bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single cell nuclei transcriptomics of human brains identify a role for homeostatic microglia in cellular senescence in Alzheimer’s disease
Authors: Yassine Hussein N , Li Boyang , Wang Shaowei , Ebright Brandon , Duro Marlon Vincent V. , Kerman Bilal Ersen , Asante Isaac , Arvanitakis Zoe , Louie Stan G 
Published: January 2025

AbstractBackgroundCellular senescence is a hallmark of aging and has been implicated in several neurodegenerative diseases including Alzheimer’s disease (AD). Senescence cells undergo changes in gene expression and metabolism and can exhibit a so‐called “senescence‐associated secretory phenotype” (SASP) characterized by increased secretion of pro‐inflammatory molecules and factors which can damage nearby cells, contributing to AD pathology progression.MethodIn this study, we determined mechanisms of cellular senescence using human postmortem brain samples, cellular models, and APOE4 animal models. Bulk (n = 632) and single‐cell nuclei transcriptomic profiling (n = 427) of the human dorsolateral prefrontal cortex (DLPFC) from the Religious Order Study/Memory Aging Project (ROSMAP). Lipidomic profiling was performed on a subset of 200 brains from the midfrontal cortex of ROS.ResultOur findings revealed upregulation of cellular senescence signatures in postmortem AD brain tissues across different cell types in comparison with controls. We identified a strong correlation between SASP and arachidonic acid (AA) metabolism (P<0.001) in bulk RNA. In single cell nuclei transcriptomics, AA Activation was strongly correlated with P2RY12 (homeostatic) microglia (P<0.0001), and was associated with worse performance on all cognitive domains (p<0.001) and AD neuropathology (P<0.001) as shown in the figure. Lipidomic analysis of postmortem brain tissues confirmed activation of AA derived eicosanoids. Pathway analysis implicated the activation of calcium dependent phospholipase A2 (cPLA2). Inhibiting cPLA2 by treatment with ASB14780 reduced senescence‐associated eicosanoids in APOE4 mouse models.ConclusionThis work implicates the sustained activation of homeostatic microglia as an underlying mechanism of cellular senescence in the AD brain.
Using anti‐Aβ antibodies to modulate the multi‐pronged human microglia response to Aβ pathology
Authors: Albertini Giulia , Zielonka Magdalena , Cuypers Marie‐Lynn , van Lieshout Veerle , Snellinx An , Pasciuto Emanuela , Wolfs Leen , Craessaerts Katleen , Horré Katrien , Jaspers Tom , Fiers Mark , Dewilde Maarten , De Strooper Bart 
Published: January 2025

AbstractBackgroundWhile social and medical debate about the efficacy and safety of anti‐Aβ immunotherapy is ongoing, one thing that emerged is that we have little understanding of the working mechanisms of these antibodies and this lack of knowledge complicates the interpretation of the clinical results. Here, we aimed to establish if microglia are required for the efficacy of Lecanemab, one of the most promising FDA‐approved disease‐modifying therapy for AD (Van Dyck et al. N Engl J Med 2023).MethodTo do so, we crossed AppNL‐G‐F mice with Csf1rΔFIRE/ΔFIRE mice (Rojo et al. Nat Commun 2019) to generate mice that show key features of Aβ pathology but genetically lack mouse microglia. We then assessed the effect of Lecanemab treatment on Aβ load and neuritic dystrophy.ResultWe demonstrate that Lecanemab lacks efficacy in the absence of microglia. On the other hand, when we xenotransplant human microglia into the brain of these mice (as described in Mancuso et al. Nat Neurosci 2019), we show that Lecanemab treatment significantly ameliorates both Aβ load and neuritic dystrophy. Furthermore, by employing scRNAseq on sorted human microglia, we demonstrate that Lecanemab treatment affects the transcriptome of the microglia by inducing a number of genes related phagocytosis, interferon response and immune activation. Functionally, we also established that Lecanemab‐treated human microglia ingest more amyloid‐β in vivo.ConclusionOverall, we provide the first evidence that microglia are crucial for the efficacy of anti‐Aβ immunotherapy and provide real insight into the working mechanisms of this first disease‐modifying therapy for AD.
Preserved unfamiliar face identity discrimination ability in Alzheimer’s disease: electrophysiological evidence
Authors: David Justine , Quenon Lisa , Hanseeuw Bernard J , Ivanoiu Adrian , Koessler Laurent , Rossion Bruno 
Published: January 2025

