bluuebunny/crossref_metadata_2025_split huggingface dataset:
Baricitinib Treatment in RNU7‐1‐Associated Aicardi–Goutières Syndrome in a South African Child: A Case Report
Authors: Spracklen Timothy F. , Akhalwaya Shehnaaz , Ackermann Sally , Uggenti Carolina , Seabra Luis , Crow Yanick J. , Webb Kate 
Published: January 2025

ABSTRACTAicardi–Goutières syndrome (AGS) is a rare monogenic type I interferonopathy. Janus kinase (JAK) inhibition has emerged as a potential treatment for AGS. RNU7‐1 is one of the most recently discovered genes for AGS, and the clinical effects of JAK inhibition in these patients have not been reported. Here, we describe the diagnosis and treatment of a South African infant with RNU7‐1‐related AGS. The patient presented with developmental delay at age 5 months and was diagnosed with cerebral palsy due to a suspected congenital infection. By 18 months of age, he had a vasculitic rash, prominent generalized dystonia, persistent transaminitis, recurrent stomatitis, moderate‐range global developmental delay, and difficulty sleeping. AGS was considered after finding neuroimaging features of the disease; the diagnosis was confirmed when genetic investigations revealed two likely pathogenic RNU7‐1 compound heterozygous variants in the patient. Elevated interferon gene expression was noted in the patient and his mother who was a carrier of one RNU7‐1 variant. Baricitinib treatment was started, leading to modest, transient improvements in some clinical manifestations and a reduction in interferon‐stimulated gene expression. Liver function, dystonia, and neurological function did not improve even after increasing the baricitinib dose. Baricitinib was discontinued due to persistent and worsening adverse effects.
Intranasal Chlamydia pneumoniae Infection Induces Neuroinflammation and Cognitive Decline in Mice
Authors: Subedi Lalita , Martinon Daisy , Vit Jean‐Philippe , Fuchs Dieu‐Trang , Lane Malcolm E. , Mita Marianne , Chen Shuang , Gaire Bhakta Prasad , Koronyo Yosef , Arditi Moshe , Koronyo‐Hamaoui Maya , Crother Timothy R 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive irreversible dementia characterized by beta‐amyloid protein plaque deposition and hyperphosphorylation of tau forming neurofibrillary tangles, and neurodegeneration. An emerging theory posits that infections could be one of the triggering factors in AD development and progression. Multiple lines of evidence have linked Chlamydia pneumoniae (Cp), a gram‐negative obligate intracellular bacterium with AD. Cp has been detected in the post‐mortem brain tissues of AD patients, however, pathomechanisms associated with Cp in AD remain unknown.MethodTransgenic APPSWE/PS1∆E9 (ADtg) mice and non‐tg wildtype (WT) littermates were infected with Cp intranasally and sacrificed either 1 week or 6 months after infection. Mice were perfused with saline, and the brains were harvested for subsequent analysis, including PCR, flow cytometry, immunofluorescence, and live Cp growth. Neurobehavioral functions were assessed through an open field, visual‐stimuli X maze, and Barnes maze tests. Primary microglia and astrocytes were infected with Cp and cytokine and chemokines production was measured by ELISA.ResultWe found Cp in the olfactory bulb and brain of mice 7 days after infection and the infiltration of inflammatory cells into the brain. Cp infection resulted in microglial activation. Immunohistochemical analysis also revealed the activation of microglia and astrocytes in the Cp‐infected mouse brain. In addition, Cp infection led to increased mRNA expression of neuroinflammatory mediators such as cytokines and chemokines. Primary astrocytes and microglia cultures could sustain Cp growth and produce proinflammatory cytokines and chemokines in response to infection. Live Cp in the brain was also observed 7 months after infection and the Cp load was higher in ADtg mice than WT. Cp infection resulted in significant cognitive decline in both WT as well as ADtg mice together with increased AD‐related neuropathology.ConclusionIntranasal Cp infection leads to brain colonization and altered Iba1 immunoreactivity. Both primary astrocytes and microglia support Cp growth and produce neuroinflammatory cytokines. Long‐term Cp infection promotes neuroinflammation and cognitive decline in mice along with increased Aβ deposits. Cognitive impairment in Cp‐infected ADtg and WT mice as well as increased Aβ in ADtg mice suggest that Cp infection may play an important pathological role in AD development.
