bluuebunny/crossref_metadata_2025_split huggingface dataset:
The role of human microglia and microglial LRRK2 in tau pathogenesis
Authors: Karabova Maria Kreger , Cowley Sally A. , James William S. 
Published: December 2022

AbstractBackgroundThe G2019S mutation in leucine‐rich repeat kinase 2 (LRRK2) is the most common genetic determinant of Parkinson’s disease (PD), reported in both familial and sporadic PD cases. Even though tau‐positive pathology features prominently in the G2019S PD patients, the role of LRRK2 in tau pathogenesis remains poorly understood. Human microglia – the chief brain‐resident phagocytes of the innate immune system ‐ become one of the highest LRR2K expressing cells upon IFN‐y stimulation. Moreover, microglia have been recently implicated in increasing pathological tau transmission by secreting exosome‐bound, seeding‐competent tau into the extracellular space. Using human iPS‐macrophages, a simple but physiologically relevant and genetically tractable model of human microglia, we set out to define the role of microglial LRRK2 in uptake, degradation, and secretion of disease‐associated tau protein.MethodWe have developed a quantitative phagolysosomal proteolysis assay based on dequenching of DQ‐BSA fluorogenic substrate attached to silica microspheres, allowing us to investigate cell‐autonomous phagocytic and degradative capacity of G2019S, LRRK2 KO and isogenic control iPS‐macrophages. In parallel, we have optimised purification and in vitro aggregation of endotoxin‐free, human recombinant 2N4R tau to study tau‐induced phagolysosomal proteolysis deficits in the said iPS‐macrophages.ResultWe have found that human iPS‐macrophages readily internalize extracellular tau monomer and fibrils, and LRRK2 is required for macrophage uptake of tau monomer. Degradation of internalized tau is concentration and incubation‐length dependent regardless of genotype. However, G2019S macrophages show deficits in degradation of internalized tau fibrils. Moreover, non‐degraded tau fibrils present within G2019S cell‐ lysates 24h post incubation retain seeding competency and induce aggregation of naïve tau monomer in K11 tau RT‐QuIC assay, unlike tau fibrils internalized by LRRK2 KO macrophages.ConclusionLRRK2 expressed by iPS‐macrophages is important for monomeric tau entry, degradation, and seeding capacity of internalized tau fibrils. Future studies will focus on elucidating the molecular mechanisms behind the LRRK2 and tau interaction.
Application of the Preclinical Alzheimer’s Cognitive Composite for tracking progression in cognitively unimpaired older adults with known Amyloid status: A 24‐month Interim Analysis of the Chariot‐Pro cohort
Authors: Novak Gerald P , Udeh‐Momoh Chinedu T. , Price Geraint J , Baker Susan , de Jager Celeste A , Giannakopoulou Parthenia , Middleton Lefkos T 
Published: December 2022

AbstractBackgroundThe ongoing CHARIOT‐PRO Substudy aims to estimate the rate of cognitive change in the early Alzheimer’s pathological continuum, comparing individuals with and without baseline biomarker evidence of amyloid deposition, over a 4.5yr follow up. We previously reported subtle cognitive differences between the two groups at baseline. Here we extend follow‐up to 24m.MethodCognitively unimpaired individuals aged 60–85 years, in good general health and with global Clinical Dementia Rating (CDR) scale = 0, underwent amyloid assessment via PET or lumbar puncture; approximately equal numbers of amyloid positive (A+) and amyloid negative (A‐) individuals were enrolled. This report focuses on the preclinical Alzheimer’s cognitive composite (PACC) total score and the CDR, performed at baseline and at M12 and M24. Subtle deficit at baseline was defined as PACC scores below the 15th percentile of A‐ individuals. The A+ and A‐ groups were compared on rate of progression to CDR > 0 and annualized change from baseline in PACC. Individuals with and without progression at any point in the CDR were compared with respect to PACC baseline and change scores.ResultA+ participants had lower PACC scores at baseline (‐0.39 (2.56) vs 0.40 (2.71), p = 0.001). There was a trend for less improvement at M24 (0.29 (2.1) vs 0.62 (1.76), p = 0.068). More A+ than A‐ participants progressed to CDR = 0.5 (Figure 1; Kaplan‐Meier survival 84.6% vs 93.1%, respectively, p = 0.004). Those with subtle deficit at baseline were more likely to progress to CDR = 0.5 (14.1% vs 5.9%, OR = 2.63, p = 0.008). Participants with progression to CDR = 0.5 at any time had lower PACC scores at baseline (‐1.30 (2.72) vs 0.24 (2.59), p < 0.0005) and greater decline at M24 (‐0.30 (2.20) vs 0.55 (1.88), p = 0.014).ConclusionIn A+ individuals, a greater decline in mean PACC scores trended towards significance at 24m, a larger proportion had change in CDR, and CDR progression was associated with declining PACC. In addition, low baseline PACC predicted subsequent increase from CDR = 0. These findings provide further evidence that the PACC has sufficient sensitivity to measure subtle cognitive deficits and serve as an indicator of progression on the early Alzheimer’s pathological continuum.
Modeled Impact of APOE4 Genotype on ARIA‐E Incidence in Patients Treated With Lecanemab
Authors: Reyderman Larisa , Hayato Seiichi , Reddy Harsha , Takenaka Osamu , Yasuda Sanae , Swanson Chad J , Willis Brian A , Hussein Ziad 
Published: December 2022