AbstractBackgroundWhile Alzheimer Disease (AD) patients’ difficulty to recognize face identity (Werheid & Clare, 2007) has been mainly attributed to episodic and semantic memory impairments, these patients can also show abnormal difficulties at matching of unfamiliar faces for their identity, suggesting impaired perceptual function (Lavallée et al., 2016). However, since this latter evidence is based on explicit behavioural measures, the difficulties of AD patients can be due to many factors (e.g., task understanding, stress, motivation, attention, decision making…).MethodsTo obtain an objective and implicit measure of face identity discrimination ability we coupled electroencephalographic (EEG) recordings and fast periodic visual stimulation (FPVS). FPVS consists in the presentation of visual stimuli at a defined frequency that produces EEG responses at the exact same stimulated frequency. 22 diagnosed AD patients (CSF‐positive for AD, MMSE ≤27) and 22 healthy controls matched in sex and age (Fig.1) were tested with a well‐validated FPVS paradigm (>30 published studies) consisting in the presentation of a same identity face 6 times per second (base frequency: 6Hz) with variable other identities presented every fifth image (i.e., oddball frequency: 6/5 = 1.2Hz)(Fig.2). EEG responses at 1.2 Hz reflect an individual’s identity discrimination ability (e.g., Liu‐Shuang et al. 2014, Neuropsychologia; Rossion et al., 2020, Eur. J. Neurosci.).ResultsAt the 1.2 Hz oddball frequency and harmonics, a highly significant amplitude response was found at bilateral occipito‐temporal site for both groups (Fig.3; AD: 0.43 µV, p <.001; CTR: 0.58 µV, p <.001). Since this response becomes negligible when the same faces images are presented upside down (AD: 0.02 µV, p>.05; CTR:0.0009 µV, p >.05), the 1.2 Hz response reflect high‐level cognitive processes. ANOVA analyses revealed a significant effect of Condition (i.e., upright vs. inverted; p<.001). However, despite a lower response overall in AD patients (Fig.3), there was no significant effect of Group (p = .53) or interaction (p = .07).ConclusionThese results provide evidence with an implicit and objective neural measure that unfamiliar face identity discrimination ability is largely preserved in AD, suggesting that abnormal difficulties at matching pictures of unfamiliar faces for their identity in this population is due to other factors than visual discrimination.
NLRP3 genetic polymorphisms are associated with the onset of mild cognitive impairment in Chinese
Authors: Gao Ruonan , Ma Suk Ling 
Published: January 2025

AbstractBackgroundNucleotide‐binding domain and leucine‐rich repeat (LRR)‐containing family protein 3 (NLRP3) is involved in neuroinflammation in Alzheimer’s Disease (AD). Single nucleotide polymorphisms (SNPs) in the NLRP3 gene are associated with the risk of AD in different populations, however the relationship between NLRP3 SNPs and Hong Kong population has not been studied.MethodIn this study,12 intron SNPs and 2 exon SNPs were genotyped in 233 healthy controls and 323 mild cognitive impairments (MCI) patients from Hong Kong. Gene expression levels of NLRP3 and other inflammation‐related genes were evaluated in peripheral blood mononuclear cells (PBMC) from the subjects by quantitative PCR (qPCR).ResultOur results showed that rs10754558 (C/T) and rs7525979 (G/C) were associated with an increased risk of MCI. The T allele of rs12564791 was associated with higher gene expression level of NLRP3 (p<0.001), IL18 (p<0.001) and IL1beta (p = 0.044) in PBMC. The G allele of rs3806268 was negatively correlated with NLRP3 gene expression (p = 0.048). Functional studies by dual‐luciferase assay showed that rs10754558 G to C mutation and rs10754555 G to C mutation led to a lower relative luciferase activity.ConclusionThese results suggested that genetic variations of NLRP3 were associated with the cognitive decline. In addition, NLRP3 SNPs might be associated to the gene expression of NLRP3.
Autophagy Deficits Underly Selective Neuronal Vulnerability to Alpha Synuclein Fibrils in Alzheimer’s and Parkinson’s iPSC Derived Neurons
Authors: Abey Ajantha S , Ng Bryan , Heon‐Roberts Rachel , Carlyle Becky C. , Bengoa‐Vergniory Nora , Wade‐Martins Richard 
Published: January 2025

