bluuebunny/crossref_metadata_2025_split huggingface dataset:
The loss‐of‐function variant in MFSD3 could play a crucial role in the pathogenesis of dementia with Lewy bodies
Authors: Kimura Tetsuaki , Suganuma Mutsumi , Sawamura Kayoko , Asanomi Yuya , Shimoda Nobuyoshi , Ogiso Noboru , Hosoyama Tohru , Niida Shumpei , Ozaki Kouichi , Shigemizu Daichi 
Published: January 2025

AbstractBackgroundDementia with Lewy bodies (DLB) is the second most common form of degenerative dementia in older people. The clinical feature of DLB includes cognitive impairment, visual hallucinations, parkinsonism, and fluctuating attention. Three genes, SNCA (‐synuclein), APOE (apolipoprotein E), and GBA (glucosylceramidase), have been convincingly demonstrated to be associated with DLB. Our previous studies reported that a variant in MFSD3 (rs143475431, c.888T>A:p.C296*) is associated with DLB in the Japanese population through whole‐genome sequencing and association studies. However, the precise mechanisms that this variant contributes to DLB development remains unclear.MethodWe introduced the MFSD3 p.C296* variant into a human neural stem cell line using the CRISPR/Cas9 system. Subsequently, the mutant cells were analyzed for cell proliferation rate using CyQUANT Cell Proliferation Assay Kit. The mutant cells were further induced to differentiate into neurons and astrocytes to assess their differentiation ability. Additionally, we generated the homologous Mfsd3 knockout (KO) mice using the CRISPR/Cas9 system. The neurogenesis was evaluated by the number of doublecortin positive cells in the hippocampus. The behavior of Mfsd3 KO and wild‐type mice was analyzed using IntelliCage.ResultWe revealed that the MFSD3 p.C296* variant was associated with decreased cell proliferation and reduced neurogenesis in the human neural stem cell line analyses. This decline in neurogenesis was also observed in the hippocampal dentate gyrus of Mfsd3 KO mice, and the Mfsd3 KO mice had smaller hippocampi compared to the wild‐type mice. Furthermore, Mfsd3 KO mice exhibited a reduced level of curiosity about the new environment.ConclusionOur results demonstrate that loss of function of MFSD3 affects neurons and the brain, as indicated by our studies using human neural stem cell lines and Mfsd3 KO mice. Further functional verification will contribute to elucidating the mechanism of DLB pathogenesis.
Neuropsychiatric Symptom Profile in Alzheimer’s Disease and Their Effects on Functional Decline
Authors: Zhu Carolyn W. , Schneider Lon S. S. , Aloysi Amy , Elder Gregory , Grossman Hillel , Neugroschl Judith A. , Schimming Corbett , Soleimani Laili , Sano Mary 
Published: January 2025

AbstractBackgroundNeuropsychiatric symptoms (NPS) are core features of Alzheimer’s disease (AD) and have significant impact on patients, caregivers, and families. Worse NPS scores are associated with worse function and higher need for care. It is unclear if individual NPS symptoms may differentially affect functional decline and may be more effectively targeted to improve patient outcomes.MethodData are drawn from participants enrolled in the National Alzheimer’s Coordinating Center Uniform Data Set (9/2005‐11/2022). Participants were diagnosed with Mild Cognitive Impairment or AD at baseline, had a primary etiologic diagnosis of AD, and had at least one annual follow‐up visit (average follow‐up = 4 years). Participants’ function was measured using the Functional Assessment Questionnaire (FAQ). NPS were reported by ADC study clinicians using the “Clinician Judgment of Symptoms” (Form B9) evaluating whether each of the following symptoms manifested as a meaningful change in behavior (yes = 1, no = 0): apathy‐withdrawal, depressed mood, visual or auditory hallucinations, delusions, disinhibition, irritability, agitation, and anxiety. Dementia severity was measured using the CDR. Multivariable analyses of the effects of each NPS on decline in function were performed using linear mixed models. Covariates included baseline age, gender, race/ethnicity, education, referral source, number of visits, comorbidities, APOE genotype, and number of medications.ResultBaseline sample characteristics (N = 9,358): mean age = 74±9, 47% male, 78% non‐Hispanic white, 11% black, 8% Hispanic, education = 15±4; 52% CDR = 0.5, 35% CDR = 1, and 13% CDR≥2; FAQ = 12±9. Baseline presence of NPS: apathy (34%), depressed mood (33%), anxiety (31%), irritability (28%), agitation (13%), disinhibition (10%), delusions (9%), and hallucinations (5%). Apathy was the most persistent of NPS with 37% of all participants had clinician endorsed apathy in ≥50% all of their visits, followed by depressed mood (28%), irritability (27%), anxiety (21%), agitation (14%), disinhibition (11%), delusions (9%), and hallucinations (5%). Functional decline was faster in those with persistent (≥50% of all visits) apathy, agitation, and delusions.ConclusionDifferent behavioral symptoms have differential effects on functional decline, a major driver of caregiver stress and institutionalization. Better understanding of these differential effects on function is crucial in designing trials for treatment in AD. Assessing for these behavioral symptoms should be a standard component of cognitive evaluations.
Single‐cell spatial transcriptomic and proteomic characterization of a novel mouse model of late‐onset AD
Authors: Kwang Nellie , Green Kim N. , Swarup Vivek 
Published: January 2025

