bluuebunny/crossref_metadata_2025_split huggingface dataset:
Propionate Decreases Microglial Activation and Alters Phagocytic Machinery in Response to Aggregated Amyloid Beta in vitro
Authors: Gold Andrew , Zhu Jiangjiang 
Published: January 2025

AbstractBackgroundMicroglia, the innate immune cells of the brain, are a principal player in Alzheimer’s Disease (AD) pathogenesis. Their surveillance of the brain leads to interaction with the protein aggregates that drive AD pathogenesis, most notably Amyloid Beta (Aβ). Aβ can elicit attempts from microglia to clear and degrade it using phagocytic machinery, spurring damaging neuroinflammation in the process. SCFAs, abundant microbial byproducts of dietary fiber fermentation, are blood‐brain‐barrier permeable molecules that have recently been shown to modulate microglial function. Further, as dietary manipulation can drastically alter SCFA abundances and thus modulate AD microglia, it is crucial to understand SCFAs effects. Propionate, one SCFA, is more poorly characterized than the rest, and thus we attempted to conduct a detailed characterization of propionate’s impact on microglial function in an AD‐relevant in vitro experiment.MethodUsing a multi‐omics approach, we characterized the transcriptomic, metabolomic, and lipidomic responses of immortalized murine microglia following 1 hour of Aβ stimulation, as well as characterizing secretion of reactive nitrogen species (RNS) in response to Aβ, using RNA sequencing, LCMS‐based metabolomics, and a fluorescently coupled RNS detector, respectively.ResultPropionate significantly blunted the early inflammatory response driven by Aβ, driving down the expression of many Aβ‐stimulated immune genes, including those regulating inflammation, the immune complement system, and chemotaxis. Further, it reduced the expression of inflammation‐promoting Aβ‐binding scavenger receptors such as cd36 and msr1 in favor of more neutral lpl. Finally, propionate shifted microglial metabolism, altering phospholipid composition and shunting arginine synthesis away from nitric oxide synthesis, which resulted in decreased nitric oxide production.ConclusionAltogether, our data demonstrate a modulatory role of propionate on microglia that may dampen immune activation in response to Aβ and potentially improve AD pathogenesis.
Longitudinal association between CSF markers of Alzheimer Disease and inflammation in preclinical Alzheimer Disease
Authors: Sarty Isabel MacKenzie , Picard Cynthia , Labonte Anne , Breitner John C.S. , Poirier Judes 
Published: January 2025

AbstractBackgroundInflammation is central to Alzheimer Disease (AD), as astrocyte reactivity accompanies the appearance of Aβ and phosphorylated tau (Bellaver et al., 2023). As expected, therefore, AD patients have elevated levels of CSF inflammatory cytokines (Onyango et al., 2021). To understand the importance of these phenomena, exploration of individual inflammatory markers before and at the time of dementia onset is needed. To uncover key CK/Rs involved in the early pathogenesis of AD, we investigated selected cytokines and their receptors (CK/Rs) in the preclinical stages of the disease.MethodWe analyzed 433 longitudinal CSF samples from 104 participants in the PREVENT‐AD cohort. These persons, who were symptom‐free at baseline but at enhanced risk of developing AD because of their family history, have now been followed for over 10 years. We used ELISA to analyze Aβ42, p181, and total tau in the CSF [Fujirebio Innotest, Ghent, Belgium], while CK/Rs were assayed using the Olink proximity extension assay Target 96 Inflammation panel [Upsala, Sweden]. Linear mixed model analyses controlled for participant age and APOE4 status.ResultWe found that IL10RB, IL18, and CD40 levels in the CSF were significantly associated with both p(181)tau and Aβ42 levels in the CSF over time. IL10RB, IL18, and CD40 each showed significant positive association with p(181)tau levels across time (F(1,213.191) = 7.013, p = 0.009; F(1,237.624) = 9.972, p = 0.002; F(1,246.859) = 8.211, p = 0.005). The longitudinal effects of IL10RB and IL18 on Aβ42 were contingent on both sex and time (F(5,55.406) = 2.548, p = 0.038; F(5,54.792) = 4.280, p = 0.002), while the significantly positive association of CD40 levels on Aβ42 across time was stronger in females than in males (F(1, 59.669) = 4.099, p = 0.047).ConclusionThese investigations of CSF proteins in preclinical AD persons identified inflammatory markers that exhibited specific relationships with p(181)tau and Aβ42 across time and sex. These results may guide further study of biomarkers for detection of AD in its preclinical stages, and/or therapeutic strategies. Of special importance, characterization of the pathogenesis of pre‐symptomatic AD may facilitate development of early interventions for the prevention of AD dementia.
