bluuebunny/crossref_metadata_2025 huggingface dataset:
Tau‐induced astrocyte senescence and dysfunction in AD tauopathy
Authors: Makhlouf Haneen
Published: January 2025

Background

Cellular senescence is defined as cell cycle arrest and the acquisition of a proinflammatory ‘senescence‐associated secretory phenotype’ (SASP). In Alzheimer’s disease (AD), tau protein in neurons undergoes hyperphosphorylation and misfolding, resulting in the formation of pathogenic soluble aggregates known as tau oligomers. Tau oligomers are released from neurons during neuronal activation and are transmitted to postsynaptic cells in a prion‐like fashion. In addition to neurons, tau is expressed in various brain cell types, including astrocytes. In the present study, we tested the central hypothesis that soluble pathogenic tau can be transmitted to astrocytes and that tau transmission to astrocytes induces cytoskeleton destabilization and cellular dysfunction, contributing to the progression of AD.

Methods

to test the molecular consequences of tau transmission, we exposed primary human astrocytes with purified tau oligomers and we measured markers of senescence (cell and nuclear size, cell cycle arrest, and SASP activation) using advanced biochemical tools, immunocytochemistry, and live‐cell microscopy. We also measured cell cycle arrest and SASP activation in the whole brain and astrocyte fractions isolated from hTau mice, a mouse model of AD tauopathy. In addition, we co‐cultured human astrocytes undergoing tau‐induced senescence with primary mouse or non‐human primate neurons to determine the impact of senescent astrocytes on neurons (using immunocytochemistry and 3D image analyses to measure aspects of dendrite and spine abundance and morphology).

Results

Our findings reveal that pathogenic soluble tau is readily transmitted to primary human astrocytes in vitro and in vivo and that pathogenic tau transmission triggers phosphorylation of endogenous astrocyte tau, leading to the destabilization of the microtubule cytoskeleton. Further, we found that transmission of pathogenic tau to astrocytes potently upregulated multiple markers of cellular senescence, demonstrating for the first time pathogenic tau‐induced astrocyte senescence. Moreover, density of dendritic spines and dendritic area was pronouncedly decreased in neurons exposed to astrocytes undergoing tau‐induced senescence.

Conclusion

Our study showed that pathogenic tau is transmitted to cultured human astrocytes and that transmission of pathogenic tau to astrocytes triggers astrocyte senescence in a mouse model of AD tauopathy. Our data suggest that senescent astrocytes may be critical mediators of neuronal dysfunction in AD tauopathy.
Molecular environment in Alzheimer’s disease brain revealed by the hybrid imaging analyses
Authors: Ogawa Tadayuki , Homma‐Takeda Shino , Umemura Tomonari , Hirata Takafumi , Saito Yuko
Published: January 2025

Background

Although amyloid deposition in brain is one of the hallmark pathological features of Alzheimer’s disease (AD), the upstream events and its molecular environment in AD brain remain largely unknown. Recent advances in analytical methods such as mass spectrometry can provide the cutting‐edge tools to unveil the AD pathogenesis at molecular and atomic level.

Method

In order to gain the comprehensive information about AD pathology at molecular level, postmortem brain sections of AD patients were analyzed by the hybrid molecular imaging methods composed of the conventional histological analyses, matrix assisted laser desorption ionization mass spectrometry imaging (MALDI‐MSI) for small molecules, laser ablation inductively coupled plasma mass spectrometry (LA‐ICP‐MS) imaging for metals, and particle induced X‐ray emission (PIXE) imaging for elements. Principal components analysis (PCA) was also applied to discover the differences between the spectra datasets of AD and healthy control brains. Specific distribution of molecules and elements were visualized on the brain slice. (Ethics Approval: Dokkyo Medical University No.2021‐004, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology No.R20‐003).

Result

MALDI‐MSI showed abnormal distribution of lipids, such as phospholipids, sphingolipids, and their derivatives in AD brain. LA‐ICP‐MS visualized the distribution of elements, including some metals in the wide‐field brain section. PIXE imaging displayed the specific concentration of atoms nearby the pathological tangles detected by anti‐ubiquitin antibody. PCA proposed the effective classification to distinguish AD from control based on mass spectra.

Conclusion

Our data suggest the molecular and atomic environment in brain that is closely linked to AD pathology. Further analyses should be conducted to elucidate the fundamental mechanism of AD pathogenesis and prevention.
Tackling selective neuronal vulnerability: Subnuclei involvement of amygdala‐predominant Lewy body disease in early‐onset Alzheimer’s disease
Authors: Fischer D. Luke , VandeVrede Lawren , Seeley William W. , Spina Salvatore , Wekselman Fattin , Lago Argentina Lario , Grinberg Lea T.
Published: January 2025

Background

Lewy body disease (LBD) often co‐occurs with Alzheimer’s (AD), resulting in more significant cognitive decline than AD or LBD alone. LBD’s hallmarks, asyn‐positive Lewy bodies and neurites, propagate from the enteric system or olfactory bulb to the amygdala, which acts as a gatekeeper for spread to other structures. Initially, LBD appears in the central or cortical nuclei, reflecting brainstem or olfactory origins. A third pattern of LBD is quite prevalent in sporadic and familial early‐onset AD (EOAD). This amygdala‐predominant LBD (AP‐LBD) type does not conform with the most used staging systems for LBD and has received little attention. We found a link between asyn seeding‐competent fibrils in cerebrospinal fluid (CSF) and LBD’s transition from the amygdala, supporting its gatekeeper role. The factors enabling asyn propagation in the amygdala remain unknown. Our goal is to map asyn and tau markers in EOAD cases with permissive vs. non‐permissive AP‐LBD in amygdala subnuclei, identifying spread pathways and vulnerable cell populations.