AbstractBackgroundLecanemab is a humanized IgG1 monoclonal antibody that preferentially targets soluble aggregated Aβ species with activity at insoluble fibrils. A multicenter, double‐blind, placebo‐controlled phase 2 study (Study 201 Core) was conducted in 856 patients with early Alzheimer’s disease (EAD). Patients could optionally participate in an open label extension (OLE) study at a dose of 10 mg/kg bi‐weekly (Q2W). Amyloid related imaging abnormalities — edema/effusion (ARIA‐E) was a main adverse event of special interest. Incidence of ARIA‐E was lecanemab dose‐dependent and greater in APOE4 carriers. A previously presented logistic model found steady‐state Cmax was a predictor of ARIA‐E incidence and more likely in APOE4 carriers (Hussein, 2019).MethodsThis work expands upon the previously developed logistic model by exploring the effect of APOE4 genotype (noncarrier, heterozygous carrier, homozygous carrier) on ARIA‐E incidence. Modeling was conducted using NONMEM 7.4.3 with data from Study 201 Core. Model predictions were compared to the observed incidence in the OLE study among patients newly treated with lecanemab (ie, placebo‐treated in the Core study).ResultsInclusion of APOE4 genotype as a covariate in the model with three categories (noncarrier, heterozygous carrier, homozygous carrier) led to a statistically significant decrease in model objective function (p <0.001). A model utilizing only 2 categories (homozygous carrier, others) was not significantly different from the model with 3 categories (p = 0.5297). Model‐predicted ARIA‐E rates for APOE4 homozygous carriers treated with lecanemab 10 mg/kg Q2W were 22.5% (versus 6.8% in heterozygous or 5.4% in noncarriers) and comparable to the observed 25% incidence in newly‐treated homozygous carriers (1/4) in the OLE study, and less than the 50% incidence in homozygous carriers (5/10) in the Core.ConclusionsThe incidence of ARIA‐E in subjects treated with lecanemab appears highest in APOE4 homozygous subjects. No statistically significant difference in ARIA‐E incidence was found between non‐carriers and heterozygous carriers. Data from the larger CLARITY‐AD study will be needed to confirm these findings.Reference: Hussein, et al., Population Pharmacokinetic (PK) and Exposure‐Response (ER) Analyses for Efficacy and Safety of BAN2401 in Patients with Early Alzheimer’s Disease (AD), International Conference on Alzheimer’s & Parkinson’s Diseases (AD/PD), 2019.
Risk of violent crime may be associated with hippocampal‐dependent cognitive function in older African Americans
Authors: Tan Genesis , Gimenez‐Santana Alejandro , Fausto Bernadette A. , Esiaka Darlingtina , Gluck Mark A. 
Published: December 2022

