite scores of EF at baseline and after approximately 2 years were analyzed across a sample of 714 clinically‐normal (Mini‐Mental State Examination (MMSE) ≥ 26), aged participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI2). We used multiple regression models including the interaction tem and main effects for Aβ and WMH to investigate the independent and combined associations of these pathologies with EF. Age, ApoE, education, baseline EF score, and time to follow up EF testing were entered as covariates in the regression models.ResultThe moderation regression analysis showed that additive effects on Aβ burden and WMH in relation to baseline EF with p value for the interaction term between the two pathologies 0.07, and significant interaction effects of global, frontal and cingulate Aβ burden, and WMH in relation to longitudinal EF performance with p values of 0.037, 0.03, and 0.032 respectively. The main effect from regression analysis demonstrated that baseline EF performance was predicted by the combination of Aβ burden and WMH, while Aβ burden was the only predictor for longitudinal EF performance.ConclusionThese data demonstrated that baseline Aβ and WMHs have both independent effects on EF scores at baseline and synergistic effects on longitudinal EF performance. The biological relationships and interplay between Ab and WMH responsible for the synergistic effects seen on longitudinal EF performance warrants further study.
ELUCIDATING THE COMBINED EFFECTS OF AMYLOID AND TAU IN A NOVEL BIGENIC RAT MODEL WITH HUMAN ALZHEIMER’S DISEASE‐LIKE PATHOLOGY
Authors: Emmerson Joshua T , Carmo Sonia Do , Cuello Claudio A 
Published: June 2023

AbstractBackgroundBoth amyloid beta (Aβ) and tau pathologies co‐exist in Alzheimer’s disease. While studies have shown that Aβ and tau interaction results in elevated AD pathology, it is not clearly understood how they might affect one another during early pathology stages leading to Aβ plaque formation. This study aimed at determining how and to which extent a combination of gradually developing amyloid and tau pathologies exacerbate each other in the context of Alzheimer’s disease‐like pathology in a novel transgenic rat model.MethodsHeterozygous McGill‐R‐Thy1‐APP and R955‐hTau single transgenic rats were crossed, producing a novel bigenic rat model with both human amyloid and tau pathologies, named McGill‐R‐APPxhTau955. Bigenic rats express human APP with the Swedish and Indiana mutations (KM670/671NL, V717F) as well as the longest isoform of human tau (2N4R) with the P301S mutation causative of frontotemporal dementia. Transgenic rats (n = 10‐12) were raised to cohorts at 12, 20 and 24 months of age and were subject to a battery of behavioural testing for cognition. Examination of amyloid and tau pathology, as well as inflammatory and neurodegenerative processes, was performed primarily using immunohistochemistry (IHC) and Western blot (WB). Levels of amyloid, tau and p‐tau were measured in CSF, brain and blood serum by electrochemiluminescence immunoassays. Bigenic animals were compared to single transgenics and wild‐type littermate controls.ResultsAPPxR955‐hTau bigenic rats produced a gradual accumulation of human amyloid and tau, resulting in progressive cognitive deficits and Alzheimer‐like pathology. We discovered that tau accumulation produced a compensatory effect on cognition and long‐term potentiation at 20 months, rescuing amyloid‐induced cognitive effects. However, at 24 months of age, bigenic rats displayed worsened cognition compared to single transgenics in spatial learning and memory. Reflective of these findings, bigenic rats developed an increased phosphorylaton of tau at 24 months and increased Aβ plaque pathology. Status of biomarker levels, neuroinflammation and neurodegeneration are actively under investigation and are expected to trend similarly.ConclusionsThe McGill‐R‐APPxhTau novel bigenic rat, developing slow progressing amyloid and tau pathologies, is an attractive model for the further investigation of mechanisms by which both proteins effect one another, the observation of biomarker changes and elucidation of early disease stages.