Method

We identified all postmortem EOAD cases with AP‐LBD from the UCSF Neurodegenerative Disease Brain Bank (n = 47), 14 of which have banked CSF for asyn seeding amplification testing. We are using multiplex immunofluorescence to label: phosphorylated asyn; phosphorylated, mis‐conformed, or truncated tau; and all neurons. Markers will be quantified from digital pathology scans, and we will analyze the degree of colocalization by region for the central nucleus, basolateral nuclei, and cortical nucleus.

Result

Pending analysis, we will report the pattern of LBD across subnuclei. Of eight CSF samples, 37.5% were positive for asyn seeding with six samples pending. Asyn and tau markers by subnucleus will be compared between CSF‐positive and ‐negative cases.

Conclusion

Mapping AP‐LBD across amygdala subnuclei may yield insights into selectively vulnerable neurons. This research has the potential to enhance our understanding of AP‐LBD and its underlying mechanisms, ultimately contributing to the development of more targeted diagnostic and therapeutic strategies in the realm of neurodegenerative diseases.
Understanding the blood‐brain barrier breakdown and vascular dysfunctions in new AD mouse models
Authors: Chiu Yuanpu
Published: January 2025

Background

Alzheimer’s disease (AD), the leading cause of dementia accounting for 70% of cases, involves complex pathogenesis with amyloid, tau, and cerebrovascular dysfunction contributing significantly. Vascular changes and impairment are strongly associated with AD pathogenesis in new knock‐in models from the MODEL‐AD consortium – early‐onset AD (EOAD) and late‐onset AD (LOAD) mice – which can be influenced by spatial transcriptomic genetic factors.

Method

We will thoroughly characterize vascular dysfunction in these models over time: 3, 6, 9 months for EOAD mice; 4, 8, 12 months for LOAD mice. Age‐matched C57BL/6J mice will serve as controls. Additionally, we will apply cutting‐edge spatial transcriptomics with subcellular resolution (Stereo‐seq) to one EOAD and one LOAD model to uncover molecular changes underlying neurovascular dysfunction. We will integrate the obtained data with existing resources.

Result

The pathological phenotypes of the new AD mouse models are expected to express microglial responses that are positively correlated with amyloid beta aggregation, leading to tau pathology. Vasculature is also expected to be impaired. The distribution of the phenotypes tends to be in cortical and hippocampal regions.

Conclusion

Our outcomes will provide an enhanced understanding of blood‐brain barrier (BBB) breakdown and vascular contributions in physiological AD models, guiding future mechanistic and therapeutic studies of vascular‐directed strategies to mitigate neurodegeneration.
Vascular pathology: a key neuropathological feature in young and middle age individuals
Authors: Leite Renata Elaine Paraizo , Socher Karen L R , Rodriguez Roberta Diehl , Brucki Sonia , Ferretti‐Rebustini Renata Eloah de Lucena , Ferriolli Eduardo , Jacob‐Filho Wilson , Pasqualucci Carlos Augusto , Grinberg Lea T. , Suemoto Claudia Kimie , Nitrini Ricardo
Published: January 2025

Background

Clinicopathological studies suggest a role of minor cerebrovascular changes in the cognitive decline of individuals with a low neurodegenerative burden. However, it remains unclear whether small vascular brain lesions can impact cognition in middle aging individuals. Additionally, recent clinicopathological studies have shown that even a low Alzheimer’s disease (AD) neuropathological burden can significantly impact neuropsychiatric function. This study aims to evaluate the presence of AD neuropathological changes and their relationship with cognitive impairment, neuropsychiatric symptoms and risk factors in a multiethnic group under the age of 65.

Method

A post‐mortem study evaluating individuals aged 30‐64 years from the Biobank for Aging Studies at the University of Sao Paulo, Brazil. Neuropathological examinations were carried out based on accepted criteria, using immunohistochemistry. The clinical diagnosis was established through a postmortem interview with an informant using the Cognitive Dementia Rating (CDR). We compared the frequency of neurofibrillary tangles, neuritic plaques, lacunar infarct, hyaline arteriolosclerosis, cerebral amyloid angiopathy, synucleinopathy, and siderocalcinosis between groups. We also described the frequency of neuropathological diagnoses and neuropsychiatric symptoms.

Result

Among participants with neuropathological disease (n = 61), vascular dementia (VaD) was the most frequent diagnosis (42,7%), followed by AD (11,5%) (Figure 1). A higher frequency of vascular pathology (p<0.001) was found in individuals with cognitive impairment (Table 2). Some degree of neurofibrillary pathology was found in 54.2% of the individuals, while neuritic plaques were found in 9.7% of the cases, regardless of the presence of cognitive impairment or neuropsychiatric symptoms. AD‐type pathology burden was higher in individuals with cognitive impairment. The frequency of NPS was higher in CI individuals with significant difference in almost all subitems of the NPI, except in appetite changes. High frequency of cerebrovascular risk factors such as hypertension (60.7%) and smoking (61.1%) was also observed in the entire sample (Table 1).

