bluuebunny/crossref_metadata_2025_split huggingface dataset:
Myeloid Differentiation Factor 2 Inhibition Attenuates Brain Pathologies in the Obese Pre‐diabetic Condition
Authors: Oo Thura Tun , Nawara Wichwara , Arunsak Busarin , Chunchai Titikorn , Apaijai Nattayaporn , Pratchayasakul Wasana , Liang Guang , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundExcessive high‐fat diet (HFD) consumption develops the obese pre‐diabetic condition, which initiates neuroinflammation and numerous brain pathologies, resulting in cognitive decline (1). A cinnamamide derivative compound (2i‐10) is recently identified as a novel myeloid differentiation factor 2 (MD‐2) inhibitor, and has been shown to attenuate inflammation via toll‐like receptor 4 (TLR4) signaling pathway (2). However, the effects of 2i‐10 on the neuroinflammation, brain pathologies and cognitive function in the obese pre‐diabetic rats have never been studied.MethodMale Wistar rats were fed one of two diets for 16 weeks: either a normal diet (ND; n = 8) or a high‐fat diet (HFD; n = 32). At week 13, ND‐fed rats were intraperitoneally administered a vehicle for 4 weeks, while HFD‐fed rats were randomly divided into 4 groups (n = 8/group). Each subgroup was intraperitoneally administrated either vehicle, 10mg/kg/day of 2i‐10, 20mg/kg/day of 2i‐10, or 40mg/kg/day of 2i‐10 for 4 weeks. At the end of week 16, the novel object location (NOL) test was examined in each rat. Brains were rapidly removed to determine hippocampal inflammation, adult hippocampal neurogenesis, brain oxidative stress, dendritic spine density, amyloidogenic pathology.ResultHFD‐fed rats developed the obese pre‐diabetic condition. Hippocampal inflammation was observed in HFD‐fed rats, as evidenced by increased hippocampal TLR4 and TNF‐α expressions. Moreover, HFD‐fed rats not only had significantly higher hippocampal amyloid‐β/APP ratio and brain MDA levels, but also had significantly lower levels of adult hippocampal neurogenesis, hippocampal dendritic spine density, resulting in cognitive decline. Although all doses of 2i‐10 attenuated systemic insulin resistance, brain pathologies and cognitive impairment, 2i‐10 (40mg/kg/day) showed the highest efficacy in attenuating brain inflammation, brain oxidative stress, amyloid‐β deposition, as well as improving adult hippocampal neurogenesis, hippocampal dendritic spines, resulting in the restoration of cognitive function in obese pre‐diabetic rats (P < 0.05, Figure 1).ConclusionThese findings suggest that MD‐2 inhibition could be the potential strategy for attenuating brain dysfunctions in the obese pre‐diabetic condition.
Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer’s disease via cGAS‐STING
Authors: Gao Dan 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear.MethodAPP/PS1 AD mice were treated with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) at 40 mg/kg/day and 80 mg/kg/day respectively for 5 consecutive months, and then the Morris water maze test (MWM) and the novel object recognition test were performed to assess the effect of TSG on the cognitive and memory ability of AD mice. Moreover, central microglia activation, peripheral inflammation as well as the correlated cGAS‐STING signal pathway were analysed by Immunostaining and ELISA, which was further verified in BV2 cell experiments.ResultTreating with TSG, learning‐memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN‐γ induced microglia activation showed that TSG reversed the polarization status of M1‐type microglia to restore the quiescence, and cGAS‐STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL‐1β, IL‐6, TNF‐ α, IFN‐ αand IFN‐β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN‐γ‐stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS‐STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS‐STING inhibitors.ConclusionOur findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS‐STING signaling pathway in AD.