The participation of activating transcription factor 6 alpha, ATF6α, in Alzheimer’s disease
Authors: Chauvet Mariana Gomes , Isaac Alinny Rosendo , Lourenco Mychael V 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is the leading cause of dementia in elderly humans worldwide. More than 40 million people currently suffer from AD, and this prevalence tends to increase considerably in the coming decades due to increased longevity. The unfolded protein response (UPR) is an adaptive signaling mechanism that aims to maintain cell viability under misfolded protein accumulation and endoplasmic reticulum stress. UPR activation is associated with neurodegenerative diseases, such as AD, leading to synaptic loss and neuronal death. A key but understudied branch of the UPR depends on the activation of transcription factor 6 α (ATF6α). ATF6α was recently proposed as a therapeutical target in heart disease. Nonetheless, the association between ATF6α signaling and AD remains elusive. Here, we investigated whether dysfunctional ATF6α associates with AD, using both human post‐mortem brain tissues and mouse models.MethodATF6α protein levels were measured in post‐mortem cerebral cortex from healthy controls (HC) and AD patients, as well as in the hippocampus of APP/PS1 transgenic mice. Using an online database (Aging, dementia and TBI study from the Allen Institute) ATF6α mRNA expression was analyzed in HC and AD subjects.ResultInitial results suggest that ATF6α protein levels are reduced in AD patients. Using the Allen Institute database, we also found reduced ATF6α mRNA expression, in relation to the Braak scale of tau pathology in the parietal neocortex and hippocampus. Conversely, we found increased ATF6α protein levels in the hippocampus of the APP/PS1 transgenic mouse model of amyloid pathology.ConclusionTogether, our results indicate that ATF6α may be differentially altered in AD. Further investigation of the ATF6α pathway in AD may offer a novel therapeutic perspective for cognitive decline.
How gut bacteria influence the brain barriers, neuroinflammation and Alzheimer’s disease: a role for bacterial metabolites and extracellular vesicles
Authors: Vandenbroucke Roosmarijn E ,   Barriers in Inflammation lab, VIB‐UGent Center for Inflammation Research, Ghent, Belgium
Published: January 2025

AbstractBackgroundThe brain is shielded from the peripheral circulation by central nervous system (CNS) barriers, comprising the well‐known blood‐brain barrier (BBB) and the less recognized blood‐cerebrospinal fluid (CSF) barrier located within the brain ventricles. The gut microbiota represents a diverse and dynamic population of microorganisms that can influence the health of the host, including the development of neurological disorders like Alzheimer’s disease (AD). However, the intricate mechanisms governing the interplay between the gut and brain remain elusive, and the means by which gut‐derived signals traverse the CNS barriers remain unclear.MethodsMicrobiota was removed via antibiotics treatment or using germfree mice. AppNL‐G‐F mice were used as mouse model for AD. Helicobacter pylori (H. pylori) and total microbiota‐derived extracellular vesicles (EVs) were purified using size exclusion chromatography (SEC) and density gradient, followed by quality control. Bacterial‐derived metabolites and EVs were administered to mice via oral gavage. Brain barrier tightness was analyzed using FITC‐dextran leakage, tight junction visualisation and immune cell infiltration in the brain. AD pathology was determined via Aβ plaque load (ELISA & plaque immunostainings) and cognitive behavioural tests. Neuroinflammation was determined via analysis of glial activation, qPCR, cytokine analysis and immune cell infiltration into the brain.ResultOur research uncovers the essential role of gut microbiota in the formation and maintenance of tight CNS barriers. Notably, certain metabolites reinforce CNS barrier integrity, irrespective of vagal nerve influence, safeguarding against AD‐related deterioration of brain integrity. Additionally, specific pathogens like H. pylori generate EVs, so called outer membrane vesicles (OMVs) that trigger brain inflammation, accelerating AD‐associated neuropathological processes, depending on complement 3 (C3) signaling. Interestingly, utilizing germ‐free AppNL‐G‐F mice, we observed that also oral administration of gut microbiota‐derived bacterial EVs (bEVs) exacerbate Aβ pathology and disrupt astrocyte‐microglia‐neuron networks.ConclusionIn summary, the influence of bacteria‐derived metabolites and EVs on brain barriers and AD pathogenesis underscores the significance of unraveling these mechanisms. Such understanding offers fresh insights, potentially guiding the development of innovative therapeutic strategies for neurological disorders.