Phospholipase D3 (PLD3) Regulates Lysosomal Biogenesis
Authors: Wang Yongchao , Fernandez Wilber Romero , Carvajal‐Tapia Cristian O , Shostak Alena , Rieschick Paige , Appelbaum Nathan , Schrag Matthew 
Published: January 2025

AbstractBackgroundGenome‐wide association studies suggest mutations in endolysosomal genes are linked to Alzheimer’s disease (AD). Defective lysosomal function has been corroborated as a feature of AD by neuropathological and cell biology studies. PLD3 is a homolog of the phospholipase D family localized to lysosomes. Genetic variants in PLD3 are associated with increased risks for AD. Nevertheless, being a resident lysosomal protein, PLD3’s role in lysosome homeostasis has not been completely characterized. In this study, we conducted studies that combine transcriptomics, proteomics and cell biology to investigate the role of PLD3 in lysosome homeostasis.MethodWe generated PLD3 knockout (KO) SH‐SY5Y cells through the CRISPR/Cas9 approach. To identify the individual genes or gene sets impacted by PLD3 KO, RNA sequencing was performed with RNA isolated from wildtype (WT) and PLD3 KO neurons, followed by differential gene expression and gene set enrichment analyses. To narrow down to the targets that have direct lysosomal relevance, a proteomic study was conducted on the lysosome fraction of lysates from WT and PLD3 KO cells. To characterize lysosome morphology and function, lysosomes in these cells were labeled with Lysotracker or dextrans, followed by imaging, quantification and statistical analysis with CellInsight High Content Analysis platform. Lastly, we also examined the effects of PLD3 on lysosomal biogenesis by immunocytochemistry and Western blot.ResultIn RNA‐Seq analysis, the genes or gene sets relevant to endocytosis, autophagy and lysosomal biogenesis were significantly enriched in PLD3 KO cells. In line with these findings, our proteomic analysis also demonstrated an increase in lysosomal proteins in PLD3 KO cells. PLD3 loss caused an increase in lysosome size and endocytic activity and a decrease in the pH value of lysosomes, but it had no significant impact on lysosome number and positioning. Mechanistically, PLD3 deficiency promoted TFEB‐mediated lysosomal biogenesis.ConclusionPLD3 plays a role in lysosomal biogenesis. As endolysosomal abnormalities are increasingly appreciated as the causal agent for the pathogenesis of AD, this study may position the PLD3 pathway as a therapeutic target for the treatment of AD.
