bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma high‐density lipoprotein levels is associated with preserved hippocampal volume in Alzheimer`s disease individuals without vascular co‐pathology
Authors: Rodrigues Matheus Scarpatto , Oliveira Markley Silva , Lussier Firoza Z , Ferreira Pamela C.L. , Povala Guilherme , Bauer‐Negrini Guilherme , Felix Cynthia , Abbas Sarah , Zalzale Hussein , Soares Carolina , Saha Pampa , Madeiros Marina Scop , Bloomquist Madeleine , Hong Chang‐Hyung , Roh Hyun Woong , Karim Helmet T. , de Oliveira Jade , Karikari Thomas K , Tudorascu Dana , Zimmer Eduardo R. , Bellaver Bruna , Son Sang Joon , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundDysregulation of cholesterol metabolism contributes to the increase of cerebral vascular diseases, favoring the development of dementia. In this sense, high levels of high‐density lipoprotein (HDL) are considered protective against the outcomes associated with cardiovascular diseases. However, little is known about the effect of plasma HDL levels to alterations of cerebral volume in non‐vascular AD and vascular AD individuals. Here we evaluated the association of plasma HDL levels with alterations in brain volume and with plasma neurofilament light chain (NfL) levels.MethodWe analyzed 135 AD individuals from the Biobank Innovations for Chronic Cerebrovascular Disease with Alzheimer’s Disease Study [BICWALZS] cohort. Based on Fazekas scale for brain white matter lesions, we stratified AD individuals into two groups: non‐vascular AD [Fazekas score = 1 and amyloid‐β (Aβ) positive/n = 76], and vascular AD [Fazekas score = 2, 3 and Aβ positive/n = 59] (Figure 1A). Linear regression models accounting for vascular co‐pathology APOEε4 carriership, age and sex were used to test associations of plasma HDL with the variables of interest.ResultWe observed a significant interaction between plasma HDL levels and presence of vascular pathology on total brain white matter (b = 0.375, p = 0.019, Fig. 1B; Table 2). Analyzing the hippocampal atrophy through the global Schelten`s scale, we observed that high plasma HDL levels was negatively associated with hippocampal atrophy only in non‐vascular AD individuals (b = ‐0.405, p < 0.001, Fig. 1C). However, no effect of plasma HDL levels on total gray matter and hippocampal volume was observed (Table 1). Non‐vascular AD individuals with high hippocampal atrophy scores showed reduced plasma HDL levels compared to non‐vascular AD individuals with low hippocampal atrophy scores (p < 0.01, Fig. 1D). Furthermore, no associations of plasma HDL with NfL levels were detected, regardless of the brain vascular status (Fig. 1E).ConclusionWe showed that high plasma HDL levels is associated with less white matter pathology and reduced hippocampal atrophy scores, without changing plasma NfL levels. Together our findings indicate that high HDL levels seem to be associated with preserved brain volume only in AD individuals with no vascular co‐pathology.
Aquaporin‐4: Unraveling the Link Between Reactive Astrogliosis and Neuroinflammation in Down syndrome with Alzheimer’s Disease Pathogenesis
Authors: Stringer Cherie A , Miyasato Haley , Camey Kevin , Ngo Phong , Andrews Elizabeth J. , Lai Florence , Ikonomovic Milos D , Kofler Julia , Wright Sierra , Phelan Michael J. , Head Elizabeth 
Published: January 2025

AbstractBackgroundDown syndrome (DS) is characterized by the overexpression of the amyloid precursor protein gene (APP) and pro‐inflammatory genes, leading to progressive beta‐amyloid (Aβ) accumulation. This accumulation in DS may exacerbate neuroinflammation, contributing to the pathogenesis of Alzheimer’s Disease (AD). Experimental models suggest that aquaporin 4 (AQP4), an astrocytic water channel implicated in Aβ clearance, is mislocalized with increased Aβ burden. It is unclear whether the mislocalization of AQP4 is observed and connected with reactive astrogliosis in response to Aβ and the progression of AD in DS. We hypothesize AQP4 expression is increased and mislocalized from astrocytic endfeet, contributing to an astrocytic neuroinflammatory response in DS with AD pathogenesis.MethodsThis study analyzed AQP4 distribution and expression via immunohistochemistry for AQP4 in 70 frontal (FR) and 64 occipital (OC) cortical human post‐mortem brain samples. Diagnostic classes