Phospholipase gamma2: A candidate genetic risk factor for Alzheimer’s disease that can alter synaptic function in DG‐perforant pathway of hippocampus
Authors: Roy Avishek , Erhardt Anael , Deforges Severine , Mulle Christophe 
Published: January 2025

AbstractBackgroundPhospholipaseC γ2 (PLCG2) is known to have direct link with genetic risk factors for Alzheimer’s like dementia (AD). PLCG2 has been previously demonstrated to have association with Aß uptake through microglia. And mostly expressed in dentate gyrus (DG) network of hippocampus.MethodWT mouse were transfected with sh‐RNA of LV‐PLCG2 (U6 promotor, GFP as reporter; shRNA) or scrambled (used as control; shNT). Whole‐cell patch‐clamp recordings were performed on acute slices with glass pipette (<3‐4MΩ) at ‐70mv, which was accompanied with morphometry of perforant pathway (PP)‐DG circuitry. Two‐tailed Mann‐Whitney test was used for statistics unless otherwise mentioned, p<0.05 was considered to be significant.ResultWe found significant increase in APhalf width (p = 0.0274), rheobase (p = 0.0046) in shRNA on the other hand, input resistance (p = 0.0159), number of spike vs current injection (p = 0.0268) was significantly decreased. However, there were no significant change was observed in APonset (p = 0.6105), APamplitude (p = 0.7345), RMP (p = 0.7591) and firing threshold (p = 0.5247) in shRNA group when compared to shNT. mEPSC amplitude was found to be reduced (p = 0.0288) in shRNA condition, even the cumulative probability of mEPSC amplitude was also found to be significantly altered after silencing of PLCG2 gene in DG cells (p = 0.0014; Kolmogorof‐Smirnov test). mEPSC frequency of the miniature activity of transfected DG cells were did not show significant change (p = 0.7707). Sholl analysis of the DG cells expressing shRNA showed a decrease in the number of intersections vs distance from soma (P<0.05), accompanied by significant decrease in dendritic length (p = 0.0501), dendritic volume (p<0.0001) and dendritic surface area (p = 0.0273). When spine density was measured we have found a significant decrease in cumulative distribution of spine density (p<0.0001; Kolmogorof‐Smirnov test), which is tightly associated with decrease in spine length (p = 0.0209) and spine head diameter (P<0.0001). Furthermore, these dendritic and spine morphometric alteration is also accompanied with the decrease in the volume of mossy fiber gigantic bouton (mfB) with alteration in the number of filopodia per mfBs (p<0.05).ConclusionResults from the study, reflect critical insight of PLCG2 regulating neuronal and/or synaptic activity, which may underlie the cognitive dysfunction (viz. recognition memory) and synaptic alteration to the PP‐DG circuitry seen in AD.
Enrichment of somatic cancer driver mutations in Alzheimer’s disease microglia and its association with neuroinflammation
Authors: Huang August Yue , Zhou Zinan , Talukdar Maya , Miller Michael B , Chhouk Brian , Enyenihi Liz , Rosen Ila , Stronge Edward , Zhao Boxun , Kim Dachan , Choi Jaejoon , Khoshkhoo Sattar , Kim Junho , Ganz Javier , Travaglini Kyle J , Gabitto Mariano I , Hodge Rebecca D , Kaplan Eitan S , Lein Ed S , De Jager Philip L. , Bennett David A. , Lee Eunjung Alice , Walsh Christopher A 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD), an age‐associated neurodegenerative disorder, is characterized by progressive neuronal loss and the accumulation of misfolded proteins such as amyloid‐β and tau. While neuroinflammation, mediated by microglia and brain‐resident macrophages, plays a pivotal role in AD pathogenesis, the intricate interactions among age, genes, and other risk factors remain elusive. Somatic mutations, known to accumulate with age, instigate clonal expansion across diverse cell types, impacting both cancer and non‐cancerous conditions.MethodUtilizing molecular‐barcoded deep panel sequencing, which enables sensitive detection of somatic mutations with allele fractions as low as 0.1%, we profiled clonal somatic mutations among 149 cancer driver genes in 311 prefrontal cortex samples from AD patients and matched controls. Fluorescence‐activated nuclei sorting and single‐nucleus RNA sequencing were further used to study the cell‐type composition and transcriptomic impact of somatic mutations.ResultOur study unveiled an elevated occurrence of somatic