Photobiomodulation Therapy Increases Brain Cortex Neuroprotective Gene Expression and Improves Motor Function in an APP/PS1 Male Mouse Model of Alzheimer’s Disease
Authors: Barnett Mackenzie J , Haghkar Mahdi , Santos Carla Rocha Dos , McDevitt Ross A , Zernetkina Valentina I , Wei Wen , Syed Sunayana Begum , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V 
Published: January 2025

AbstractBackgroundPhotobiomodulation (PBM) therapy, using low intensity near‐infrared light is a noninvasive form of treatment with no side effects can be used to treat Alzheimer’s disease (AD). In a double‐transgenic mouse model of AD (APPswe/PS1dE9), chronic PBM therapy has been shown to reduce Aβ plaques accumulation in specific regions of the brain, including the neocortex and hippocampus. The aim of this study was to analyze the effects of PBM therapy on brain cortex neuroprotective gene expression and behavior in this APPswe/PS1dE9 mouse model.MethodsSix‐month old male AD (AD‐PBM, n = 7) and wild type litter mate mice (WT‐PBM, n = 8) were exposed to near‐infrared light (wavelength 850 nm, 4.5 J/cm2, 3min/day, 5 days/week) for 6 months. Control mice (AD‐CNT, n = 7; WT‐CNT, n = 7) were placed under the PBM apparatus without turning the light on for 3min/day, 5 days/week. Motor function was assessed with treadmill‐based gait analysis, with metrics including hind propel, hind stance and hind step angle (DigiGait), and open field test (OFT; anxiety‐like behavior) following 6 months of treatment. Gene expression sampled from cortex was analyzed by qPCR. Data were analyzed by 2‐way ANOVA.ResultsIn the AD group, PBM therapy significantly increased the expression of neuroprotective genes TGFb1, INFG, EGFR and MMP2, but did not affect the expression of these genes in WT (Fig. 1A‐D). In the gait analysis, PBM groups significantly reduced hind step angle in AD, but not WT (Fig. 1E). In the OFT, genotype had a significant effect on the amount of distance and time spent in the center of the arena (Table); non‐treated WT mice exhibited lower anxiety level vs. non‐treated AD mice (Fig. 1F). PBM did not have a significant effect, but the percent of distance spent in the center out of total distance had an increasing trend (Fig. 1F) indicating a trend in a reduction of anxiety in the AD group. Two‐way ANOVA analysis results are presented in Table 1.ConclusionPBM therapy significantly increased neuroprotective cortical gene expression and improved motor function in AD mice. It is possible that PBM treatment contributes to the upregulation of neuroprotective genes that reduced anxiety behavior and improved motor function.
Evidence for a role of adaptive immunity in Tau‐mediated neurodegeneration
Authors: Holtzman David M. 
Published: January 2025

AbstractBackgroundRecent evidence suggests both the innate and adaptive immune system are involved in the pathogenesis of Alzheimer’s disease. We recently showed that the number of T cells, especially cytotoxic T cells, are increased in areas of tauopathy both in an animal model of tau‐mediated neurodegeneration as well as in the AD brain. We also found that depletion of T cells as well as microglia were both strongly neuroprotective in P301S tau transgenic mice (PMID: 36890231). We have been further characterizing T cells in this model as well assessing for other evidence for a role of the adaptive immune system in this model.MethodWe crossed P301S mice with Rag2KO mice that lack both T and B cells and then analyzed the mice at 9.5 months of age.ResultP301S/Rag2KO mice have few to no T cells in the brain but also have strong suppression of the brain’s innate immune response and have significantly less brain atrophy and loss of synapses and compared to P301S mice.ConclusionThis provides further evidence of a role for the adaptive immune response in tau‐mediated neurodegeneration.
Integrative multi‐omics epigenome‐wide association study identifies dysregulated DNA methylation near oligodendrocyte genes that associate with tau levels in the AD brain
Authors: Oatman Stephanie R , Reddy Joseph S. , Wang Xue , Quicksall Zachary , Atashgaran Amin , Vanelderen Floor , Bergman Jeremiah , Is Ozkan , Carrasquillo Minerva M. , Liu Chia‐Chen , Yamazaki Yu , Nguyen Thuy , Heckman Michael G. , Zhao Na , DeTure Michael , Murray Melissa E. , Bu Guojun , Kanekiyo Takahisa , Dickson Dennis W. , Allen Mariet , Ertekin‐Taner Nilüfer 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is neuropathologically characterized by amyloid‐β (Aβ) plaques and tau neurofibrillary tangles often quantified by Thal phase and Braak stage, respectively. Aβ also frequently deposits in the cerebrovasculature with severity categorized by a cerebral amyloid angiopathy (CAA) score. These and related measures often show high variability within AD suggesting distinct underlying mechanisms. We hypothesize that, within the AD