Characterization of Language Profiles in Cognitively‐Defined Subgroups of Alzheimer’s Disease
Authors: Gallée Jeanne , Gibbons Laura E. , Mukherjee Shubhabrata , Scollard Phoebe , Choi Seo‐Eun , James Bryan D , Klinedinst Brandon S , Lee Michael L. , Mez Jesse , Trittschuh Emily H. , Saykin Andrew J. , Crane Paul K. 
Published: January 2025

AbstractBackgroundThe relationship between Alzheimer’s disease (AD) pathology and the associated clinical syndrome a patient presents with remains indeterminate. Cognitively‐defined subgroups of AD have revealed distinctions based on relative cognitive impairments, including AD‐Language, where challenges in language are substantial, and AD‐No Domain, where no relative asymmetries across cognitive domains occur. Pathological features of AD have been associated as the primary neuropathology of the logopenic variant of primary progressive aphasia (lvPPA). Hallmark clinical features of lvPPA include relatively spared comprehension in the face of decline in naming and repetition abilities. This work aimed to test the hypothesis that the lvPPA language profile was overrepresented in AD‐Language when compared to AD‐No Domain.MethodMeasures of verbal comprehension, confrontation naming, and phrase‐level repetition were obtained from all participants from the Religious Orders Study (ROS), the RUSH Memory and Aging Project (MAP) and the Minority Aging Research Study (MARS) using confirmatory factor analyses. We subsetted the data to include participants belonging to the AD‐Language and AD‐No Domain groups at their initial AD diagnosis visit. We compared patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition. Pearson’s Chi‐squared tests with Yates continuity correction was used to test if the language patterns were statistically different between the two AD subgroups.ResultsWe analyzed language performance in 642 participants across AD‐Language (31.8%) and AD‐No Domain (68.2%) groups (Table 1). Thresholds were based on AD‐No Domain and set as the median for each subdomain (comprehension = ‐.101, naming = ‐.957, repetition = .233) to establish whether a score represented a relative strength or weakness in the language profile. Eight patterns of language profiles based on strengths and weaknesses in comprehension, naming, and repetition were formed (Figure 1). The distribution of language patterns differed significantly between AD‐Language and AD‐No Domain (χ2 = 97.6, p <.001). Furthermore, the lvPPA pattern was found more frequently in AD‐Language (χ2 = 28.1, p <.001).ConclusionHeterogeneity within the AD‐Language spectrum includes a significant proportion that is consistent with the language profile of lvPPA. Relative performance in domains of verbal comprehension, confrontation naming, and phrase‐level repetition varied by AD subgroup.