Conclusion

Our data show that AD neuropathological changes can begin in mid‐age and corroborate findings from other series predominantly involving older Caucasians with high educational attainment, which have demonstrated the role of vascular pathology in cognitive impairment. As vascular risks are preventable, implementing aggressive measures to reduce these factors may impact the prevalence of cognition‐related dysfunction.
Whole genome sequence‐based association of cognitive decline and retinal thickness in the Japanese population
Authors: Taira Makiko , Fuse Nobuo , Saykin Andrew J. , Nagami Fuji , Kinoshita Kengo , Yamamoto Masayuki
Published: January 2025

Background

Dementia is age‐related with a significant genetic contribution, yet genome‐wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole‐genome sequencing (WGS) data in the Japanese population may reveal population‐specific susceptibility loci for dementia. Retinal imaging with optical coherence tomography (OCT) is noninvasive, reproducible, and can detect thinning associated with progressive neurodegeneration. Association of population‐specific genetic susceptibility loci with retinal thinning and cognitive decline may reveal novel aspects of dementia risk and pathophysiology.

Method

Among participants with WGS data from the Tohoku Medical Megabank Organization (ToMMo) Ophthalmology Study (“ToMMo Eye Study”), individuals with adequate quality data on retinal nerve fiber layer and ganglion cell layer thickness from spectral‐domain optical coherence tomography (SD‐OCT) scans were selected. Since retinal thinning also occurs in glaucoma, we performed a GWAS using age, sex, and 10 principal components as covariates using SAGE1.2 to obtain a set of genes responsible for glaucoma and confirm that the genotyping was successful. We then attempted to identify susceptibility loci for cognitive decline by using (1) the Mini‐Mental State Examination, Japanese version (MMSE‐J), (2) the Montreal Cognitive Assessment, Japanese version (MoCA‐J), and (3) the Mini‐COG© (a simple screening for early detection of dementia, Japanese version) scores as associated factors, respectively. Furthermore, these validation results were also compared with those obtained from GWAS using imputation data performed on custom arrays (Japonica ArrayTM, v2 or NEO) for Japanese.

Result

84 significant (p < 5.0E‐8) genome‐wide susceptibility loci (hg38) of RNFL were detected on 14K WGS‐based study (the top hit locus: Chr14, SIX6 gene, P = 4.50E‐46). There were many genetic loci that have already been reported to be associated with glaucoma susceptibility, including the above locus. Among the results of GWAS for cognitive decline combining the three cognitive scores after normalization to z‐scores, several loci have shown significant susceptibility in both of RNFL and cognitive rating scale. Some loci suggested more than a high or moderate effect of altering protein efficacy.

Conclusion

We present an initial WGS‐based genetic study of retinal thickness and cognitive decline in the Japanese population.
Agitation and mortality in dementia: application of the syndromic International Psychogeriatric Association criteria‐based approach to survival analyses
Authors: Ismail Zahinoor , Hosseinpour Zahra , Hao Chenhui , Goodarzi Zahra , Smith Eric E. , Seitz Dallas
Published: January 2025

Background

Agitation in dementia is associated with poor outcomes, including mortality. However, the lack of a consensus definition of agitation has hampered research, historically driven by variable approaches to symptom identification. Accordingly, prevalence estimates range widely (5%‐88%) and interventions are hard to compare meaningfully. The International Psychogeriatric Association (IPA) consensus definition advanced the field from a symptomatic to a syndromic criteria‐based approach. As per the validated IPA criteria, agitation behaviors can manifest as verbal aggression (VA), physical aggression (PA), and/or excessive motor activity (EMA). We determined the three‐year mortality rate for syndromic agitation and each of the three IPA agitation domains. We hypothesized 1) higher mortality for those with agitation; and 2) PA would have the highest mortality of the three domains.

Method

National Alzheimer’s Coordinating Center (NACC) participants (n = 3226), with baseline dementia diagnosis were included. Neuropsychiatric Inventory Questionnaire (NPI‐Q) items identified IPA domains as follows: VA (irritability); PA (agitation/aggression); and EMA (aberrant motor activity). Agitation+ status was based on item scores ≥1. Kaplan‐Meier survival curves were used to visualize and compare group trajectories. Cox proportional hazards regressions modelled: 1) three‐year mortality for Agitation±; and 2) three‐year mortality for combinations of agitation domains relative to VA alone, adjusted for age, sex, race, education, and MMSE. To address potential confounding, propensity scores were applied using inverse probability treatment weighting. Sex differences in outcomes across exposure groups were assessed.

Result

Participants (age 74.5±9.7 years, 51% female) who were Agitation+ had a 1.37‐fold higher mortality rate (CI:1.12–1.69, p<0.001) relative to Agitation‐ (Figure 1). Higher agitation‐related mortality was seen in males (HR = 1.52, CI:1.18‐1.97, p = 0.001) and females (HR = 1.51, CI:1.1‐2.06), p<0.001); between‐sex HRs did not differ (multiplicative interaction test HR = 0.97, CI:0.8‐1.17, p = 0.96). Domain analyses revealed 1) generally higher hazards when >1 agitation domain was observed; and 2) higher hazard for mortality for EMA than PA in reference to VA (Figure 2).

Conclusion

This study provides further validation of the IPA Agitation criteria and the syndromic approach to agitation in dementia. Previously underappreciated relative to PA, and contrary to our hypothesis, EMA emerged as an important IPA agitation domain, having the greatest mortality risk.
Genetic correlation analysis identifies genetic loci shared between Alzheimer’s disease and primary psychiatric disorders
Authors: Kumar Ajneesh , Ray Nicholas R. , Cuccaro Michael L. , Beecham Gary , Huey Edward D. , Reitz Christiane
Published: January 2025

Background

Neuropsychiatric Symptoms (NPS) (e.g., aggression, psychosis, anxiety, apathy, depression, agitation, sleep disturbances, repetitive behaviors) occur in 85% of AD patients, and are associated with accelerated decline, out‐of‐home placement, increased costs, and greatly increased suffering of patients and families. Our understanding of the etiology of NPS in AD is inadequate, with treatments for NPS often being ineffective and associated with serious adverse effects. Pharmacological treatments have generally been borrowed from their indications for psychiatric illness, despite limited understanding to what extent the molecular and genetic architectures underlying AD‐associated NPS overlap with that of primary psychiatric disorders.