AbstractBackgroundLate‐onset Alzheimer’s disease (LOAD) represents the majority of human AD cases, yet the availability of animal models that accurately reflect LOAD progression and pathology is limited. Traditional transgenic mouse models including 3xTg‐AD and 5xFAD rely on supraphysiological overexpression of familial AD risk genes, failing to adequately replicate the disease progression observed in LOAD. Here, we present the first characterization of MODEL‐AD1 (MAD1), a platform mouse developed by the Model Organism Development and Evaluation for Late‐onset Alzheimer’s Disease (MODEL‐AD) Consortium. MAD1 features replacements of murine Aβ (App), Mapt, and Apoe alleles with their human counterparts hAβ, hMAPT (H2), and hAPOE4. These humanized alleles are regulated similarly to their murine equivalents and expressed at physiological levels.MethodBrain sections from 4‐month‐old (mo) MAD1 and B6J (WT) (n = 3/sex/group) mice were analyzed using NanoString CosMx single‐cell hybridization‐based spatial transcriptomics and antibody‐based spatial proteomics to probe region‐specific differences in gene expression and protein distribution. Further, to examine the role of demyelination in AD pathology, snRNA‐seq analysis was performed on hippocampal and cortical samples of 8‐mo MAD1 mice treated with cuprizone (n = 3M,2F/group), a copper chelator that causes oligodendrocyte degeneration and myelin loss. Finally, snRNA‐seq findings were validated with immunohistochemistry by staining for glial and AD markers.ResultSpatial transcriptomic and proteomic analyses revealed distinct differences in gene expression and protein distribution between MAD1 and WT mice. Key genes involved in neuroinflammation, synaptic function, and neuronal survival showed altered expression in MAD1 mice, indicating a shift towards an AD‐like state. Congruent with our spatial analyses, snRNA‐seq analysis revealed increased glial cell activation in MAD1 compared to WT. Additionally, 8‐mo MAD1 mice treated with cuprizone exhibited marked microgliosis and astrogliosis compared to MAD1 controls, as demonstrated by immunohistochemistry and snRNA‐seq. These pronounced glial changes were not sufficient to induce Aβ or tau formation at this stage.ConclusionThese exciting preliminary findings establish MAD1 as a novel platform model for testing various interventions in AD research, including demyelination. Future studies will explore the effects of aging, diet, remyelination, and other factors on MAD1 mice to elucidate the mechanisms of LOAD.
The involvement of human CD33 in the pathogenesis of Alzheimer’s disease mouse model
Authors: Su Tzu‐Ching , Hung Wei‐Chien , Cheng Irene Han‐Juo 
Published: January 2025

AbstractBackgroundGenome‐wide association studies demonstrated that immune suppressive receptor CD33 variants are associated with high susceptibility to developing Alzheimer’s disease (AD). Human CD33 (hCD33) regulates microglial immune response and clearance ability. However, the differential regulation of phagocytosis by human and mouse CD33 imposes constraints on utilizing the mouse model for investigating the role of CD33 in AD. Therefore, we investigate the pathogenesis progression of the AD mouse model with hCD33 knockin.MethodWe generated conditional hCD33 knock‐in mice on microglia in the J20 AD mouse model. At 6 months, Morris water maze and Barnes maze were applied to examine their spatial learning and memory. The ELISA and immunohistochemistry were used to examine the accumulation of soluble and insoluble Aβ, microglial activation, in‐vivo Aβ uptake, and synaptic dysregulation.ResultIn the presence of hCD33, Aβ accumulation was decreased in the AD mouse. Conversely, a more diffuse and less condensed plaque structure was observed. In hCD33 knock‐in mice, microglia failed to form a compact barrier covering plaque deposits. Under hCD33 expression, AD mice had more neurotoxic dystrophic neurite around plaques, suggesting a higher plaque‐associated neurotoxicity. However, spatial learning and memory retention had no significant differences between the control AD mice and hCD33 knock‐in AD mice in the Morris water maze.ConclusionOur findings suggested that the presence of the AD risk gene human CD33 incurred neurotoxicity and altered the structure of Aβ deposition by manipulating microglial barrier formation against AD stress.
Dissecting the mechanisms of CASK deficiency on the clearance of Aβ in microglia
Authors: Chang Jacky , Cho Yen Ting , Lin Yu Yi , Cheng Irene Han‐Juo 
Published: January 2025