included aged controls, DS, DS with AD, and sporadic AD (sAD). Semi‐quantitative analysis compared AQP4 distribution across diagnostic classes and brain regions. AQP4 expression was quantified using QuPath. Immunofluorescence (IF) assessed co‐localization and distribution of neuroinflammatory markers complement C3 (C3) and S100β with GFAP‐labeled astrocytes.ResultsAQP4 immunolabeling was observed for expression, distribution, and astrocytic morphology. In DS with AD, AQP4 was expressed away from endfeet, indicating a higher prevalence of reactive astrocytic morphologies compared with DS and control groups. Two‐Way ANOVA analysis revealed increased AQP4 expression in DS with AD compared with DS in both FR (p<0.0001) and OC (p = 0.0007) regions. IF for C3 exhibited a plaque‐like distribution and S100β co‐localized with GFAP‐labeled astrocytes in DS with AD and sAD not seen in DS and controls.ConclusionThe observed increased expression and mislocalization of AQP4 from endfeet, coupled with heightened AQP4‐labeled reactive astrocytic morphology, supports our hypothesis that AQP4 is involved in AD pathology in DS. Altered neuroimmune marker distribution and co‐localization in DS with AD, compared to DS alone, further supports the hypothesis that AQP4 localization contributes to reactive astrogliosis. Subsequent investigations will explore correlations between AQP4 localization changes, Aβ levels, and increased expression of neuroinflammatory markers, including C3 and S100β.Funding: NINDS (T32 NS121727‐01), ADRC (P30AG066519), ABC‐DS (U19AG068054), and Brightfocus (BFF17_0008).
Older adults at‐risk for type 2 diabetes exhibit decreased performance on spatial and working memory tasks using classic and novel cognitive testing
Authors: Ghosh‐Swaby Olivia R , Al‐Shaikh Jennifer Hanna , Palmer Daniel , Khan Ali R. , Thornton Jane , Bussey Timothy J , Saksida Lisa M , Liu‐Ambrose Teresa , Nagamatsu Lindsay 
Published: January 2025

AbstractBackgroundType 2 diabetes (T2D) and older age are well‐known risk factors for dementia. Indeed, there is evidence that older adults not diagnosed, but at‐risk for T2D can show early signs of cognitive decline, further exacerbated by excessive body weight or high blood glucose levels. Such a finding would have implications for early treatment strategies; however, the evidence is still sparse. We examined the correlation of risk factors for diabetes with cognitive function in older adults at‐risk for T2D using a battery of touchscreen tasks translated from their rodent versions, as well as traditional pen‐to‐paper cognitive tests.MethodSixty‐five older adults (69.39 ± 10.31 years old, 68% female) at‐risk for T2D (BMI ≥ 25 kg/m2, hemoglobin A1c ≥ 6.0%, CANRISK score ≥ 21) completed 3 novel touchscreen tasks: paired associative learning (PAL) (learning and object‐in‐location memory), progressive ratio (motivation), and trial unique, non‐matching to location (TUNL) (spatial pattern separation and working memory). They were also tested on pen‐to‐paper cognitive tests: trail‐making (task switching), Stroop (selective inhibition), and digit span (working memory). A correlation analysis was performed between BMI or HbA1c and cognitive performance. Performance on touchscreen tasks was analyzed using a repeated measures one‐way ANOVA.ResultHigher HbA1c levels were correlated with lower digit span scores (r2 = 0.12, p = 0.011). There was no correlation between breakpoint (motivation level) and BMI or HbA1c during the progressive ratio task (r2 = 0.0, p = 0.38). Interestingly, this population performed at chance level (59.7 ± 5.3% accuracy) on the PAL task, indicating they were unable to learn object‐location paired associates. When manipulating the spatial similarity in distance between stimuli during the TUNL task, older adults at risk for diabetes were 10% lower in accuracy when stimuli were close together compared to further apart (p<0001). Participants also responded more slowly to stimuli at choice during the TUNL task during the heaviest working memory load condition (p = 0.003).ConclusionOlder adults at‐risk for T2D exhibit decreased performance on tasks with higher demands on spatial and working memory. Future research will compare performance on all tasks to healthy age‐matched controls and reassess performance after a six‐month exercise intervention.