Method

To characterize the genetic overlap between AD and major psychiatric disorders and identify potentially shared biological processes we conducted local genetic correlation analyses between AD and bipolar disorder, depression, and schizophrenia using LAVA (Local Analysis of [co]Variant Association), capitalizing on the largest most recent GWAS summary statistics for these traits (AD: n = 401,577; bipolar disorder: n = 413,466; depression: n = 1,154,267; schizophrenia: n = 130,644).

Result

Local genetic correlation analyses identified fifteen loci shared between Alzheimer’s disease and depression and two loci shared between AD and bipolar disorder after adjusting for multiple testing. Finemapping and functional analyses of the identified loci are in process.

Conclusion

These findings support the notion of genetic overlap between AD and bipolar disorder, and AD and depression, respectively. Functional characterization of these loci will be critical to characterize the specific underlying causative genes and biological processes.
Repeated reactivation of HSV‐1 in mouse brain spreads radially from the trigeminal ganglion, altering expression of synaptic and immune genes in patterns similar to early AD
Authors: Funk Cory C , Darvas Martin , Johnston Christine , Robinson Max , Schaffer Caitlyn , Battaglia Christian , Aubert Martine , Wiley Jesse C
Published: January 2025

Background

The immerging role of CD8+T cells, interferon and the adaptive immune response in AD is consistent with previous observations of the putative role of neurotrophic herpesvirus family infections contributing to Alzheimer’s Disease pathophysiology. An outstanding question is how chronic viral infections over decades may contribute to AD pathogenesis. Our HSV‐1 reactivation model aims to provide insights to this question.

Method

We infected 2 month old C57B6/J mice containing humanized APP and APOE4 with 106 PFU HSV‐1 strain 17 via corneal scarification. We reactivated the virus with the bromo‐domain compound JQ1 at 4, 7 and 10 months, with 1x, 3x and 6x reactivations respectively and harvested the brainstem, hippocampus, entorhinal cortex and dural sinuses, for RNAseq. To identify common changes in gene expression between our HSV‐1 reactivation model and AD, we compared the gene expression profiles of our mice to both human and mouse model gene profiles using 19 AD‐specific categories (BioDomains).

Result

We found reactivation by JQ1 resulted in increased HSV‐1 detection by qPCR in a progressive manner, emanating outward from the trigeminal ganglion, towards more distal brain regions. We observed changes in RNAseq expression profiles in a time‐dependent manner, with the greatest number of differentially expressed genes at 7 months. We observed changes in synaptic and immune genes in both the entorhinal cortex and hippocampus. We also saw decreases in gene expression in lipid metabolism, myelination, and the endolysosomal pathways.

Conclusion

Our HSV‐1 reactivation mouse model identifies changes in gene expression that are similar to those observed in humans and mouse AD models, with observed, distinct changes in synaptic‐ and immune‐associated genes in multiple brain regions. Activation of immune genes was highest in the brain stem, where detection of HSV‐1 was highest. The greatest changes in gene expression occurred at 7 months, with fewer changes following at 10 months. These changes are most similar to changes in early disease and support the role of HSV‐1 contributing to AD pathophysiology.
Alzheimer’s disease histopathology in the human Down syndrome retina and in hiPSC‐derived retinal organoids
Authors: Vergara M. Natalia , James Ethan , Ha Michael , Aguilera‐Rico Citlali
Published: January 2025

Background

Down Syndrome (DS) is a genetic disorder caused by the triplication of human chromosome 21 that affects approximately 1 in 700 people born in the U.S. People with DS are at a greater risk of developing Alzheimer’s disease (AD), with practically all individuals developing AD histopathology and more than half progressing to dementia. However, the histopathological manifestations of AD in the DS retina have not yet been investigated. Closing this knowledge gap could lead to improved AD diagnosis and treatment for individuals with DS, since retinal structural and functional features are increasingly being explored as biomarkers of AD. In this study, we evaluated the presence of AD histopathology in human cadaver retinas from donors with DS as well as disomic controls. Moreover, we developed the first retinal organoid (RO) models of DS using patient‐derived induced pluripotent stem cells (iPSC) and evaluated their ability to recapitulate AD histopathology.

Method

De‐identified human cadaver eyes from individuals with DS and disomic controls were obtained from the Miracles in Sight Eye Bank, fixed, embedded in paraffin or OCT, and sectioned for histopathological analysis. Human iPSC‐derived ROs were generated from disomic controls and donors with DS using the Zhong et al. (2014) protocol and collected at 100 days of differentiation. AD histopathology was assessed by immunoblotting and immunofluorescence staining, including retinal cell type‐specific markers and amyloid‐β (Aβ), phosphorylated Tau (pTau), and NIAD‐4 staining for amyloid plaques.

Result

Histopathological analysis of human cadaveric donor retinas indicated an increased deposition of Aβ plaques and pTau in retinas from individuals with DS compared to control donor retinas, consistent with the pathology observed in the brain. DS‐ROs developed a full component of neural retinal cell types and exhibited elevated levels of Aβ plaques and pTau compared to control ROs, mirroring the phenotype observed in the native DS retina.