brain, neuropathology and levels of core AD‐related proteins are influenced by variations in DNA methylation (DNAm). To test this, we performed epigenome‐wide association studies (EWAS) using DNAm measures from the temporal cortex (TCX) and cerebellum (CER) with AD‐related neuropathologic measures (Braak, Thal, CAA) and brain biochemical levels of five proteins (apoE, Aβ40, Aβ42, tau, p‐tau).MethodsDNAm from neuropathologically‐confirmed AD cases was measured by reduced representation bisulfite sequencing (RRBS) from 471 TCX samples, 200 of which also had CER RRBS. TCX levels of five AD‐related proteins from three tissue fractions (buffer‐, detergent‐, and in‐soluble) were measured previously by ELISA (Liu 2020). CpG methylation (CpGm) was binned by a 15‐state chromatin model (Kundaje 2015) and averaged into CpGm clusters (rCpGm). rCpGms were tested for association with each AD endophenotype and expression levels of nearby genes through multi‐variable linear regression. Replication of significant rCpGms was performed in two independent datasets with AD‐related endophenotypes (Shireby 2022, De Jager 2014).ResultsOur innovative binning method demonstrated biologically relevant CpGm patterns. We found epigenome‐wide significant associations primarily with tau‐related endophenotypes including 93 that had significant and concordant associations in the replication datasets. These rCpGms also significantly associated with expression of nearby genes showing enrichment in oligodendrocyte marker genes including those related to myelination. In vitro validation of tau effects on oligodendrocyte gene expression through DNAm is ongoing.ConclusionsAlthough all endophenotypes tested are core to AD pathophysiology, our results suggest each has a distinct epigenetic architecture underlying their variability in the AD brain. In particular, we found evidence of DNAm variability associating with brain oligodendrocyte gene expression and TCX tau levels. By discovering AD brain endophenotype‐specific DNAm changes, we can identify core components of complex mechanisms revealing important biological insights into AD pathophysiology.
Bias in estimating brain‐cognition associations by clinical diagnosis: A simulation study
Authors: Gavett Brandon E , Fletcher Evan , Widaman Keith F. , Farias Sarah Tomaszewski , Mungas Dan M. 
Published: January 2025

AbstractBackgroundResearchers often divide heterogeneous samples into homogeneous subgroups for analysis. For example, a sample of participants with normal cognition, mild cognitive impairment (MCI), and dementia might be divided into subgroups to answer questions about whether some exposure variable (e.g., brain atrophy) predicts some outcome variable (e.g., cognitive decline) differently across groups. It is unclear, however, whether subgroup analysis provides greater insight into the associations between neurodegeneration and cognitive decline, or whether it is counterproductive. The current study employed statistical simulation to address this issue.MethodsUsing data from the Alzheimer’s Disease Neuroimaging Initiative, we estimated the correlation between gray matter volume slopes and episodic memory slopes. This correlation (r = .813) and subgroup descriptives formed the population parameters upon which simulations were based. We generated plausible scenarios where the correlations in the three subgroups could differ while maintaining the same overall correlation in the combined sample. Diagnostic subgroups were derived by simulating a global CDR score (0 cognitively normal; 0.5 MCI; 1+ dementia) for each simulated case. We also manipulated the relative sample size differences between the three groups. The primary outcome variable was the amount of bias (difference between simulated sample correlation and known population correlation) in estimating the strength of association between gray matter change and cognitive change. Samples were (1) combined and (2) analyzed separately by diagnostic group.ResultsEstimates specific to a diagnostic subgroup were least biased when the analyses were limited to samples drawn from that population (e.g., an MCI sample to make inferences about the MCI population). In contrast, when making inferences about the entire spectrum of cognitive aging, more nuanced findings appeared. In general, the least bias was observed in the combined sample, but this was only true when cognitively impaired cases were adequately represented.ConclusionDecisions about whether to stratify analyses by diagnostic subgroup require consideration of the target of inference. If the goal of cognitive aging research is to understand the cognitive manifestations of neurodegeneration across the full spectrum of disease, then subgroup analysis is likely to be more biased than the combined sample. With representative samples, both approaches may provide complementary information.