Kinetic Modulation of Amyloid‐β (1‐42) Fibrillation and Alleviated Cytotoxicity with Rationally Designed Point Mutants
Authors: Im Dongjoon , Kim Hugh Inkon 
Published: June 2023

AbstractBackgroundMost Alzheimer’s disease (AD) treatments focus on symptomatic relief by boosting the availability of neurotransmitters in the brain. Aside from symptomatic therapies, the amyloid‐β (Aβ) targeting approach has recently been established to reduce or postpone the production of Aβ plaques.1 Therefore, understanding the pathogenesis of AD requires regulation of Aβ fibrillation.MethodWe used the CamSol method and molecular dynamics simulations to find a group of residues that were significantly associated with Aβ fibrillation. To investigate the suppressed amyloid aggregation and reduced cytotoxicity of the designed mutants, we performed multiple in vitro experiments such as thioflavin T assay, circular dichroism spectroscopy measurement, transmission electron microscopy image analysis, liquid chromatography‐mass spectrometry based quantification, and cell viability test. We also characterized structural dynamics of the designed mutants using a multidisciplinary biophysical approach with small‐angle X‐ray scattering, ion mobility‐mass spectrometry, additional in silico experiments, and mass spectrometry.ResultWe rationally designed mutant constructs to suppress the fibrillation process using comprehensive molecular dynamics simulations and the atomic resolution structure of fibrils. Then, we used a multidisciplinary biophysical technique to investigate the physicochemical characteristics and unveil the structural basis associated with reduced self‐assembly. Lastly, cell‐based tests were performed to evaluate the alleviated cytotoxicity of designed mutant candidates.ConclusionMore generally, our method for modulating the self‐assembly property of the pathologically disordered proteins offers a novel viewpoint to treating neurodegenerative diseases and other protein folding‐related issues.Reference:1. Sevigny, J., et al. “The antibody aducanumab reduces A beta plaques in Alzheimer’s disease.” Nature 2016, 537(7618), 50‐56.
Cell‐autonomous role of the AD susceptibility gene BIN1 in the regulation of hiPSC‐derived neurons network activity
Authors: Saha Orthis , De Farias Ana‐Raquel Melo , Pelletier Alexandre R , Kilinc Devrim , Delahaye Fabien R , Queiroz Claudio M , Lambert Jean‐Charles , Costa Marcos R 
Published: June 2023

AbstractBackgroundAlzheimer’s disease (AD) is a multifactorial disease with a strong genetic background. Recent genomic wide association studies have identified several loci linked to an increased risk of AD. However, genes regulated by these variants and the pathophysiological mechanisms regulated by those genes remain largely elusive. In this work, we studied the role of Bridging Integrator 1 (BIN1), the second most important AD risk gene after APOE, in neurons generated from human induced pluripotent stem cells (hiPSCs) in bi‐dimensional cultures and cerebral organoids.MethodWe generated isogenic BIN1 wild‐type (WT), heterozygous (HET) and knockout (KO) hiPSC lines and used these cells to generate human‐induced neurons (hiNs) in bi‐dimensional (2D) and three‐dimensional (cerebral organoids) cell cultures. Next, we used calcium imaging and multi‐electrode array electrophysiology to study the functional properties of hiNs networks. Single‐nucleus RNA‐sequencing (snRNAseq) was used to identify gene expression alterations in individual cell types/subtypes. APP processing and TAU phosphorylation was assessed by western blotting and Alphalisa.ResultWe observed that deletion of BIN1 is sufficient to cause neuronal hyperactivation and network desynchronization in a cell‐autonomous fashion. These functional changes are observed both in 2D cultures and cerebral organoids, and are correlated with increased Tau phosphorylation and transcriptional changes similar to those observed in the brains of AD patients, particularly in glutamatergic neurons.ConclusionOur results reveal a role for BIN1 in the regulation of electrical activity in human neurons and suggest that its implication in AD pathogenesis could be related to the neuronal and network dysfunctions observed in the AD brain.