AbstractBackgroundResearch on Area Deprivation Index (ADI) suggests that the social environment and neighborhood stressors (e.g., violent crime risk) play a role in later‐life cognitive function. However, most of the research linking ADI and cognitive function has been conducted on non‐Hispanic white American samples. Further, while the ADI is useful in facilitating efficient integration of social determinants of health (SDOH) into models of cognitive aging, it does not take into account micro‐level measures of neighborhood stressors which may also affect cognitive function. Therefore, the purpose of the current study is to determine whether violent crime risk contributes to later‐life cognitive function above and beyond ADI in older African Americans.MethodsParticipants are part of an ongoing study at Rutgers University‐Newark called the Pathways to Healthy Aging in African Americans, a university‐community collaboration fostered over 16 years (2006‐2022) of community engagement, health education, and public service. Analyses included 149 older African Americans aged 60 and above (Mage = 68.68, SD = 7.25; Medu = 13.99, SD = 2.43; n = 149). Cognitive function was assessed via the acquired equivalence task, a measure of one’s ability to generalize past learning to novel task demands. Violent crime risk was calculated using the Risk Terrain Modeling technique, a geospatial risk assessment that evaluates the influence of the built environment on the distribution of crime.ResultsA multiple linear regression was run to examine the relationship between violent crime risk and cognitive function. Violent crime risk was significantly associated with acquired equivalence task performance, F(6, 142) = 5.948, p = .024, adj. R2
= .167, even after controlling for ADI, age, education, and depression. The results showed that individuals living in areas with higher risk of violent crime had poorer ability to generalize past learning to novel task demands.ConclusionOur findings suggest that for African Americans in an urban setting, hyper‐local violent crime risk appears to be supplemental with ADI at capturing the impact of neighborhood disadvantage on cognitive function and Alzheimer’s disease risk. Thus, for African American individuals’ later‐life cognitive health, it is important to consider micro‐level measures of neighborhood stressors such as violent crime risk.
Parenchymal CSF Fraction and DTI‐ALPS in Brain Aging
Authors: Zhou Liangdong , Nguyen Thanh D , Li Yi 
Published: December 2022

AbstractBackgroundThe perivascular space (PVS) functions as part of a brain clearance system that drains interstitial fluid and solutes including Aβ and tau from brain parenchyma and is associated with the development of AD. Recent developed imaging tools of cerebral parenchymal CSF fraction (CSFF)1 and diffusion tensor imaging along perivascular spaces index (DTI‐ALPS)2 provide an insight of the perivascular CSF flow and early PVS pathology in the cerebral cortex. We applied CSFF and DTI‐ALPS in an elderly cognitive normal cohort to investigate its value in brain aging.MethodA total of 27 cognitive normal subjects in this study are within age 57 and 82 years (mean=67.7, std=6.4). We conducted MR FASTT2 scan for CSFF, T1W, T2W for PVS burden, and DTI for DTI_ALPS index. CSFF was fitted using three compartment model with 6 TEs = 0, 7.5, 17.5, 67.5, 147.5, 307.5 ms. PVS burden was calculated by using imaging processing based PVS segmentation on enhance PVS image (T2W/T1W). DTI_ALPS was calculated by mean(D𝑥_𝑝𝑟𝑜𝑗,D𝑥_𝑎𝑠𝑠𝑜𝑐)/mean (D𝑦_𝑝𝑟𝑜𝑗, D𝑧_𝑎𝑠𝑠𝑜𝑐), where Dx, Dy and Dz are the diffusivity along x‐, y‐ and x‐axis, and the projection, association regions. Multi‐variate linear model Age∼1+DTI_ALPS+CSFF was compared with Age∼1+DTI_ALPS+PVS_burden.ResultFigure 1 (a) and (b) show the PVS mask on T2W and CSFF map. Figure 2 shows the scattered plot of linear model between age and PVS burden+DTI_ALPS, which is not significant (p=0.06, R2=0.14). Figure 3 is the plot of the model between age and CSFF+DTI_ALPS, which is significant (p<0.01, R2=0.34).ConclusionThe preliminary results showed CSFF and DTI‐ALPS can better predict brain aging. The conventional PVS burden only measures the MRI visible PVS in brain white matter while CSFF can assess micro‐scale PVS along small arteriole and capillary in the cerebral cortex, which is closely related to glymphatic system and may reflect the PVS function alert at early stage. CSFF and DTI‐ALPS could be a potential marker for detecting early stage of dysfunction of glymphatic clearance.
Reference: 1. Liangdong Zhou, BioRvix:2021.02.01.429067, 2021. 2. Toshiaki Taoka, Jpn.J.Radiol. 2022;40:147–58.3.
Investigating the role of tau loss‐of‐function in Alzheimer’s Disease pathogenesis
Authors: Schwarze‐Taufiq Tiara A. , Frankowski Harald , Lemieux Madeline , Link Christopher D. , Young Jessica E. 
Published: December 2022