AbstractBackgroundAmyloid‐beta (Aβ) deposition is a key pathological characteristic of Alzheimer’s disease (AD). Microglia serves as a crucial system responsible for clearing Aβ. Activated microglia migrate towards Aβ deposits, engulf them, and breakdown Aβ through cathepsins within the lysosome. Calcium/calmodulin‐dependent serine protein kinase (CASK) regulates microglia’s migration and phagocytic activity. Notably, our findings revealed a reduction in the expression of microglial CASK upon Aβ treatment. Nevertheless, the specific function of CASK in activated microglia remains undiscovered.MethodThe chemotaxis and migration of CASK KO BV2 microglia were examined via transwell and wound healing assays with Aβ presence variations. Focal adhesion kinase (FAK) protein levels were assessed through western blotting. Phagocytic capacity will be tested by using fluorescence‐labeled Aβ and microbeads after activated by LPS and Aβ. Vinculin, CD68 or lysosome associated membrane (LAMP1) were visualized using immunostaining. Actin was stained with phalloidin. The colocalization was measured by ImageJ. Expression of cathepsin B, D, and S, and Aβ‐degrading enzymes in CASK KO microglia were measured via qPCR. Lysosome morphology was tracked using lysotracker.ResultThe expression of microglial CASK was reduced upon Aβ treatment. The chemotaxis and migration capabilities of CASK KO microglia are notably inferior to WT microglia. After Aβ treatment, FAK protein levels were significantly higher in WT but not CASK KO microglia. Moreover, CASK KO microglia had lower vinculin‐lamellipodia colocalization and lamellipodia area than WT microglia. Conversely, CASK deficiency in microglia increased Aβ engulfment and the number of lysosomes. In addition, LAMP1‐Aβ colocalization was diminished in CASK KO microglia. CASK KO microglia had higher levels of cathepsin B, D, and S, as well as and Aβ‐degrading enzymes than WT microglia.ConclusionOur investigation revealed the critical roles of CASK in regulating microglial migration and phagocytic functions, particularly in the context of Aβ treatment. These findings necessitate further exploration into the nuanced functions of CASK in activated microglia, potentially offering insights into novel therapeutic avenues for AD.
Shared Genetic Risk Factors Contribute to the High Comorbility between Alzheimer’s Disease and COVID‐19 in European and African Populations
Authors: Chen Jingchun 
Published: January 2025

AbstractBackgroundThe global outbreak of COVID‐19, caused by the SARS‐CoV‐2 virus, has been linked to long‐term neurological complications, including Alzheimer’s disease (AD) among seniors. However, the precise genetic impact of COVID‐19 on long‐term AD development remains unclear.MethodThis study leveraged genome‐wide association study (GWAS) data and genotype data to explore the genetic correlation between AD and various COVID‐19 phenotypes across European ancestry (EA) and African ancestry (AA). We first calculated the polygenic risk scores (PRSs) of three COVID‐19 phenotypes in AD cases and controls from both EA and AA populations, then determined the genetic correlations between COVID‐19 PRSs and AD by logistic regression analyses with or without adjusting for age, sex, and APOE genotypes. Furthermore, shared SNPs and genes were identified through variant mapping and gene annotation from the large GWAS data of both diseases.ResultOur study identified significant positive correlations between AD diagnosis and COVID‐19 in both populations. Notably, correlations were stronger from AA as compared to the EA population. In addition, significant shared variants and genes were identified in the chr17q21.31 region, suggesting common biological mechanisms may contribute to the high comorbidity between AD and COVID‐19.ConclusionFurther functional studies are required to understand their causal relationships, leading to enhanced prevention and treatments for both conditions.
Investigating the Interplay between Air Pollution and APOE Clusters in Taiwan: Implications for Alzheimer’s Disease Susceptibility
Authors: Fuh Jong‐Ling , Lo Yen‐Li , Lin Yung‐Shuan , Lee Wei‐Ju , Fann Cathy SJ 
Published: January 2025