APOEε4 Allele Modulates Region‐Specific Transcriptomic Changes in Epigenetic Control Pathways: Implications for Late‐Onset Alzheimer’s Disease Risk
Authors: Delatorre Nicole , Van Rossum Hannah , Parker Anna , Brinton Roberta Diaz 
Published: January 2025

AbstractBackgroundAge, sex, and APOE genotype are well‐established risk factors for late‐onset Alzheimer’s Disease (LOAD). Previous findings demonstrate that neuroinflammatory profiles of the human midlife female brain closely resemble the human AD brain. Given APOE’s role in LOAD pathogenesis, here we investigate the contribution of this risk factor on targeted AD relevant transcriptional pathways.MethodsHuman corpus callosum, hippocampus, and hypothalamus tissue samples from 31 healthy control brain donors (n = 16 females; age = 48.4yrs ±3.7) without neurodegenerative disease and 20 LOAD (n = 10 females; age = 70.2 yrs±3.6) brain donors were obtained from the NIH NeuroBioBank (University of Maryland, University of Miami, and Mt. Sinai). APOE genotype was determined by electrophoresis and classified by the presence of APOEε4 alleles (carriers n = 26). Transcriptomic analyses were conducted via NanoString nCounter neuroinflammation panel, resulting in 23 pathways. The log2 fold change of gene expression was calculated utilizing the Rosalind platform. Wherein ε4 carriers (condition) were compared to ε4 non‐carriers (control). Primary analyses compared APOEε4 carriers to noncarriers. Whole pathway significance was determined using Fisher’s exact test.ResultsAPOEε4 carriers exhibited significantly downregulated astrocyte function in the corpus callosum (p = 0.001), upregulated adaptive immune response in the hippocampus (p = 0.321), and upregulated epigenetic regulation in the hypothalamus (p = 0.007). Sub‐analyses based on sex, disease status (healthy vs. LOAD), and APOEε4 status revealed consistent within‐sex differences only for epigenetic regulation. Specifically, male (p = 0.015) and female (p = 0.001) midlife APOEε4 carriers differed significantly from non‐carrier counterparts in the hypothalamus. Significance of epigenetic regulation was also observed in AD between male and female APOEε4 carriers and their non‐carrier counterparts both in the hypothalamus (p = 0.023; 0.016) and hippocampus (p = 0.032;0.001). No between‐sex differences were identified in any sub‐analyses.ConclusionThese results provide evidence of region‐specific differences in adaptive immune and epigenetic pathways driven by and specific for the APOEε4 allele. These targeted transcriptional analyses in post‐mortem brain indicate that at late‐stage AD, APOEε4 is the principle differentiating factor in the transcriptional profile of targeted genetic pathways. Further, the data indicate activation of epigenetic control pathways within both the hypothalamus and hippocampus. The outcomes of these analyses support future studies to characterize epigenetic regulation in late‐onset Alzheimer’s disease.
Downregulation of α‐synuclein in a mouse model of Alzheimer’s Disease: neuropathological, behavioral and transcriptomic changes
Authors: Leitao Andre Direito Goulart , Ahammad Rijwan Uddin , Spencer Brian , Wu Chengbiao , Rissman Robert A. 
Published: January 2025

AbstractBackgroundNeurodegenerative disorders of aging are characterized by the progressive accumulation of proteins such as α‐synuclein (α‐syn) and amyloid beta (Aβ). Misfolded and aggregated α‐syn has been implicated in neurological disorders such as Parkinson’s disease (PD), and Dementia with Lewy Bodies (DLB), but less so in Alzheimer’s Disease (AD) despite the fact that synuclein pathology is present in over 50% of postmortem brains of AD patients. We are now expanding on our previous studies which showed positive therapeutic effects of downregulating α‐syn in AD mice to understand the overall brain transcriptomic and mechanistic changes induced by treatment.MethodWe first treated AD mice systemically with a α‐syn antisense oligonucleotide (ASO‐syn) conjugated with a LDLR‐specific peptide (ApoB11) that allows for transport across the blood‐brain barrier and measured the presence of the ASO in the brain by immunohistochemistry. We then treated both neurons in culture and 6 months‐old AD mice with the ApoB:ASO conjugates and measured α‐syn levels in both cells and brains by immunohistochemistry and Western blot to test the feasibility of this treatment to downregulate α‐syn. Finally, we performed single‐cell RNAseq to ask the question of how α‐syn interferes with neuropathology in AD, i.e. which genomic pathways are changed when mice are treated with ApoB:ASO‐syn conjugates.ResultWe found that treatment of APP transgenic (AD) mice with ApoB11:ASO‐syn leads to a significant reduction of Aβ plaques burden, rescued neuronal loss and prevented astrogliosis, as compared to untreated AD mice. Importantly, we found that AD mice treated with the ASO‐syn had significantly improved spatial memory function. We found specific single‐cell transcriptomic changes associated with this downregulation of α‐syn, highlighting possible pathways for α‐syn‐mediated vulnerability.ConclusionCollectively, our data supports the use of ApoB11:ASO α‐syn conjugates delivered systemically to downregulate α‐syn as a promising future therapeutic strategy in AD. Our work suggests that knocking down α‐syn could be necessary to prevent neuropathology in AD.