Human amyloid seeds induce a more profound pathology than seeds from old 3x‐Tg‐AD mice
Authors: Andreo‐Lopez Juana , Cantero‐Molina Francisco , Bettinetti‐Luque Miriam , Huynh Kelly Do , Nguyen Marie Minh Thu , Cheung Alwin , Tran Janine Pham , Da Cunha Celia , Trujillo‐Estrada Laura , Nuñez‐Diaz Cristina , Martini Alessandra Cadete , Forner Stefania , Gutierrez Antonia , LaFerla Frank , Baglietto‐Vargas David 
Published: June 2023

AbstractBackgroundMost age‐associated neurodegenerative disorders involve the aggregation of specific proteins within the nervous system, as occurs in Alzheimer’s disease (AD). Recent evidence indicates that Aβ can misfold and aggregate into seeds that structurally corrupt native proteins, mimicking a prion‐like process of template protein corruption or seeding. In fact, studies in animal models show that the injection of brain homogenates from AD patients or from aged APP‐transgenic mice containing Aβ aggregates, can induce some of the neuropathological hallmarks of AD. However, it is still unknown which Aβ‐misfolded species are most efficient in triggering the aggregation process. Here, we seek to perform a comparative study to determine whether Aβ seeds from humans vs a familial AD line (the 3xTg‐AD model) is more efficient to generate amyloid aggregates.MethodWe employed histological and molecular approaches to determine amyloid level, species and aggregative capacity of brain homogenates from an AD patient (stage C for amyloid, from the Alzheimer’s Disease Research Center at UCI) vs old‐3xTg‐AD mice (25‐month‐old). Such brain homogenates were injected into the hippocampus of 7‐month‐old 3xTg‐AD mice and the mice were analyzed at 18 months of age.ResultOur findings demonstrated that amyloid seeds from the human patient induce more aggressive amyloid pathology compared to seeds from aged 3xTg‐AD mice.ConclusionThese results suggest that seeds from human patients seem to be more amyloidogenic than from aged 3xTg‐AD mice. Thus, more profound understanding these factors will provide key insight on how amyloid pathology progress in AD.
Adherence to a healthy lifestyle and brain structural imaging markers: A cross‐sectional study among middle‐aged and older adults
Authors: Pan Yuesong , Shen Jie , Cai Xueli , Zhu Wanlin , Jing Jing , Zhang Yanli , Jin Aoming , Yuan Changzheng , Wang Yongjun 
Published: June 2023

AbstractBackgroundPrevious research has linked specific modifiable lifestyle factors to age‐related cognitive decline in adults. Little is known about the potential role of an overall healthy lifestyle in brain structure. We investigated the association of adherence to a combination of healthy lifestyle factors with neurodegeneration‐related brain structural markers in middle‐aged and older adults.MethodWe conducted a cross‐sectional analysis in the PolyvasculaR Evaluation for Cognitive Impairment and vaScular Events (PRECISE) study among Chinese community‐dwelling elderly adults. Participants underwent lifestyle assessments and brain 3T MRI scanning between 2017‐2019. A healthy lifestyle score (0‐5) was constructed based on five modifiable lifestyle factors: diversified diet, physically active, non‐smoking, non‐alcohol‐drinking, and healthy body weight. Validated multimodal neuroimaging markers (across tissue volume, cortical thickness, and white matter micro‐structure, etc) were derived from MRI. Multivariable‐adjusted linear and logistic regression models were used to examine the associations.ResultA total of 2370 participants (mean age 61.3 years; 53.9% female) was included in the final analysis. Compared to participants with lower healthy lifestyle score (0‐1), those with a higher lifestyle score had larger gray matter volume (GMV; β score 2‐3 = 0.34; β score 4‐5 = 0.31; p‐trend = 0.02) and lower odds of white matter hyperintensity (WMH; Odds Ratio [OR] score 2‐3 = 0.71, 95% Confidence Interval [CI]: 0.50, 1.02; OR score 4‐5 = 0.56, 95%CI: 0.35, 0.90; p‐trend = 0.003) and lacune (OR score 2‐3 = 0.62, 95%CI: 0.36, 1.06; OR score 4‐5 = 0.42, 95%CI: 0.18, 0.98; p‐trend = 0.02). In particular, diversified diet was associated with a significant lower risk of WMH and healthy body weight was associated with a variety of brain structure measures. Similar associations were observed across major subgroup variables.ConclusionAdherence to a healthier lifestyle was associated with a lower degree of neurodegeneration‐related brain structural markers in middle‐aged and older adults. Further large‐scale and longitudinal studies are warranted to confirm the study findings.