AbstractBackgroundOne hallmark of Alzheimer’s Disease (AD) pathology is hyperphosphorylation of tau protein, which leads to loss of its normal function and promotes aggregation into neurotoxic fibrillary tangles. While tau gain‐of‐toxic function is well‐documented, the exact role of tau loss‐of‐function in AD pathogenesis remains uncharacterized. We hypothesize that tau loss‐of‐function contributes to AD pathogenesis by activating the cellular stress response in neurons and astrocytes, characterized by cytoplasmic double‐stranded RNA (dsRNA) release, stress granule formation, and inflammation.MethodWe generated human induced pluripotent stem cell (hiPSC)‐derived mixed cortical cultures and primary human fetal astrocyte cultures, allowing us to model the earliest stages of AD pathogenesis in a uniquely human system. In these cultures, we depleted tau through lentiviral transduction and CRISPR‐Cas9 to model acute and chronic loss‐of‐function, respectively. We utilized quantitative real‐time polymerase chain reactions, enzyme‐linked immunosorbent assays, and immunocytochemistry to investigate the expression of genes and proteins implicated in stress and inflammation.ResultPreliminary results indicate upregulation of genes and proteins associated with inflammation and stress granule formation in tau‐depleted neurons and astrocytes. Tau‐depleted cortical cultures exhibit increased secretion of chemoattractant cytokines, and tau‐depleted astrocytes demonstrate increased glial fibrillary acidic protein expression suggestive of non‐cell autonomous pro‐inflammatory cytokine induction. Further, tau‐depleted neurons show increased levels of stress chaperones and cytoplasmic dsRNA known to induce stress granules.ConclusionTau loss‐of‐function may contribute to AD pathogenesis through promoting the release of double‐stranded RNA into the cytoplasm, stress granule formation, and inflammation.
Machine Learning to Stratify Asymptomatic Alzheimer’s Disease Progression Risk with Cerebrospinal Fluid Biomarkers
Authors: Tandon Raghav , Watson Caroline M , Seyfried Nicholas T. , Mitchell Cassie S , Zhao Liping , Lah James J. 
Published: December 2022

AbstractBackgroundChange in protein regulation begin years before Alzhiemer’s Disease (AD) functional symptom onset. The period where changes in proteins is detectable without overt cognitive dysfunction is often referred to as the asymptomatic AD stage. The ability to utilize biomarkers to determine who is most likely to transition to symptomatic AD is critical for potential future intervention development. Machine learning provides a means to stratify the asymptomatic AD population using measured biomarker levels.MethodSeventy‐five peptides were measured in the cerebrospinal fluid (CSF) of subjects in the Emory Healthy Brain Study. Subjects labeled as symptomatic AD had a clinically confirmed AD diagnosis with cognitive deficit. Quantified total‐tau to amyloid beta ratio was used to label non‐symptomatic patients as either heathy control or asymptomatic AD. Recursive feature elimination (RFE) was used to identify a small set of predictive peptides best for classifying either symptomatic AD or healthy control AD. Asymptomatic AD subjects (n = 134) were clustered based on peptide levels using t stochastic nearest neighbor embedding (t‐SNE). Finally, the selected most predictive peptides and the k‐nearest neighbors (KNN) algorithm was utilized to calculate the proximity of asymptomatic AD subjects to healthy control or symptomatic AD. The calculated proximity represented the stratified AD progression.ResultRFE successfully classified patient stage using <10 peptides (AUC > 95%, n =58 held out test subjects). Peptides mapped to the proteins NPTXR, YWHAZ, CHI3L1, VGF, APOE, SMOC1, and GAPDH were most discriminative. T‐SNE results revealed biomarker heterogeneity within the population, but cluster separation was sufficient to utilize KNN proximity as a stand‐in for approximated asymptomatic AD progression.ConclusionMachine learning of CSF biomarker levels successfully stratified asymptomatic subjects into AD‐like (more progressed) and control‐like (relatively less progressed) asymptomatic cases. Stratification of subjects based on biomarker levels could improve future clinical trial construction and assist in earlier intervention for higher risk subjects.
Role of polyelectrolytes in modulating membrane‐templated Aβ40 aggregation
Authors: Regmi Deepika , Du Deguo 
Published: December 2022