single‐nucleotide variants and insertions/deletions within cancer driver genes in AD brains. Recurrent somatic mutations, often multiple, were observed in genes associated with clonal hematopoiesis (CH). Remarkably, these somatic mutations were specifically enriched in CSF1R+ microglia and exhibited signals of positive selection, suggesting mutation‐driven microglial clonal expansion (MiCE) in AD brains. Single‐nucleus RNA sequencing of temporal neocortex samples from an additional 62 AD patients and matched controls revealed a nominal increase in mosaic chromosomal alterations (mCAs) associated with CH in AD microglia, with microglia carrying mCA exhibiting upregulated pro‐inflammatory genes, resembling the transcriptomic features of the disease‐associated state in AD.ConclusionOur findings indicate that proliferation‐related somatic mutations in microglia are prevalent in normal aging but further enriched in AD, driving MiCE and promoting inflammatory, disease‐related microglial signatures. This study provides crucial insights into microglial clonal dynamics in AD, potentially paving the way for novel approaches to AD diagnosis and therapy.
A therapeutic roadmap to restore the SORL1‐retromer recycling complex
Authors: Merchant Kalpana M. 
Published: January 2025

AbstractGenetic, cell biology and autopsied brain tissue studies indicate that deficits in the SORL1‐retromer complex play a critical role in the pathogenesis of Alzheimer’s disease (AD). SORL1 is an endosomal receptor that interacts with the retromer heterotrimer core complex consisting of VPS26‐VPS35‐VPS29. Together, SORL1‐retromer regulate endosomal recycling of several AD‐related cargos such as amyloid precursor protein. In cell and animal models, deficits in SORL1 or retromer core levels recapitulate the prototypical biomarker signature and cytopathology of AD. Thus, restoration of SORL1‐retromer recycling function offers an attractive therapeutic opportunity to slow or stop the progression of AD. This talk will detail a multi‐modality drug development strategy founded on precision neurology principles. Specifically, there will be a discussion on small molecules and gene therapy drug development programs targeting SORL1 and/or the retromer core as well as a comprehensive biomarker strategy that has been integrated into the programs to de‐risk and facilitate clinical drug development.
Chronic traumatic encephalopathy neuropathologic change is associated with higher stage limbic‐predominant age‐related TDP‐43 encephalopathy
Authors: Song Hailong , Ameen‐Ali Kamar E , Kennedy‐Dietrich Claire , Dolle Jean‐Pierre , Lee Eddie B , Smith Douglas H , Stewart William 
Published: January 2025

AbstractBackgroundTraumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE‐NC). In addition to tau, other NDD pathologies are described. Of these, deposition of abnormally phosphorylated transactive response DNA‐binding protein 43 (pTDP‐43) has been reported in association with CTE‐NC. However, to date the prevalence and distribution of pTDP‐43 in CTE‐NC and its distinction from pathology of wider NDD has not been formally assessed.MethodPatients with history of exposure to repetitive mild traumatic brain injury (rmTBI) and documented NDD (n = 30), together with age‐matched controls with no known TBI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT‐TBI archive. Whole slide digital images of standardized brain tissue sections stained for pTDP‐43 (1D3) were reviewed, and the pattern and distribution of pathology mapped.ResultOverall, prevalence of pTDP‐43 pathology was similar among rmTBI patients (40%) and their age‐matched controls with NDD (33%; p = 0.7778). However, while pTDP‐43 was typically localized in controls with NDD and in rmTBI patients without CTE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy [LATE] stage 1‐2), in patients with CTE‐NC this pathology was more often widespread and high stage (LATE stage 3; p = 0.0045).ConclusionThese results demonstrate rmTBI is associated with higher stage LATE pathology than in equivalent age matched controls and individuals with wider, non‐TBI related NDD. Further studies are required to characterize the association between TBI and TDP‐43 proteinopathy, including the contribution, if any, of this pathology to clinical sequelae of TBI related neurodegenerative disease.