Association between social support and cognitive function
Authors: Kyaw Kay Thwe , Flagiello Thomas , Levine Alec , Salinas Joel 
Published: June 2023

AbstractBackgroundObservational studies suggest social support is associated with vulnerability for cognitive decline in older adults. Because of racial/ethnic homogeneity in prior studies beings predominantly in White/European ancestry, less is known about the generalization of these putative psychosocial mechanisms. Thus, we evaluated whether better telecommunication social support systems were associated with better cognitive performance using a unique longitudinal cohort of rural South African older adults.MethodWe conducted a cross‐sectional study using 541 participants from the HAALSI (Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa) Dementia Cohort. Participants’ exposure to social support via telecommunication was measured using a standard assessment. Cognitive performance was measured using a neuropsychological battery validated in this population that assesses the domains consistent with the Alzheimer’s Disease Research Centers Uniform Data Set. Raw scores were converted into z scores and a composite global cognitive score was created as an additional indicator of global cognition. We examined cross‐sectional associations with multivariate robust regression analysis using robust S‐estimation. Telecommunication social support was modeled as the independent variable; cognitive measures were modeled as dependent variables.ResultHigher telecommunication social support was associated with better global cognitive function after adjustment for age, gender, and education (β:0.01, 95% CI: 0.006, 0.022). This association persisted after additional adjustments for depressive symptoms and vascular risk factors. Higher telecommunication social support was also associated with cognitive function assessed by mini mental status examination and tests of executive function and memory.ConclusionTelecommunication‐based social support was associated with higher levels of cognitive performance in a rural South African cohort of Black older adults. Although these findings and the potential of reverse causality need to be further validated, our results suggest that intervention studies might be specifically merited to understand whether promoting social support through telecommunication in similar samples of older adult populations lessen vulnerability for cognitive decline.
CSF proteo‐genomic studies identify an interaction between LRRK2 genetic variants and GRN, GPNMB, CTSB, and ENTPD1
Authors: Wang Lihua , Yang Chengran , Mafimoghaddam Samira , Timsina Jigyasha , Gorijala Priyanka , Wang Fengxian , Alvarez Ignacio , Aguilar Miquel , Ruiz Agustin , Pastor Pau , Sung Yun Ju , Cruchaga Carlos 
Published: June 2023

AbstractBackgroundParkinson’s disease (PD) is a movement disorder characterized by dopaminergic neurodegeneration in the substantia nigra of the brain. Another neurodegenerative disorder, Alzheimer’s disease (AD), is a progressive memory loss disorder with pathological changes mainly at hippocampus and entorhinal cortex. As dementia is also present in late stage of PD, there might be common molecular mechanism between the pathogenesis of AD and PD. Evidence has nominated Leucine Rich Repeat Kinase 2 (LRRK2), Progranulin (GRN), Glycoprotein nonmetastatic melanoma protein B () since these proteins were linked to AD and PD. Identifying genetic variants of 5 proteins will be critical to shed lights on common disrupted pathways shared by AD and PD.MethodTo identify genetic variants associated with these 5 proteins, we performed protein quantitative trait loci (pQTL) analyses of log10 transformed CSF GRN, GPNMB, CTSB, ENTPD1 and LRRK2 assayed in SomaScan platform. We considered ∼11 million sequenced variants from 787 individuals recruited at PPMI in the discovery and ∼4.3 million imputed variants from 799 Knight ADRC samples in replication. Age, sex and 10 principal