Conclusion

AD histopathology can be observed in the human DS retina and in stem cell‐derived RO models of DS. These DS‐RO models may open new opportunities for drug screening and biomarker discovery, as well as enable comparative pathophysiological studies between DS‐ROs and the recently developed AD‐ROs.
Modeling sex differences in Alzheimer’s Disease using isogenic hiPSC lines with different sex chromosome complements and APOE alleles
Authors: Filippova Gala N , Casad Michelle , Groneck Camille , Hui Katherine , Mishra Swati , MacDonald James W , Bammler Theo , Van Dyke Daniel L , Skakkebaek Anna , Gravholt Claus H , Mathieu Julie , Deng Xinxian , Berletch Joel B , Jayadev Suman , Disteche Christine M , Young Jessica E.
Published: January 2025

Background

Late Onset Alzheimer’s Disease (LOAD) is the most common neurodegenerative disorder. Carriers of an ɛ4 allele of the apolipoprotein E gene (APOE) have significantly increased risk of developing LOAD. LOAD is also strongly sex biased. Besides the well‐established role of sex hormones, the impact of genetic sex combined with APOE genotypes has not been studied. Sex chromosome dosage (SCD) is the main genetic difference between females (XX) and males (XY). Despite dosage compensation by X chromosome inactivation (XCI), some X‐linked genes remain expressed from the inactive X (Xi) and are female biased in expression. Many of these genes are related to neurological and immune functions and could contribute to neuroinflammation in AD.

Method

To understand the genetic interactions between autosomal risk (APOE) and sex‐bias in AD, we are generating isogenic sets of hiPSCs with various sex chromosome complements and APOE genotypes. We have derived XXY/XY, XY/X, and XX/X isogenic pairs by reprogramming cells from naturally mosaic individuals or by selective removal of the Xi in vitro. These lines uniquely position us to differentiate the effects of X chromosome dosage and/or presence of a Y chromosome, while minimizing genetic variability and environmental or hormonal confounders. Currently, we are also constructing APOE ɛ3 and ɛ4 alleles in our paired hiPSC lines with differing sex chromosome content using gene editing.

Result

Starting from an XXY/XY isogenic pair, we have generated an hiPSC series with six different genotypes of APOE ɛ3/ɛ3, ɛ3/ɛ4 or ɛ4/ɛ4 alleles with either the XXY or XY genotype. Preliminary results in differentiated neural precursor cells show differential expression of sex‐linked genes in relation to SCD. We also observed genome‐wide changes in gene expression and DNA methylation. Subsets of autosomal sex‐biased genes were differentially affected either by X chromosome dosage, presence of a Y, or both.

Conclusion

The new hiPSC lines are being differentiated to AD‐relevant cell types, including neurons, microglia, and cortical organoids, for transcriptomic and functional analyses to elucidate how APOE alleles and genetic sex interact to modulate risk in LOAD pathology.
Comparison among three kinds of assessment for the Mild Behavioral Impairment Checklist (MBI‐C)
Authors: Hwang Tzung‐Jeng , Yang Cho‐Hsiang , Lin Yi‐Ting
Published: January 2025

Background

Mild Behavioral Impairment (MBI) is a construct that describes the emergence of sustainable and at least mildly impactful neuropsychiatric symptoms (NPS) after age 50. The Mild Behavioral Impairment Checklist (MBI‐C) is a provisional tool used to measure the NPS of MBI. However, who should provide the information for the assessment of the NPS remained unclear.

Method

We recruited 123 MBI participant‐informant dyads from a psychiatric outpatient clinic of a university medical center. The MBI‐C was administered to both the participant (MBI‐self) and informant (MBI‐I). Then, a researcher (psychologist) compared the two results, clarified the differences, and made the final assessment (MBI‐R).

Result

There were 49 with MBI only and 74 with MBI plus MCI. Among the 123 MBI subjects, the mean MBI‐C total score was 6.06 (SD 6.7), 5.27 (SD 7.67), and 6.34 (SD 6.4) for MBI‐S, MBI‐I, and MBI‐R. There was no significant difference among the three. However, for the motivation domain, the MBI‐S and MBI‐R scoring was significantly higher than the MBI‐I scoring (p < 0.001). For the affect domain, the MBI‐R scoring was significantly higher than the MBI‐I scoring (p = 0.019). For the social domain, the MBI‐I scoring was significantly higher than the MBI‐S scoring (p = 0.012). There were no significant differences among the 3 scorings for the impulse or psychosis domains. When we examined each item in the 5 domains, the general tendency was consistent with the findings mentioned above, except that there were 3 items in the impulse domain showing a significant difference among the 3 scorings (MBI‐I, MBI‐R > MBI‐S).

Conclusion

Our findings showed there might be differences among the 3 kinds of scorings for the 5 MBI domains. If the MBI‐R scoring was treated as the gold standard, it was close to the MBI‐S scoring but higher than the MBI‐I scoring for the motivation and affect domain. For the social domain, the MBI‐R scoring was close to the MBI‐I but higher than the MBI‐S.
Identifying medical phenotypes associated with microglia‐expressing AD risk genes
Authors: Zhong Xue , Zhou Dan , Li Bingshan , Cox Nancy J
Published: January 2025

Background

A recent study with large samples of electronic health records (EHRs) suggested Shingles vaccination may reduce dementia risk. Although further investigation is needed to pinpoint the underlying mechanism, such observation adds to the evidence for a connection between peripheral and central nervous system immunity. Since microglia is the major cell type implicated in AD genetics, here, we set out to probe the shared biology between microglia in human brain and macrophages in peripheral system, through the common genes that express in both cell types.