AbstractBackgroundThere is a strong genetic component to Alzheimer’s disease (AD), as evidenced in genome‐wide association studies (GWASs) that have identified new variants associated with the disease. This is particularly true for the apolipoprotein E (APOE) gene and its neighboring genes on chromosome 19q13.3. In addition, air pollution was linked to aggravating the development of AD. A significant gap remains in the understanding of gene‐environment interactions influencing AD susceptibility. The purpose of this study is to examine how air pollution interacts with APOE clusters in Taiwan.MethodWe conducted a district‐matched case‐control study involving 3,229 AD patients and 12,916 controls aged 65 to 71 years old using data from the Taiwan Precision Medicine Initiative and the Taiwan Biobank. From 2005 to 2014, air pollutants with a size up to 2.5 micrometers (PM2.5) were sampled at one‐day intervals and assigned according to home addresses according to the Taiwan Administrative Region Map. When the PM2.5 concentration exceeded 35 g/m3, it was considered a high PM2.5 day. Logistic regression models were used to assess the association of air pollution, categorized into tertiles as low, moderate, and high exposure, with the risk of AD.ResultThe role of single nucleotide polymorphisms (SNPs) in air pollution has been demonstrated, especially for SNP rs147466807 (NECTIN2), when compared to PM2.5 (p = 0.005). A significant increase in AD risk was found among individuals living in high PM2.5 areas (more than 165 days exposed to high PM2.5 per year) who had one NECTIN2 risk allele compared to those without (adjusted odds ratio, 3.54; 95% confidence interval, 1.60‐7.03). Additionally, NECTIN2 6‐SNP haplotypes exhibited a similar gene‐environment interaction.ConclusionWe found a possible interaction between NECTIN gene polymorphisms and outdoor air pollution, emphasizing the importance of including environmental exposures in genetic etiological studies of AD.
Increasing cerebral blood flow reduces neural activity derangement in mouse models of Alzheimer’s disease
Authors: Zirkel Rick T , Isaacson Matthew , Lamont Michael , Nishimura Nozomi , Schaffer Chris B 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is characterized by progressive, irreversible neurodegeneration, leading to memory loss and cognitive decline. In mouse models of AD, global decreases in cerebral blood flow (CBF) are brought on by the plugging of capillaries by arrested neutrophils, and the administration of the neutrophil‐specific antibody against Ly6G (anti‐Ly6G) reduces these capillary stalls in minutes and improves cognitive function within hours. This suggests that at least some aspects of neural activity impairment are reversible, but the mechanism of this recovery – and what specific neural activity is normalized – is not yet known. In agreement with prior studies, we found orientation tuning selectivity to drifting gratings in primary visual cortex neurons to be broadened in mouse models of AD. Here, we hypothesized that the impaired neural response can be modified by blood flow improvement with anti‐Ly6G treatment (4 mg/kg) in the APP/PS1 mouse model of AD.MethodWe transfected neurons in layer 2/3 of the primary visual cortex (V1) of mice with a fluorescent calcium indicator using AAV9 vectors (pAAV.Syn.GCaMP6s.WPRE.SV40, 10^12 vg/mL). We also injected the fluorescent labels methoxy‐X04 to detect amyloid plaques and Texas‐red‐dextran in the vasculature to detect blocked capillaries. Drifting grating visual stimuli were presented to anesthetized mice with using MouseGoggles during recording with two‐photon microscopy before and one day after anti‐Ly6G or isotype control antibody administration (Fig. 1).ResultOne day after anti‐Ly6G administration to reduce stalls and increase CBF, we observed a significant sharpening of orientation tuning relative to baseline in the same animals, as well as a trend toward increased spontaneous activity in V1 neurons (Fig. 2). Such normalization of neural activity patterns likely underlies the improved cognitive function that is seen within hours of blood flow increase in AD mouse models.ConclusionOur data suggests some aspects of the neural and behavioral deficits in AD are acutely recoverable by increasing CBF. Such recovery demonstrates a promising avenue for future therapeutic targets to combat the symptoms of AD in humans.
Association of Structural Forms of 17q21.31 with the Risk of Progressive Supranuclear Palsy and MAPT Sub‐haplotypes
Authors: Wang Hui , Chang Timothy S , Dombroski Beth A. , Cheng Po‐Liang , Si Ya‐Qin , Tucci Albert A , Wang Li‐San , Tzeng Jung‐Ying , Geschwind Daniel H. , Schellenberg Gerald D. , Lee Wan‐Ping 
Published: January 2025