Harmonization of data from neuropsychological tests used in different prospective studies‐ Descending a Tower of Babel
Authors: Shishegar Rosita , Cox Timothy , Markovic Shaun J , Tallapragada Bhargav , Bourgeat Pierrick , Dore Vincent , Laws Simon M , Porter Tenielle , Burnham Samantha C. , Feizpour Azadeh , Weiner Michael S. W. , Hassenstab Jason J. , Morris John C. , Rowe Christopher C. , Villemagne Victor L , Masters Colin L. , Fripp Jurgen , Lim Yen Ying , Doecke James D. , Sohrabi Hamid R. , Maruff Paul 
Published: January 2025

AbstractBackgroundCognitive dysfunction is central to clinicopathological models of Alzheimer’s disease (AD). While AD prospective studies assess similar cognitive domains, the neuropsychological tests used vary between studies, limiting potential for aggregation. We examined a machine learning (ML) data harmonisation method1 for neuropsychological test data to develop a harmonised PACC score for the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) consortium.MethodADOPIC included longitudinal clinicopathological data from AIBL (N = 1765), ADNI (N = 1779) and OASIS (N = 440) cohorts (Table 1). Harmonization involved three stages. First, cognitive domains of interest and the neuropsychological tests assessing each were defined. Second, a standardized scoring and naming convention was established for demographic and neuropsychological outcomes. Third, the ML harmonisation approach1 was applied. Test scores present in one cohort, but not another, were treated as missing and imputed using ML before calculating a PACC1. Imputation utilized data from neuropsychological tests, age, sex, years of education, and APOE‐ɛ4 status. We validated the harmonized PACC (H‐PACC) by randomly simulating missing cognitive scores and analysing percentage error of imputed scores versus actual data1. Validity of harmonized scores was determined by their sensitivity to decline associated with amyloid positivity and clinical disease stage. Linear mixed models (LMMs) modelled trajectory of change on H‐PACC and AIBL PACC scores (including identical tests), with time, CDR‐global score, and amyloid status (Aβ‐/Aβ+) interactions as fixed effects. Sex and age at baseline were covariates. Variation in baseline and decline in PACC scores was modelled using random intercepts and slopes. Effect sizes for LMMs were computed with pseudo‐R‐squared.ResultPercentage errors for imputed neuropsychological test scores showed high accuracy with low standard deviations (Figure 1). Sensitivity to clinicopathological disease stage was qualitatively similar for the H‐PACC and AIBL PACC (Figure 2), both discriminating (p<0.001) annual decline rates of Aβ+ CDR 0.5 and CDR≥1 groups from Aβ‐ CDR 0 group. Effect sizes were substantial, with H‐PACC and AIBL PACC data explaining 95% and 93% of variance, respectively.ConclusionThe H‐PACC, developed via ML harmonization, was precise and has utility for aggregating neuropsychological test data to be used in prospective AD studies.References:1https://doi.org/10.1002/alz.0443022https://doi.org/10.1093/bioinformatics/btr597
Clinical presentations of atypical forms of Alzheimer's Disease and its correlates with functional imaging: the importance of early detection, a series of cases
Authors: Mariani Francesca 
Published: January 2025

AbstractBackgroundThe prevalence of Dementia in Latin America countries is growing and early presentations of Alzheimer´s Diseases with atypical forms are even more frequently. As the clinical presentation of these variants shows an overlap with other dementia disorders, the differential diagnosis is often challenging. We presented three cases of atypical forms of AD who count with cognitive assessment and pet imaging confirmation in order to being able to discuss the most important points of clinical assessment in every case.MethodCase 1: 60‐year‐old woman with a 2‐year history of progressive anterograde memory deficit, that evolved with a typical corticobasal syndrome with extrapyramidal signs and left superior limb dystonia. Case 2: 65‐year‐old woman with a 1‐year history of progressive visual loss, difficulty in stimuli detection that evolved with memory loss and Anosognosia. Case 3: 68‐year‐old man with a 2‐year history