Method

First, we identified a set of high‐confidence AD risk genes through integrative analysis of AD GWAS and human‐brain‐related genomic features. Then, we used eQTLs from human microglia to derive the eGene direction affected by AD risk alleles. For these AD‐associated eGenes, we predicted their expressions in peripheral tissues (whole blood, gut, lung, liver etc.) known to be enriched for macrophages with the use of UK biobank (UKB) data and prediction models pre‐trained by Genotype‐Expression project (GTEx) data. Finally, we tested the association of these genetically‐predicted gene expressions across ∼1000 medical phenotypes in UKB., followed by a replication analysis in the biobank of Vanderbilt University Medical Center (VUMC) to identify robust gene‐phenotype associations.

Result

The resulting associations (after adjustment for multiple testing), implicated inflammatory phenotypes, which include the association of connective tissue diseases with increased expression of CTSH, Emphysema with increased expression of TSPAN14, Edema with increased expression of PTK2B, Herpes simplex with reduced expression of PLCG2, and uterine inflammatory disease with increased expression of CD79B. The directions of these associations are all consistent with the regulatory direction in gene expression in human microglia by AD risk alleles.

Conclusion

We demonstrated that in peripheral tissues enriched for macrophages, AD risk genes that function in microglia were associated with inflammatory phenotypes in directions consistent with that observed in microglia, suggesting shared immune biology.
Cognitive impairment due to ischemic stroke in female rats is associated with secondary neurodegeneration, and attenuated with microRNA‐20a‐3p as assessed by diffusion tensor MR imaging and histological analysis
Authors: Sampath Dayalan , Singer Jacob , Gopalakrishnan Balaji , Akbari Zara , Villarreal Monserrat , Hurst David A , Noarbe Brenda P , Obenaus Andre , Sohrabji Farida
Published: January 2025

Background

Our studies show that the small non‐coding RNA, mir20a‐3p, is neuroprotective for stroke in the acute phase and also attenuates long term cognitive decline in middle‐aged female rats. Cognitive decline due to vascular diseases, such as stroke, is associated with secondary neurodegeneration in cortex and limbic structures. In this study, we assessed the volume of white matter, ventricles and regional diffusion‐weighted MR imaging measures to delineate pathological tissue characteristics from the postmortem brain of stroke rats.

Method

Middle‐aged females were subjected to ischemic stroke using the vasoconstrictor endothelin 1, injected adjacent to the left middle cerebral artery (MCA). Mir‐20a‐3p mimic (n = 10) or scrambled oligo (n = 8) was administered i.v. 4h, 24h and 70d post stroke. Animals were assessed periodically for cognitive performance up to 100d after stroke using both the cued fear conditioning test and the novel object recognition test (NORT). After perfusion fixation, T2 and diffusion tensor imaging (DTI) magnetic resonance imaging were performed on postmortem tissue. Subsequently, brains were processed for histology, including the Weil myelin stain.

Result

Stroke resulted in impairment in both the cued fear conditioning test and the NORT, which was attenuated by mir‐20a‐3p treatment (Sampath et al., 2023). Weil myelin‐stained sections showed that both the corpus callosum and internal capsule had a reduction in volume in the ischemic hemisphere as compared to non‐ischemic hemisphere in vehicle treated (scrambled oligo) MCAo animals. In contrast, sham and MCAo+Mir‐20a‐3p animals displayed no hemispheric differences in the volume in either tract. A similar volume asymmetry was also observed in the ventricles in the MCA0+ Scrambled group. Entorhinal cortex volume (diffusion tensor MR images) was also asymmetric in the MCAo+scrambled oligo group.

Conclusion

Cognitive changes measured with remote fear memory retrieval and NORT were associated with reduced density of major forebrain white matter tracts due to stroke and enlarged ventricular volume indicative of cell loss. This was observed in the entorhinal cortex, a region involved with contextual memory processing. These stroke‐induced deficits were attenuated in Mir‐20‐3p treated animals, indicating that microRNA treatment attenuated secondary neurodegeneration.
Epigenomics and single cell CRISPR screening to investigate the risk‐modifying role of microglia in Alzheimer’s disease and multiple sclerosis
Authors: Gallagher Michael D , Du Wenjuan , Hazel Katheryn EA , Aydin Zeynep , Cheng Yiran , Yuan Bingbing , Bell George W , Young Richard A , Jaenisch Rudolf , Corradin Olivia
Published: January 2025

Background

Alzheimer’s disease (AD) and other neurodegenerative diseases (NDs) cause substantial health‐related and economic burdens, but progress towards preventative or ameliorative treatments has been limited. Genome‐wide association studies have identified hundreds of risk loci containing single nucleotide polymorphisms (SNPs) that alter risk for these diseases, but >90% of these SNPs are in noncoding regions, which are cell type‐specific and difficult to study. To address this gap, we have characterized the epigenomes of iPSC‐derived neuronal and glial cells and performed CRISPRi single cell screening to dissect the molecular and cellular mechanisms underlying 10 ND risk loci.

Method

We generated neural progenitors, excitatory neurons, astrocytes and microglia from male and female iPSCs and performed RNA‐seq, H3K27ac ChIP‐seq, and Promoter Capture Hi‐C. We compared these data to those from primary uncultured (ex vivo) human neurons, astrocytes and microglia to compare their enhancer landscapes and ND risk SNP enrichment patterns. To perform CRISPRi single cell screening we integrated a dCas9‐KRAB transgene into an iPSC safe harbor locus and developed a novel lentiviral method that allows for efficient and well‐tolerated delivery of sgRNAs to iPSC‐derived microglia‐like cells (iMGLs).