AbstractBackgroundAlzheimer’s (AD) and Parkinson’s disease (PD) feature progressive neurodegeneration in a remarkably regionally selective manner. Post mortem studies have posited a role for cell autonomous mechanisms driving this, so we aimed to examine a live human induced pluripotent stem cell (iPSC) model to see whether it can replicate the phenomenon of selective neuronal vulnerability, so to better determine disease mechanisms and therapeutic targets.MethodiPSC‐derived neurons offer a rare opportunity to examine cell autonomous vulnerability in live human cells. iPSCs from patients with AD‐related presenilin‐1 mutations (n = 6), PD‐related leucine rich repeat kinase 2 mutations (n = 6), and isogenic corrected (n = 4) and healthy controls (n = 4) have been differentiated into both cortical and midbrain dopaminergic neurons to enable comparison of pre‐formed fibril induced pathology in different neuronal subtypes from the same patient. We then examined lysosomal number, morphology, degradation, pH, and calcium using live imaging assays, alongside mitochondrial biology, and electrophysiology to understand underlying drivers of vulnerability in the cell types.ResultUpon insult with alpha‐synuclein PFFs, AD and PD dopaminergic neurons produce substantial Lewy‐like pathology, whereas cortical neurons remain relatively resilient to alpha‐synuclein aggregation, suggesting cell‐type vulnerability. PSEN1‐Intron‐4‐Deletion cortical neurons, however, had significantly elevated pathology. These lines displayed hyperactivity on microelectrode arrays and abnormal lysosomal biology, including increased LAMP1 and dysregulated calcium. PFF‐insulted AD cortical neurons also have impaired neurite outgrowth, while PD cortical neurons are resilient.ConclusionThese preliminary results show relative vulnerability of AD against PD cortical neurons, and dopaminergic against cortical neurons to alpha‐synuclein aggregates for the first time. These suggest the selective vulnerability to proteinopathy in these diseases is reflected by the iPSC neuronal model and support the notion that cell intrinsic factors like autophagy drive vulnerability.
Crocetin inhibits Aβ aggregation in vitro and reduces ROS production and Aβ mediate cellular toxicity in neuronal SHSY5Y cells
Authors: GK Pratap , Priyadarshini CG Poornima 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disorder characterized by senile plaques, amyloid‐beta (Aβ), and neuroinflammation. The key targets in the treatment of AD are inhibiting the production of amyloid‐beta (Aβ), sphingomyelinase, and inflammation. Among the mechanisms, sphingolipids (specifically Ceramides) are recognized as distinctive mediators associated with the pathology of AD. Reportedly, alterations in sphingolipid metabolism and their metabolites result in mitochondrial dysfunction, autophagy impairment, dysregulation of amyloid‐beta, and disruption of neuronal homeostasis. This leads to increased production of reactive oxygen species (ROS), cytochrome c release, Bcl‐2 depletion, and caspase‐3 activation, primarily through modulation of intracellular signaling pathways, particularly those related to Akt/PKB kinase and mitogen‐activated protein kinases (MAPKs), exacerbating the progression of AD. Several natural compounds such as alkaloids, flavonoids, terpenoids, and phenolics have been reported to exhibit neuroprotective effects targeting various biomarkers including Aβ.MethodThe present study investigates the inhibition of amyloid‐β aggregation, oxidative stress markers (ROS), CD spectra, sphingomyelinase and amyloidogenic activity in vitro of Crocetin, a carotenoid isolated from Gardenia gummifera fruit.ResultOur results show that crocetin was shown to inhibit aggregation of Aβ1‐40 up to>60%. Compared to Galantamine. Further, attenuation of Aβ1‐40‐induced neuronal toxicity in SH‐SY5Y cells by up to 50% was also observed along with the prevention of reactive oxygen species accumulation.ConclusionOverall, these findings suggest that Crocetin may be a promising candidate for the management of AD
Intranasal insulin administration reduces oxidative stress‐induced damage and improves mitochondrial bioenergetics in Alzheimer disease
Authors: Tramutola Antonella , Pagnotta Sara , Domenico Fabio Di , Rolfi Lucrezia Romana , Perluigi Marzia , Barone Eugenio 
Published: January 2025