Lewy body disease stages through aging and correlations with clinical and neuropathological profile on a population‐based brain bank
Authors: Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Rodriguez Roberta Diehl , Naslavsky Michel Satya , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Zatz Mayana , Jacob‐Filho Wilson , Suemoto Claudia Kimie , Grinberg Lea T. 
Published: January 2025

AbstractBackgroundLewy body disease (LBD) is a neurodegenerative condition marked by the accumulation of neuronal alpha‐synuclein, leading to both Parkinson’s disease and Lewy body dementia. It is regarded as the second most common neurodegenerative disease associated with aging. However, there is limited knowledge of LBD prevalence in the general population, particularly among non‐whites. Our study aimed to investigate the prevalence of LBD in a large, diverse population‐based clinicopathological cohort. Additionally, we sought to explore the associations of LBD with comorbid neuropathology, clinical outcomes, and APOE genotyping.MethodWe investigated cases from the Biobank for Aging Studies from the University of São Paulo, collected between 2004 and 2023. Clinical and sociodemographic information were gathered from the next of kin using structured and validated protocols, including parkinsonism score (PS) assessment through Tanner’s questionnaire. Neuropathological evaluations adhered to USA/NACC guidelines, using immunohistochemistry to detect beta‐amyloid, tau, alpha‐synuclein, and TDP43.Results1,669 participants with complete sociodemographic, clinical, and neuropathological data were enrolled. LBD was detected in 0,84% of 50‐59 age group and the frequency increased with age reaching 15% in 90+ group. There was a trend of lower LBD presence in Black/Brown, but higher in Asians. LBD was associated with age, and higher CDR‐SOB and PS scores (Table 1). LBD prevalence increased with worse Braak‐NFT, CERAD, and LATE. The presence of LBD was associated with CDR‐SOB score in Braak PD stages ≥ III. However, Braak PD scores were not related to PS scores in adjusted analyses (Table 2). LBD interacted with LATE, CERAD, and Braak‐NFT on cognitive scores (Figure 1); no difference was observed in interaction with sex and race. Upon conducting a stratified analysis, LATE had a significant impact on cognitive abilities and LBD presence in limbic‐neocortical reas (ß = 2.30, 95%IC = 0.61; 8.59, p = 0.024).ConclusionIn an admixed population, LBD is present since middle age. The trend of less frequent LBD in Black/Brown warrants further investigations. LBD was associated with higher CDR‐SOB scores in neocortical phases (V‐VI) and more pronounced in participants with LATE.
PS1 regulates processing and angiogenic signalling of VEGFR2; effects of FAD mutants
Authors: Dey Poulomi , Pandey Rukmani , Zarrouk Amira , Tzikas Glikeria , Georgakopoulos Anastasios , Robakis Nikolaos K. R K 
Published: January 2025

AbstractBackgroundPresenilin1 (PS1)/γ‐secretase cleaves within the transmembrane domain of numerous receptor substrates. Mutations in PS1 have implications on the catalytic subunit of γ‐secretase decreasing its activity and becoming a potential causative factor for Familial Alzheimer’s Disease (FAD). This work studies the role of PS1/γ‐secretase on the processing, angiogenic signaling, and functions of VEGFR2 and the effects of PS1 FAD mutants on the γ‐secretase‐mediated epsilon cleavage of VEGFR2.MethodHEK293T cells expressing WT‐PS1 or PS1‐FAD mutants (M146V, I213T, E280A, G384A, L166P, E120K, A246E) were prepared using a lentivirus‐based transduction system and used in luminescence‐based experiments. PS1‐VEGFR2 co‐immunoprecipitation (Co‐IP) experiments were analyzed on WBs. Bimolecular fluorescence complementation (BiFc) assays were carried out in HEK293T cells overexpressing PS1 or VEGFR2 tagged with half complementary portions of the mVenus and visualized by fluorescence microscopy. The ClusPro web server was used for protein‐protein docking analyses. Anti‐PS1 siRNA technology was applied to downregulate PS1 in endothelial bEnd.3 cells.ResultLuciferase Assay shows that PS1 FAD mutants significantly decrease the γ‐secretase‐mediated epsilon cleavage of VEGFR2 when compared to WT‐PS1, leading to the production of significantly lower amount of the VEGFR2/CTF2 peptide indicating a loss of γ‐secretase proteolytic function. This loss of function is comparable to the effect of γ‐secretase inhibitor RO4929097. Co‐IP experiments show that PS1 forms complexes with VEGFR2 and BiFc experiments show that PS1 binds to VEGFR2. Docking analysis indicates that the binding is electrostatically favored. Co‐IP between the PS1‐FAD mutants and VEGFR2 show that FAD mutants do not have differential binding to the VEGFR2 compared to WT‐PS1, showing that the effect of these mutants on VEGFR2 cleavage is not due to altered binding. PS1 downregulation of endothelial cells indicates that PS1 plays a role in the regulation of the VEGFA‐induced phosphorylation of VEGFR2 at Y1175 and Y1054‐59 as well as p‐44/42 MAPK (Erk1/2) and in VEGFA‐induced tube formation in vitro.ConclusionPS1 FAD mutants decrease production of signaling peptide VEGFR2/CTF2 probably due to reduced γ‐secretase activity of FAD mutants. Interestingly FAD mutations do not seem to affect the PS1‐VEGFR2 association. Our data support that PS1 regulates downstream signaling and angiogenic functions of VEGFR2.