components were included as covariates. Genome‐wide threshold (5.0×10−8) was used in the meta‐analyses of discovery and replication for significance.ResultOn chromosome 12, exonic missense LRRK2 variant rs33939927 (MAF = 1.4%) was identified as shared pQTL for GRN (P = 7.87×10−10), CTSB (P = 8.99×10−9), GPNMB (P = 3.59×10−9), and ENTPD1 (P = 1.24×10−13). The second LRRK2 exonic missense variant rs34637584 (MAF = 11%) was pQTL consistent for 3 proteins (GRN: P = 2.34×10−8, GPNMB: P = 8.55×10−13, and ENTPD1: P = 1.75×10−13). The third LRRK2 exonic missense variant rs35303786 (MAF = 3.4%) was identified for GPNMB (P = 1.53×10−8) and ENTPD1 (P = 2.31×10−8). The risk allele of 3 SNPs were associated with higher amount of corresponding CSF proteins. No significant LRRK2 pQTL was identified. Additional analyses including colocalisation with AD and PD GWAS results are ongoing.ConclusionTwo low frequency exonic missense LRRK2 variants (rs33939927 and rs35303786) and one common exonic missense LRRK2 variant (rs34637584) were pQTL shared by GRN, CTSB, GPNMB, and ENTPD1. Our findings indicate that the LRRK2 exonic variants are the key genetic regulators of LRRK2 activity and CSF level of GRN, CTSB, GPNMB, and ENTPD1.
The development and refinement of the enhancing active caregiver training (EnACT) intervention for caregivers of persons living with dementia
Authors: Eaton Jacqueline , Neller Sarah , Cajavilca Moroni Fernandez , Johnson Julene K. , Ellington Lee 
Published: June 2023

AbstractBackgroundBehavioral symptoms affect up to 90% of persons living with dementia.1 While interventions have been developed to help caregivers manage symptoms,, these interventions show only weak to moderate effect size.2 The most successful psychoeducational interventions use active‐engagement techniques to facilitate the application of knowledge and skills.2‐5 Yet the optimization and systematic testing of active‐engagement techniques is lacking.2‐6 By optimizing active‐engagement techniques, we may strengthen caregiver preparation. Enhancing Active Caregiver Training (EnACT) is an arts‐based intervention aimed at engaging dementia caregivers by using techniques that allow them to better manage common behavioral symptoms associated with dementia. The purpose of this presentation is to describe the process of developing and refining EnACT in preparation for feasibility testing with dementia family caregivers.MethodAs part of a larger sequential qualitative‐to‐quantitative mixed‐method design to develop and test EnACT, we implemented an iterative three‐stage review process to prepare intervention materials for focus group feedback and future pilot testing. This included review from: 1) a caregiving expert/clinician, 2) two applied humanities researchers with expertise in arts‐based healthcare training, and 3) a three‐person research team completing a mock focus group.ResultIntervention materials were revised following each stage of review. In stage 1, we identified caregiving scenarios for inclusion, clarified confusing process components, and emphasized questions to ask as part of discussion and reflection activities. During Stage 2, we reorganized activities to follow a narrative structure and allow participants to explore one caregiving scenario at a time. In addition, we added application questions that ask participants to explore how scenarios relate to their own experiences. In stage 3, we expanded focus group activities to the online platform to promote access and safety. Through testing the process in advance, we refined procedural steps to facilitate caregiver engagement and identified potential barriers to participation.ConclusionWhen preparing to conduct a feasibility and acceptability trial for a behavioral intervention, seeking feedback enhances protocols to improve intervention processes. Iterative review may reduce extraneous problems, enabling focus groups to target participant feedback specific to dementia caregivers and their needs.