Result

iMGLs displayed the strongest correlation of their enhancer landscapes with those of their ex vivo counterparts, as well as highly consistent enrichment of AD and multiple sclerosis (MS) risk SNPs in microglia‐specific enhancers. Enhancer/promoter interactions in iMGLs also overlapped significantly with those from ex vivo microglia. As these results suggest that iMGLs are a suitable model for studying ND risk loci, we performed a CRISPRi single cell screen to identify the target genes and pathways affected at 10 AD and MS risk loci.

Conclusion

While the enhancer landscapes of iPSC‐derived neuronal and glial cells vary in similarity to their ex vivo counterparts, they display similar ND risk SNP enrichments in cell type‐specific enhancers, suggesting that disease risk SNP mechanisms are largely recapitulated in iPSC‐derived cells. The iMGL epigenome is notably similar to ex vivo microglia, and CRISPRi screening of AD and MS risk loci in these cells will advance our understanding of these diseases and nominate potential therapeutic targets.
Carbon Defects as Highly Active Sites for Gold Detection and Recovery
Authors: Zhang Ting , Xu Zhenmin , Xie Ya , Dong Shuyuan , Guo Zhenpeng , Wang Wanting , Chen Yao , Qian Xufang , Yu Han , Bian Zhenfeng
Published: January 2025

The use of precious metals (PMs) in many areas, such as printed circuit boards, catalysts, and target drugs, is increasing due to their unique physical and chemical properties, but their recovery remains a great challenge in terms of zero‐valent PMs as the final product. We report a highly hydrophilic carbon dot (CD) as a reductant (electron donor), in which the defects in CD served as efficient active sites for zero‐valent PMs recovery with an electron‐donating capacity of ~1.7 mmol g−1. The reduction of gold follows a two‐step dynamic model characterized by the formation of nano‐gold nuclei (initial rapid electron transfer process) followed by an Ostwald ripening process (subsequent slow process). Finite element method (FEM) simulation shows that the reaction efficiency and confinement effect of AuCl4− ions are positively correlated with defect density, indicating that the quantitative control of carbon defect density is the key to enhancing reduction activity. Combining density functional theory (DFT) with XPS and FTIR technology, we found that the electron is transferred from CD to Au(III) via hydrogen bonding. This nano carbon material can be exploited to recover gold from e‐waste water directly, with the characteristics of reducing energy consumption and avoiding environmental pollution.
Über die Rolle von Wasserstoffwanderungen im Taxadiensystem
Authors: Li Heng , Goldfuss Bernd , Dickschat Jeroen S.
Published: January 2025

Taxa‐4,11‐dien wird durch die Taxa‐4,11‐dien‐Synthase (TxS) aus Taxus brevifolia hergestellt. Die einzigartige Reaktivität des Taxansystems ist durch weitreichende Wasserstoffwanderungen bei der Biosynthese gekennzeichnet. Diese Studie zeigt, dass selektive Wasserstoffwanderungen über große Entfernungen auch eine Rolle im Hochenergieprozess der EI‐MS‐Fragmentierung von Taxa‐4,11‐dien spielen. Es wurde eine TxS‐Enzymvariante generiert, die Cyclophomacten produziert, eine Verbindung, die durch einen konzertierten Prozess gebildet wird, der eine weitreichende Protonenverschiebung und einen Ringschluss umfasst, der auch als Addition eines Methylcarbinylkations an ein Olefin beschrieben werden kann. Basierend auf einer früheren rechnerischen Studie wurde vorgeschlagen, dass der Cyclisierungsmechanismus zu Taxa‐4,11‐dien zwei Protonenwanderungen über große Entfernungen anstelle eines direkten Transfers umfasst. Ein Substratanalogon mit einer verschobenen Doppelbindung wurde mit TxS umgewandelt, um experimentelle Beweise für diesen Vorschlag zu erhalten.
Conformational Plasticity and Binding Affinity Enhancement Controlled by Linker Derivatization in Macrocycles
Authors: Buffa Vanessa , Walz Carlo , Meyners Christian , Zheng Min , Oki Sugiarto Wisely , Repity Maximilian , Achaq Hanaa , Brudy Christian , Spiske Moritz , Cica Matijas , Hausch Felix
Published: January 2025

Macrocycles are abundantly used by nature to enable cell‐permeable bioactive molecules. Synthetic non‐peptidic macrocycles are also increasingly considered as modalities for difficult‐to‐bind proteins but guidelines for macrocyclization are only beginning to emerge. Macrocycles are thought to constrain the available conformations but also to allow for residual flexibility, the latter being poorly understood. Here we show that even medium‐sized macrocycles display an unexpected high conformational plasticity, even when bound to their protein target. Minor modification of the linker region of macrocycles can shift the conformational ensemble to distinct conformational subclasses, each constituting distinct three‐dimensional scaffolds for further optimization. This led to several new ligands with improved affinity and beneficial physicochemical parameters for the FK506‐binding protein 51, a promising target for depression, obesity and chronic pain. Importantly, none of the beneficial modifications could have been identified by classical medicinal chemistry as they only work in the macrocyclic context.