Identifying Tau proteopathic species isolated from human brains with Alzheimer’s disease
Authors: Quittot Noé , Sivasankaran Dhanush , Derosla Victoria , Wiedmer Anne , Perbet Romain , Hyman Bradley T. T 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), the spread of Tau proteopathic seeds across the cerebral cortex parallels the disease progression. Previously, it was shown that isolating high‐molecular‐weight (HMW) Tau species via size exclusion chromatography (SEC) from human brain lysate of AD patients resulted in the enrichment of Tau aggregation‐prone species. However, whether the HMW Tau population contain a homogenous or heterogeneous mixture of Tau species is still unknown. Therefore, this research proposal aims at fractionating the HMW Tau population to identify Tau proteopathic seeds.MethodHuman brains tissue from 9 AD cases have been homogenized in PBS and the resulting lysates were then run through a SEC to isolate the HMW Tau. The HMW Tau population was then fractionated according to net charge of the Tau species by anion exchange chromatography (AIEX). Following each chromatographic strategy step, the bioactivity of the different fractions was assessed via a cell‐based assay to track the aggregation‐prone Tau species.ResultFirst, we have demonstrated that these chromatographic strategies can be carried out under near‐physiologic pH and salt conditions, maintaining Tau proteopathic seeds bioactivity and hence their bioactive conformation. Second, we confirmed the presence of HMW Tau subspecies, and more importantly both non‐bioactive and bioactive HMW Tau species that co‐elute from the size column. Finally, the AIEX separation technique revealed that the bioactive species were eluted later than the non‐bioactive, suggesting that the bioactive species are more negatively charged and more heavily post‐translationally modified.ConclusionThe HMW Tau population contains various subspecies with both non‐bioactive and bioactive species, that can be separated according to their charge and their retention time on an AIEX column. In sum, these results suggest that the HMW fraction purified by SEC is a mixture of subspecies, and that the overall net charge of these subspecies appears to be a crucial biochemical feature correlating with HMW Tau bioactivity.
A common microvascular endophenotype in head injuries and Alzheimer’s disease
Authors: Xia Shangzhou , Zhao Zhen 
Published: January 2025

AbstractBackgroundCerebrovascular injury is a common pathological feature of a spectrum of neurological disorders, including traumatic brain injury (TBI), stroke, Alzheimer’s disease (AD), and aging. Vascular manifestations among these conditions are similar indeed, including the breakdown of the blood‐brain barrier (BBB). However, whether there is a unique molecular mechanism underlying the vascular changes among these conditions remains elusive.MethodWe performed single‐cell RNA (scRNA‐seq) sequencing and obtained 29,114 high‐quality cells combined from ipsilateral hemispheres of WT C57BL/6J Sham mice and mTBI mice at day 1, 3 and 7.ResultJoint clustering of all groups revealed 7 cell populations using their specific genetic markers, including vEC, vcapEC, capEC, acapEC, aEC. Next, we identified differential expression genes between Sham and day 1 or day 3 or day 7 post‐mTBI within each endothelial cell cluster.ConclusionBased on transcriptomic analysis on cerebrovascular scRNA‐seq datasets, we identified a common molecular signature between mTBI and aging vasculature, involving a novel transmembrane protein gene Tmem252. Tmem252 upregulation in brain endothelial cells may represent a shared endophenotype of microvascular injuries in different pathological conditions, and therapeutically targeted for treating BBB breakdown and vascular dysfunctions.