AbstractBackgroundBrain insulin resistance (bIR) heavily impacts on the core pathological processes of aging and Alzheimer disease (AD) since insulin regulates brain metabolism and cognitive functions. A close link among bIR, oxidative stress (OS) and mitochondrial defects exists, that contributes to brain dysfunctions observed in AD. Intriguingly, several studies suggest that intranasal insulin treatment (INI) enhances cognitive performance and reduced AD neuropathology both in humans and murine models of AD. We focused on the interplay between OS and bIR, by testing the hypothesis that rescuing brain insulin signaling activation by INI results in improved mitochondrial functions and reduced OS‐induced damage to proteins in a mouse model of AD (3xTg‐AD).Method12‐month‐old 3 × Tg‐AD and wild‐type (non‐Tg) mice were treated with INI (2 UI) or vehicle (saline) every other day for 2 months. Insulin signaling pathway and OS marker levels, i.e., PC, 4‐HNE and 3‐NT were evaluated in the frontal cortex. Then, due to the link between bIR and nitrosative stress, a redox proteomics approach was used to identify specific protein targets of 3‐NT modifications. Mitochondrial functions were evaluated by measuring mitochondrial complexes (OXPHOS) and activities in all experimental groups.ResultINI administration improved insulin signaling and reduced OS levels in 3xTg‐AD mice. In particular, a consistent reduction of 3‐NT levels was observed. Redox proteomics allowed to identify several proteins with reduced 3‐NT modifications, that belong to key pathways, such as protein degradation and energy metabolism, known to be involved in the progression of AD. Remarkably, reduced 3‐NT levels on mitochondrial proteins were responsible for an improvement of mitochondrial activity and brain energy metabolism.ConclusionWe propose that INI represents a promising approach to reduce OS‐induced damage to proteins and restore mitochondrial bioenergetics in AD brain.
Pluripotent stem cell based and crispr engineered models of neurodegeneration to assess neuronal networks
Authors: Ahlenius Henrik 
Published: January 2025

AbstractBackgroundStem cell based models of neurodegeneration are emerging as valuable tools to study neuronal networks as well as for drug discovery and testing. Drugs identified using stem cell based models are now entering clinical trials.MethodWe have generated CHMP2B, APP, PSEN and Tau‐mutated and transgenic human embryonic and induced pluripotent stem cell lines, using CRISPR genome editing, with the purpose to create human in vitro disease models. To date, most studies have focused on neuronal alterations; however, we have developed co‐culture systems in which neurons and glia are independently generated from human pluripotent stem cells and combined in vitro. We are now using these models to study neuronal networks and the involvement of astrocytes in FTD and AD.ResultWith this approach, we have identified alterations in the endolysosomal system of FTD astrocytes, a higher capacity of astrocytes to uptake and respond to glutamate, and neuronal network hyperactivity as well as excessive synchronization. Overall, our data indicates that astrocyte alterations precede neuronal impairments and could potentially trigger neuronal network changes, indicating the important and specific role of astrocytes in disease development.ConclusionHere we present our improved and updated strategy and results of combining pluripotent stem cells, CRISPR genome engineering and forward programming to generate complex co‐culture models to study neuronal network alterations in cardinal neurodegenerative disorders.
Clinical Phenotypes of Alzheimer’s Disease: Atrophy Patterns and their Pathological Correlates
Authors: Reijner Niels , Frigerio Irene , Bouwman Maud M.A. , Boon Baayla D.C. , Guizard Nicolas , Jubault Thomas , Hoozemans Jeroen J.M. , Rozemuller Annemieke J.M. , Bouwman Femke H. , Barkhof Frederik , Gordon Elizabeth , van de Berg Wilma D.J. , Jonkman Laura E. 
Published: January 2025

AbstractBackgroundRecent studies highlight distinct patterns of cortical atrophy between amnestic (typical) and non‐amnestic (atypical, with subtypes: behavioural, dysexecutive, logopenic and visuospatial) clinical phenotypes of Alzheimer’s disease (AD). The current study aimed to assess regional MRI patterns of cortical atrophy across AD phenotypes, and their association with amyloid‐beta (Aβ), phosphorylated tau (pTau), axonal degeneration (NfL) and microvascular deterioration (COLIV).MethodPostmortem In‐situ 3DT1 3T‐MRI data was collected for 33 AD (17 typical, 16 atypical) and 16 control brain donors. Images were segmented and AAL3 atlas regional volumes were obtained using QyScore®. At subsequent autopsy, eight brain regions were selected, immunostained for Aβ (4G8), pTau (AT8), Neurofilament‐light (NFL), and Collagen‐IV (COLIV), and quantified using qupath. Group comparisons and volume‐pathology associations were analyzed using linear models and partial correlations with covariates age, sex, postmortem delay, and intracranial volume.ResultsCompared to controls, AD phenotype groups showed overall lower cortical volume, while only minor volume differences were observed between AD phenotype groups, observed primarily in limbic regions (Fig. 1). Across pathological markers, AD phenotype groups showed consistently higher immunoreactivity than controls, while atypical AD showed consistently higher immunoreactivity than typical AD (Fig. 2). Moreover, different patterns of pathology could be observed between atypical subtypes (e.g. distinctly higher pTau load in the occipital gyrus of the visuospatial subtype). In typical AD, global volume loss was associated with lower Aβ and higher pTau, NFL and COLIV immunoreactivity, while in atypical AD, global volume loss was primarily associated with higher NFL immunoreactivity (Fig. 3a). Regionally, AD phenotype differences in atrophy‐pathology association were most pronounced in the (para) hippocampal regions. This distinction was mainly characterized by negative associations for NFL and COLIV, which was only observed in typical AD (Fig. 3b‐c).ConclusionAtrophy patterns between AD phenotypes showed only minor differences, potentially attributable to the on average later disease stage of the study cohort. The higher immunoreactivity for pathological markers found in atypical AD might suggest a more severe disease burden. (Para) hippocampal volume decline was associated with axonal and microvascular deterioration in typical AD, but not in the higher pathologically burdened atypical AD group, suggesting a differential susceptibility between AD phenotypes.
SNX19 contributes to neurodegeneration by disrupting the endolysosomal system in neurons
Authors: Ma Liang , Aguirre Luis , Holstein Debroah , Estevez Vanesa , Lechleiter James , Hsieh Jenny , Seshadri Sudha 
Published: January 2025