Beta‐amyloid is the most promising target for Alzheimer’s disease treatment
Authors: Solomon Beka 
Published: January 2025

AbstractBackgroundAmyloid filaments formation is a complex kinetic and thermodynamic process. The dependence of peptide polymerization on peptide–peptide interactions to form a β‐pleated sheet fibrils and the stimulatory influence of other proteins on the reaction suggest that amyloid formation may be subject to modulationMethodIn vitro formation of β‐amyloid was induced by incubation of an aqueous solution of AβP (10 mg/ml) for 7 days at 37°C. The extent of β‐amyloid formation and disaggregation were monitored using a panel of well characterized mAbs raised against soluble AβP fragments. The aggregation of Aβ was measured by the ThT binding assay, in which the fluorescence intensity reflects the degree of β‐amyloid fibrillar aggregation.ResultThe epitopes of the anti ‐aggregated antibodies were localized employing a library of filamentous phage displaying random combinatorial hexapeptides. Among 44 phages, the consensus sequence EFRH was carried by 40 clones. The EFRH (3‐6) of AβP located at the N‐terminal is exposed for antibody binding in both forms, either in solution or an aggregate, suggesting that he is involved in the aggregation process and acts as a regulatory site controlling both the prevention and the disaggregation process.ConclusionOur pioneering data were recently confirmed by successful Aducanumab (3‐7) and Lecanemab (1‐16) antibodies that recognize the N terminus of Aβ and selectivity bind to aggregated Aβ species. Naturally occurring anti‐AβP antibodies have been found in human CSF and in the plasma of healthy individuals, from where Aducanumab was derived, but were significantly lower in Alzheimer’s disease patients.
Genome‐wide association meta‐analyses in Chinese and European individuals yield new insights into the etiology of Alzheimer’s disease
Authors: Ge Yi‐Jun , Chen Shi‐Dong , Wu Bang‐Sheng , Zhang Ya‐Ru , Wang Jun , Yu He Xiao‐ , Zhao Qianhua , Wang Yan‐Jiang , Jia Jian‐Ping , Yu Jin‐Tai 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a devastating neurological disease with complex genetic etiology, yet most known loci were only identified from the late‐onset type of European ancestry.MethodWe performed a two‐stage genome‐wide association study (GWAS) of AD totaling 6,878 Chinese and 487,511 European individuals.ResultWe demonstrated a shared genetic architecture between early‐ and late‐onset AD. In addition to the APOE locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry‐specific variant within EGFR (rs1815157). Notably, the TCN2 locus showed genome‐wide significant associations with AD in both discovery and replication stages in Chinese populations. More replicated variants were observed in the Chinese (31%) than European samples (4%). Combining genome‐wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome‐wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might be protective against AD.ConclusionThe current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology.
Reactive oxygen species from mitochondrial complex III are induced by NCLX to promote astrocytic STAT3‐linked transcription and dementia‐related pathology
Authors: Barnett Daniel , Zimmer Till S , Booraem Caroline , Palaguachi Fernando , Meadows Samantha M. , Xiao Haopeng , Chouchani Edward T , Orr Anna G. , Orr Adam L 
Published: January 2025

AbstractBackgroundMitochondrial reactive oxygen species (mROS), such as superoxide and hydrogen peroxide (H2O2), are implicated in aging‐associated neurological disorders, including Alzheimer’s Disease and frontotemporal dementia. Mitochondrial complex III of the respiratory chain has the highest capacity for mROS production and generates mROS toward the cytosol, poising it to regulate intracellular signaling and disease mechanisms. However, the exact triggers of complex III‐derived ROS (CIII‐ROS), its downstream molecular targets, and its functional roles in dementia‐related pathogenesis remain unclear.MethodHere, we investigated the drivers and consequences of CIII‐ROS production in primary mouse astrocytes and mouse models of dementia‐linked proteinopathy using site‐selective mROS suppressors and genetic approaches together with live‐cell imaging of sub‐compartmental H2O2 dynamics, stoichiometric redox proteomics, and transcriptomics.ResultWe found that specific disease‐related factors transiently increase astrocytic CIII‐ROS levels, and this effect is dependent on a mitochondrial sodium‐calcium exchanger. CIII‐ROS oxidized specific cysteines on astrocytic proteins associated with disease, amplified STAT3 phosphorylation and nuclear translocation, and promoted gene expression changes linked to STAT3 and related neuroimmune pathways. Inhibition of other sites of ROS production, including mitochondrial complex I and NADPH oxidase, had no effects on mROS responses or STAT3 signaling, demonstrating the specificity of CIII‐ROS induction and its context‐dependent modulation of STAT3 activities. Blockade of CIII‐ROS in transgenic mouse models of dementia with a site‐selective and brain‐penetrant suppressor reduced astrocytic alterations, neuropathology, and premature mortality.ConclusionOur data suggest that dementia‐associated factors induce site‐specific mROS production and that CIII‐ROS promote precise post‐translational redox modifications and amplify STAT3‐linked signaling and changes in gene expression. Together, our findings reveal CIII‐ROS as an important node of mitochondrial‐nuclear communication in pathogenic conditions, whereby mROS transients are converted into long‐lasting changes in gene transcription and cell function. CIII‐ROS and redox signaling offer new therapeutic opportunities for aging‐associated neurological disorders.