AbstractBackgroundAmyloid fibril formation is associated with protein‐misfolding disorders and is a key pathway for the pathogenesis of Alzheimer’s disease (AD). The fibrillar structure of amyloid beta‐protein (Aβ) is the hallmark of amyloid plaques in the brains of patients with Alzheimer’s disease (AD). The interaction between the cell membrane and the Aβ40 peptide may induce membrane disruption and membrane leakage and may be related to the toxicity in Alzheimer’s disease (AD).MethodIn this regard, we evaluated the competitive effects of different polyelectrolytes such as chitosan (CHT), N‐trimethyl chitosan (TMC), heparin and dextran on peptide‐phospholipid membrane interactions and Aβ40 fibrillation. The impact of polyelectrolytes on AB aggregation at membrane interface and fibrillation of Aβ40 peptide was evaluated by utilizing biophysical techniques such as ThT binding assays and atomic force microscopy.ResultThe polyelectrolytes and lipid membranes co‐exist extensively in the cellular environment, we demonstrate that the interactions of polyelectrolytes and Aβ may substantially influence the role of the N‐terminal charged region of Aβ in initiating and guiding adsorption and aggregation of the peptide on the membrane surface.ConclusionHence, there is a great deal of interest in polyelectrolytes that can bind to the Aβ40 peptide and interfere with the Aβ40 peptide‐membrane interactions and manipulate amyloid formation in Alzheimer’s disease (AD).
Optogenetic regulation of phosphatidylinositides in cellular and mouse models of Alzheimer’s disease
Authors: Costa Ana Paula , Acquarone Erica , Lazarian Artur , Herman Mathieu A , Arancio Ottavio , Hussaini S Abid , McIntire Laura Beth 
Published: December 2022

AbstractBackgroundMajor disappointments in late‐stage clinical trials have made it clear that additional therapeutic targets beyond amyloid β‐peptide (Aβ) and tau are urgently required for Alzheimer’s disease (AD). Phosphatidylinositol 4,5‐biphosphate [PI(4,5)P2] has previously been established as an important signaling lipid at the synapse and in a mouse model of Alzheimer’s disease. We hypothesize that the level of PI(4,5)P2 in the plasma membrane may be an early and critical determinant of AD associated molecular and behavioral deficits in cellular and mouse models of the disease.MethodWe tested the ability of a light‐inducible dimerization system to modify phosphoinositide content in vitro using a PC12 cell line overexpressing cryptochrome‐interacting basic‐helix‐loop‐helix (CIBN) fusion to a membrane targeted CAAX domain (CIBN‐CAAX), and blue‐light mediated binding of cryptochrome 2 (CRY2) fused with the catalytic domain of phosphatidylinositol 4‐phosphate 5‐kinase (CRY2‐PIP5K2A‐CD). We detected PI(4,5)P2 using the PI(4,5)P2 sensor plextrin homology domain of phospholipase C δ (PH‐PLCδ). Using virally mediated transduction of these constructs in mouse brain, we manipulated PI(4,5)P2 levels in hippocampus of a mouse model of AD, harboring the Amyloid Precursor Protein transgene (APP‐Tg). Behavioral deficits were assessed using novel object recognition (NOR). Brains were analyzed for detection of phosphoinositide using Imaging Mass Spectrometry.ResultIn PC12 cells, initial results indicate that after optogenetic stimulation, cytosolic labeling by PH‐PLCδ was largely lost, and plasma membrane labeling was observed. In a mouse model of AD (APP‐Tg) after stimulation with blue light or control yellow light, behavioral paradigms including NOR were completed. NOR discrimination index was significantly reduced for Tg+/control compared to other groups (WT/control, WT/Opto) as expected. However, Tg+/Opto was not significantly different than WT/control or WT/Opto indicating amelioration of behavioral deficits in Tg+/Opto through optogenetic stimulation of PI(4,5)P2 production. Experimental groups did not show significant changes in motor function in the open field task. Our data indicate that optogenetic stimulation of PI(4,5)P2 accumulation in brain is able to rescue behavioral AD associated behavioral deficits.ConclusionUsing sophisticated and specific optogenetic manipulation we have demonstrated that stimulation of PI(4,5)P2synthesis rescued behavioral deficits in a mouse model supporting the critical role of PI(4,5)P2 levels in AD.