of speech difficulties with reduced fluency and verbal initiative, compromise in naming, repetition and understanding of syntactic relationships. Associate alexia and agraphia. In evolution adds executive and memory impairment, visuoconstructional deficits and ideomotriz apraxia. The three cases count with 18F‐FDG and 11C‐PIB PET/ CT studies supported the diagnosis of Alzheimer’s disease.ResultThis are three cases of atypical presentations of AD with imaging biomarkers confirmation and its particular cognitive assessment characteristics. In two cases, the beginning of the functional history is what marks the differential, in the third case, the evolution is what marks the characteristics of the disease.ConclusionEven when we have imaging studies, and especially when we do not have them, which is the majority of cases in Latin America, the clinical examination and in‐depth history are crucial to detect early symptoms. These symptoms could constitute the key elements for an adequate differential diagnosis. Likewise, atypical cases invite us clinicians to carry out rigorous and timely follow‐up, without taking the clinical presentation of our patients for granted. The advancement of technology and imaging biomarkers has changed the way we do clinical work, but we must not forget the value of the latter.
Tau different conformers; seeds ‐ how do the first ones arise?
Authors: Lövestam Sofia ,   Scheres and Goedert
Published: January 2025

AbstractBackgroundIntermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention.MethodWe used time‐resolved cryogenic electron microscopy (cryo‐EM) to study the in vitro assembly of recombinant truncated tau into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy.ResultWe report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302‐316. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain.ConclusionTau filaments assemble via polymorphic intermediates.
Introduction to what we still need to learn about ARIA
Authors: Sperling Reisa A 
Published: January 2025

AbstractThe short introduction will highlight what we have learned about amyloid related imaging abnormalities (ARIA) since 2011 and the critical questions that remain to be elucidated. In particular, we need to better understand the risk factors and mechanisms that underlie the relatively rare symptomatic cases. We will highlight the importance of bi‐directional translational research to bring insights from the laboratory to the clinic and findings from clinical trials back to the bench.
CAA and ARIA: Emerging Concepts and Opportunities for Translation
Authors: Greenberg Steven M. 
Published: January 2025

AbstractTwo broad classes of mechanisms have emerged for understanding the Amyloid‐Related Imaging Abnormalities (ARIA) associated with anti‐beta‐amyloid immunotherapy. One set of mechanisms proposes that ARIA is driven by large‐scale transfer of antibody‐bound amyloid from brain parenchyma to the perivascular and vascular compartments. This class of mechanisms is indirectly supported by neuropathological evidence that immunotherapy substantially clears plaque amyloid while increasing vessel‐associated amyloid, but has been difficult to directly demonstrate.The second set of mechanisms proposes that ARIA is substantially driven by direct antibody binding to vascular amyloid deposits (cerebral amyloid angiopathy or CAA). The role of CAA in generating ARIA is supported by observations on propensity of transgenic mouse models with vascular amyloid to develop ARIA. Another line of supporting evidence comes from the striking neuroimaging similarities between ARIA and the spontaneous occurring syndrome of CAA‐related inflammation, a clinical entity that appears to be triggered by generation of anti‐amyloid autoantibodies. This class of mechanism predicts that CAA present prior to initiating immunotherapy should increase ARIA risk, a hypothesis supported by recent identification of cerebral microbleeds and cortical superficial siderosis on baseline MRI as independent risk factors for subsequent ARIA.Identifying causative pathways to ARIA—the role of preexisting CAA in particular—should provide a blueprint towards future trials aimed at preventing or mitigating ARIA’s clinical impact.