AbstractBackgroundThe H1/H2 haplotype on 17q21.31 represent the foremost genetic factor contributing to the risk of progressive supranuclear palsy (PSP). Various structural forms of 17q21.31 characterized by the number of copies of α, β, and γ duplications have been identified. However, the specific effect of each structural form on the risk of PSP has never been evaluated in a large cohort study.MethodWhole genome sequencing data of 1,684 (1,386 autopsy confirmed) individuals with PSP and 2,392 control subjects were obtained from the Alzheimer’s Disease Sequencing Project (ADSP) Umbrella NG00067.v7. Copy numbers of α, β and γ were called by CNVpyter (Version 1.3.1). Expectation‐maximization algorithm was used to infer the sturctural forms of 17q21.31 for each individual. Then, a case‐control study was conducted to investigate the association of copy numbers of α, β, and γ duplications and structural forms of 17q21.31 with the risk of PSP.ResultThe copy number of γ was independently associated with the increased risk of PSP. Each additional duplication of γ was associated with 1.10 (95% CI, 1.04‐1.17; P = 0.0018) fold of increased risk of PSP when conditioning H1 and H2. For H1 haplotype, addition γ duplications displayed a higher odds ratio for PSP: the odds ratio increases from 1.21 (95%CI 1.10‐1.33, P = 5.47 × 10‐5) for H1β1γ1 to 1.29 (95%CI 1.16‐1.43, P = 1.35 × 10‐6) for H1β1γ2, 1.45 (95%CI 1.27‐1.65, P = 3.94 × 10‐8) for H1β1γ3, and 1.57 (95%CI 1.10‐2.26, P = 1.35 × 10‐2) for H1β1γ4. Moreover, H1β1γ3 is in linkage disequilibrium with H1c (R2 = 0.31), a widely recognized MAPT sub‐haplotype associated with increased risk of PSP. The proportion of MAPT sub‐haplotypes associated with increased risk of PSP (i.e., H1c, H1d, H1g, H1o, and H1h) increase from 34% in H1β1γ1 to 77% in H1β1γ4.ConclusionThis study identified that the copy number of γ was associated with the risk of PSP. H1 haplotypes with more γ duplication showed a higher odds ratio and were associated with MAPT sub‐haplotypes with increased risk of PSP. These findings expand our understanding of how the complex structure of H1/H2 affect the risk of PSP.
Cortico‐hippocampal dysfunction in APP‐KI and PS1 mouse models
Authors: Hernández‐Frausto Melissa , Chinea Francesca , Basu Jayeeta 
Published: January 2025

AbstractBackgroundLateral entorhinal cortex (LEC), medial entorhinal cortex (MEC), and hippocampal area exhibit cell damage due to B‐Amyloid depositions, intracellular tau aggregates, and neurofibrillay tangles. AD mouse models allow us to investigate how AD neurodegeneration affects specific brains circuits and resulting behaviors. Specifically, the PS1 and APP NL‐G‐F knock in (APP‐KI) mouse models are relevant due to their genetic modifications, episodic memory impairment, early AD pathophysiology, and novelty designed for study. Nevertheless, the circuit mapping of entorhinal cortex in the medial and lateral portion within the hippocampal area during the progression of AD remains elusive.MethodBy using anatomical tracing and cognitive freely moving behaviors we compared the progression of cognitive deficits in the PS1 and APP‐KI mouse models. First, with AAV viral infection we expressed a green fluorophore in excitatory cell bodies in LEC and MEC, we examined through confocal microscopy the density of the projections in hippocampal area. Then, we compared with the behavioral performance in two cognitive tasks involved in the cortico‐hippocampal function; Novel Object Recognition (NOR) and Novel Object Location (NOL).ResultOur confocal imaging show a reduced density of the excitatory projections from LEC and MEC neurons in hippocampus compared to controls. Likewise, when evaluated the cognitive performance in NOR and NOL tasks, mice have a cognitive impairment performance in NOR and NOL.ConclusionOur findings suggest that during an age period when Alzheimer’s disease phenotypes are already established, there is a markedly reduction in the connectivity between LEC, MEC and hippocampus with an episodic memory performance impaired. Current analysis to determine the precise period of the cortico‐hippocampal dysfunction appears during the disease progression are underway.