AbstractBackgroundSNX19 is a key player in endolysosomal and autophagy pathways, which have been extensively reported in neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggests SNX19 contributes to neuropathology, the underlying mechanisms remain unknown. Here, we propose to study the mechanism in aging postmortem brain tissue at single cell level and model SNX19 in human induced pluripotent stem cell (hiPSCs) derived brain organoids.MethodWe collected human postmortem brain dorsolateral prefrontal cortex (DLPFC) single‐cell RNA‐seq data from Religious Orders Study/Memory and Aging Project (ROSMAP N = 48). We obtained two human induced pluripotent stem cells (hiPSCs).ResultSingle‐molecule in situ hybridization experiments found that SNX19 is highly expressed in neurons, particularly excitatory neurons, compared to glia in human postmortem brains. Our single‐cell RNA‐seq data further demonstrated that SNX19 gene expression is significantly associated with neuritic plaques in excitatory neurons in postmortem brains.Cerebral organoid technology has made it possible to model human neurophysiology and disease with increasing accuracy in human‐derived tissue cultures. We performed advanced CRISPR gene editing in hiPSCs to knockout SNX19. We then differentiated them into 2D neurons and 3D cerebral organoids to evaluate the SNX19 impact. Our preliminary data has shown that SNX19 knockout can increase synaptic markers’ expression in hiPSC‐derived neurons. We observed morphological changes in SNX19 knockout organoids and replicated the synaptic markers’ change in the SNX19 knockout brain organoids.ConclusionOur study identified novel AD factors at SNX19 in human postmortem brains and will define its role in AD using human‐derived tissue cultures.
Copy number variation of whole genome sequence in 1519 patients with Alzheimer’s disease in China
Authors: Shen Lu , Yang Qijie , Xiao Xuewen , Xu Tianyan , Zhu Yuan , Jiao Bin 
Published: January 2025

AbstractBackgroundSingle nucleotide polymorphism (SNP)‐based genetic studies have identified many risk genes for Alzheimer’s disease (AD), but only explain part of the heritability. Structural variation (SVs) may account for some of this otherwise unexplained heritability. In this study, we sequenced 1,519 AD patients and 2,010 controls using 30X whole‐genome sequencing (WGS).MethodUsing six complementary CNV callers, we generated a high‐confidence CNV set. We reviewed rare variants within the reported 117 causal genes for dementia in our cohort. We also assessed the linkage disequilibrium (LD) between single nucleotide variants (SNVs) and copy number variants (CNVs).ResultWe identified 66990 deletions and 10906 duplications. On dementia genes, we observed the a total of 28 AD patients carried with rare CNVs in APP (duplication, 1 EOAD, Known pathogenicity), OPTN (deletion, 6 AD and 2 control), PRKAR1B (duplication, 1 EOAD), VPS13A (deletion, 1 EOAD), and et al. LD Analysis revealed that a 5.2 Kb deletion in NBEAL1 intron highly LD (R2 = 0.95) with rs139643391 (chr2:202878716) and a 291bp deletion in TMEM106B highly LD (R2 = 0.97) with rs5011436 (chr7: 12229132).ConclusionOverall, our findings suggest that the occurrence of APP locus duplication appears to be less common in the Chinese population. Other rare CNV variants in dementia genes may have potentially pathogenic and further validation of their pathogenicity is needed.