Pyramidal neurons of CA1 neuron in organotypic slice
Authors: Roy Avishek , Deforges Severine , Mulle Christophe 
Published: January 2025

AbstractThis is a maximal intensity projection of CA1 pyramidal cell transfected with plasmid with the reporter GFP using single cell electroporation technique. In this particular case the organotypic slices were prepared from p5‐7 pups in a tissue chopper (McIlwain). And maintained in MEM bases media with added glutamax with a change in 2 alternative dyas at 37°C and 5% CO2 for 4 days in‐vitro (DIV) before electroporating with a glass pipette of 7‐10mΩ resistance by applying 4 square pulses of ‐ve voltage of −2.5 V, for 25 ms duration at 1 Hz frequency. Then maintained in the same medium for one four more days before fixing them in PFA(4‰ v/v) and amplified with anti‐GFP antibody (ab290, 1:1000 dil) and imaged in SP2 confocal microscope (Leica) for z‐stack.
The VLPO analog in the human hypothalamus shows tau‐driven extreme loss of sleep‐regulating neurons in PSP and Alzheimer’s disease: unveiling the basis of NREM sleep dysfunction in tauopathies
Authors: Rastegar‐Pouyani Shima , Lew Caroline , Satpati Abhijit , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Spina Salvatore , Seeley William W. , Walsh Christine M , Neylan Thomas C. , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundSleep dysfunction is commonly seen in Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP), potentially worsening these conditions. Investigating early neuropathological changes in human sleep‐promoting neurons, which often precede cognitive decline, is crucial for understanding the basis for sleep dysfunction as possible treatments yet remain underexplored. We used postmortem brains of AD and PSP patients to quantify neuronal numbers and tau burden in the intermediate nucleus of the hypothalamus (IntN), VLPO analog, known for its role in sleep maintenance.MethodPostmortem human brain tissues from three groups were used: healthy controls, progressive AD stages, and PSP. Formalin‐fixed, celloidin‐embedded hypothalamic tissue was cut at 30‐micron. Slides were immunostained for galanin (GAL), an IntN neuronal marker, phosphorylated‐tau (p‐tau) antibodies, and counterstained with Gallocyanin. The total number of GAL‐expressing neurons and/or p‐tau deposition were estimated using the stereology.ResultsIn a cohort of 7 cases (Table 1), we found a significant decrease in neuronal population and volume in the IntN in both AD and PSP patients, with a more pronounced decline in PSP. However, the neuronal density was not changed in any of the AD or PSP conditions, reflecting a simultaneous neuronal and volume loss. GAL‐positive neurons were more resilient in AD, showing better preservation than in PSP. In both AD and PSP, p‐tau‐positive neurons increased compared to the controls. Notably, in AD, tau aggregates were present in both GAL‐positive and negative neurons, while in PSP, GAL neuronal population decreased more than the others, and tau aggregates were only observed in GaL‐negative neurons (Fig. 1).ConclusionIn both AD and PSP, our research reveals substantial neuropathological changes in the IntN, with PSP exhibiting more pronounced alterations. These changes align with observed sleep dysfunction in both conditions. PSP features severe insomnia, although wake‐promoting neurons remain relatively intact, thus a significant reduction in neurons controlling NREM‐sleep could account for its clinical sleep disturbances. Conversely, AD displays a decline in wake‐promoting neurons and a gradual, moderate loss of NREM neurons, both leading to excessive daytime sleepiness and sleep fragmentation, yet overall preserved total sleep time. These findings deepen our understanding of NREM sleep dysfunction in tauopathies, offering insights for targeted interventions.