Our results show that macrocyclization can do more than keeping loose ends together but rather provide a platform for multiple series of macrocycles with distinct binding modes.
Stimuli‐Responsive Polyurethane Actuator Triggered by Light and Heat Reinforced With Disulfide Bonds
Authors: Ren Zhi‐Hui , Cui Zhishuai , Li Naqi , Yue Xiaolei , Zhang Yujie , Li Peng , Zeng Wen , Guan Zheng‐Hui
Published: January 2025

The photoisomerization behavior of mesogenic azobenzene makes it possible to convert light energy into mechanical action. However, achieving durability, configurability, and flexibility of light‐responsive actuators for artificial intelligence applications remains challenging. Here, a light responsive polyurethane (AzoPU‐SS) with remarkable anti‐fatigue and anti‐stress properties has been synthesized through the combination of dynamic disulfide bonds and mesogenic azobenzene functional groups. The AzoPU‐SS film demonstrated excellent photo‐induced bending, under ultraviolet (UV) light exposure, indicating effective transfer of molecular deformation from the microscopic to the macroscopic level. Moreover, the AzoPU‐SS material's elongation at break was greatly increased, due to the dynamic and reversible nature of the flexible S‐S and H bonds, enabling the coordinated motion of azobenzene groups and producing significant deformation. Such a reinforced strategy could be used to design smart actuators with superior stretchability and toughness, helping to broaden the applications of light‐responsive actuator materials.
Degradation Behavior of Rice Husk Fiber‐Reinforced PLA/PBAT Composites in Short‐Term Hydrothermal Environment
Authors: Wang Lei , Wang Zidong , Peng Lian , Wang Liping , Deng Bo
Published: January 2025

The rice husk fiber‐reinforced polylactic acid (PLA)/polybutylene adipate terephthalate (PBAT) composites were prepared by using an injection molding technique. An in‐depth investigation into degradation behavior within a short‐term hydrothermal environment, which encompassed a multi‐faceted analysis that included surface analysis, degradation process analysis, microstructure analysis, and structure strength analysis. Results show that performance of composites could be attributed to the weak interfacial adhesion, these interfacial defects can be seen as observed in the electron micrographs. In the presence of water molecules, it was observed that available interfacial bonds were susceptible to water during deformation. Moreover, the degradation behavior of the resultant network from the filler‐polymer composites could be monitored through available functional groups changes, which could provide an insight into the degradation pattern.
Haemato‐biochemistry, erythromorphology, and histopathology of Oreochromis niloticus as influenced by Aeromonas hydrophila infection and florfenicol therapy
Authors: Sharon Joshi , Abraham Thangapalam Jawahar , Sen Arya , Das Ratnapriya , Sinha Priyanka , Boda Satyanarayana , Patil Prasanna Kumar
Published: January 2025

Aeromonas hydrophila infection is one of the key factors limiting tilapia production, and antibiotics play important roles in the control of diseases. This study evaluated the effectiveness of florfenicol (FFC) when administered orally at the therapeutic dose of 15 mg/kg fish biomass/day for 10 days against A. hydrophila infection in Oreochromis niloticus in terms of survival, changes in haemato‐biochemistry, erythrocyte morphology, and histoarchitecture of the vital organs. A. hydrophila was moderately virulent to tilapia with an LD50 of 1.15 × 107 cells/fish. When challenged, it caused systemic infection in fish. The challenged fish were lethargic, wandered around the corners, rested at the bottom, swam vertically, and darkly pigmented. The FFC therapy effectively reduced bacteria‐induced mortalities and physiological stress as the measured haemato‐biochemical parameters indicated. The histopathological findings suggested alterations in tissue architecture of the kidney and liver tissues, which improved in the treated fish. Erythrocytes of the challenged fish showed elongated, irregular‐shaped, tear‐drop‐shaped, crenated, and hypochromic erythrocytes, ragged cytoplasmic membranes, vacuolation, hypertrophied nucleus, and eccentric nucleus. These morphological alterations were reduced with FFC therapy. Compared to the untreated group, the FFC treatment normalized the haemato‐biochemical parameters, improved wound healing, and promoted fish recovery against bacterial infections. The results hinted at the effectiveness of FFC against A. hydrophila infection in O. niloticus juveniles at the therapeutic dose. However, care must be taken for its judicious aquacultural application to avoid its negative impacts on fish, the environment, and consumers.
Death by AI: Will large language models diminish Wikipedia?
Authors: Wagner Christian , Jiang Ling
Published: January 2025

We argue that advances in large language models (LLMs) and generative Artificial Intelligence (AI) will diminish the value of Wikipedia, due to a withdrawal by human content producers, who will withhold their efforts, perceiving less need for their efforts and increased “AI competition.” We believe the greatest threat to Wikipedia stems from the fact that Wikipedia is a user‐generated product, relying on the “selfish altruism” of its human contributors. Contributors who reduce their contribution efforts as AI pervades the platform, will thus leave Wikipedia increasingly dependent on additional AI activity. This, combined with a dynamic where readership creates authorship and readers being disintermediated, will inevitably cause a vicious cycle leading to a staling of the content and diminishing value of this venerable knowledge resource.
Lanthanide‐Based Metal–Organic Frameworks Offering Hydrogen Bonding Cavities: Luminescent Characteristics and Sensing Applications
Authors: Ahlawat Deepti , Pachisia Sanya , Aashish  , Gupta Rajeev
Published: January 2025

This work presents the synthesis and characterization of three isomorphous lanthanide‐based metal‐organic frameworks (Ln‐MOFs) (Ln3+=Eu (1), Tb (2), and Sm (3)) supported by a pyridine‐2,6‐dicarboxamide‐based linker offering appended arylcarboxylate groups. Single crystal X‐ray diffraction studies highlight that these Ln‐MOFs present three‐dimensional porous architectures offering large cavities decorated with hydrogen bonding (H‐bonding) groups. These Ln‐MOFs display noteworthy luminescent characteristics. The mixed‐metal strategy affords a series of Ln‐MOFs exhibiting color‐tunable emissions. The Eu‐MOF was utilized for the nanomolar sensing of both nitrobenzene and 4‐nitrophenol. The critical role of H‐bonding in detecting these analytes is validated through multiple spectroscopic, ξ potential, and molecular docking studies. The Eu‐MOF illustrated notable anticounterfeiting as well as practical sensing applications.