SUVN‐L3307032, A Positive Allosteric Modulator (PAM) at Muscarinic M4 Receptor for the Treatment of Neuropsychiatric Symptoms
Authors: Shinde Anil , Guduru Naga Sai Soma Chandra Sekhar , Das Ankit , Bitra Keerthi Sai , Bobbili Hima Bindu , Mukkollu Kavya Sree , Allu Chaitanya Sree , Vanga Shivani , Shyam Radhey , Kallepalli Rajesh , Abraham Renny , Nirogi Ramakrishna 
Published: January 2025

AbstractBackgroundCentrally acting muscarinic acetylcholine receptor antagonists like atropine and scopolamine can induce psychosis‐like symptoms. Xanomeline, a muscarinic M1/M4 preferring agonist attenuated the effects of amphetamine (animal model for schizophrenia) in the wild‐type mice, however, such effects were absent in muscarinic M4 knockout mice. In addition, xanomeline was also found to be effective in attenuating neuropsychiatric symptoms. Thus, muscarinic M4 agents can modulate brain circuitry that is dysregulated in disease states.MethodThe effects of SUVN‐L3307032 on the allosteric site of the M4 receptor were evaluated using the cell‐based reporter gene assay. The pharmacokinetic properties of SUVN‐L3307032 were studied both in rodent and non‐rodent species. SUVN‐L3307032 was assessed for its effects on amphetamine‐induced hyperlocomotion in rats at doses of 3, 10, 30, and 60 mg/kg. Preliminary toxicity studies were conducted in rats and dogs to evaluate the safety of SUVN‐L3307032.ResultSUVN‐L3307032 was found to be a positive allosteric modulator of muscarinic M4 (M4‐PAM) receptor. SUVN‐L3307032 showed good oral bioavailability in rats and dogs. It also has excellent brain penetration with an adequate free fraction in the brain. SUVN‐L3307032 showed dose‐dependent receptor occupancy at tested doses of 3, 10, 30, and 60 mg/kg. At the tested doses, SUVN‐L3307032 dose‐dependently attenuated amphetamine‐induced hyperlocomotion. The observation from the amphetamine‐induced hyperlocomotion assay correlated well with the occupancy at the allosteric site of muscarinic M4 receptors.Preliminary toxicity studies did not show any concerns for further development.SUVN‐L3307032 is being further characterized in animal models for neuropsychiatric symptoms.ConclusionSUVN‐L3307032 could be a promising agent for the management of neuropsychiatric symptoms.
Cerebral Amyloid Angiopathy like pathology accompanied by intense gliosis in T2D‐induced APPxhQC mice
Authors: Babalola Joshua , Neddens Joerg , Leitinger Gerd , Hutter‐Paier Birgit , Hoefler Gerald 
Published: January 2025

AbstractBackgroundCerebral Amyloid Angiopathy (CAA), characterized by the presence of amyloid β (Aβ) deposits in cerebral blood vessels has been associated with cognitive impairment and Alzheimer’s disease (AD). Vascular risk factors, such as type 2 diabetes (T2D), are known to affect vascular pathology and CAA‐like depositions. Furthermore, Aβ deposition in blood vessels accompanied my inflammation especially gliosis, has been reported in the transgenic AD mouse models 5xFAD and APPSL that express human Aβ. In this study, we therefore investigated the prevalence of CAA‐like pathology in T2D‐induced APPxhQC transgenic mice.MethodMale transgenic APPxhQC mice, expressing human APP751 with the Swedish and the London mutation and human glutaminyl cyclase (hQC) enzyme, were used. Mice were either fed with high fat (HFD) or control diet and daily treated with streptozocin for 3 days. Brain concentrations of soluble and insoluble Aβ 1‐38, 1‐40 and 1‐42 peptides were determined using an immunosorbent assay. Aβ deposits and gliosis were detected by immunofluorescent labelling.ResultsExceptionally strong but hollow Aβ deposits in the thalamus that go in medio‐lateral direction were found surrounding deposit free areas. These hollow Aβ deposits were accompanied by intense microglia and astrocytic activation upon HFD‐streptozocin treatment. The location and course of these hollow deposits indicated that they surrounded blood vessels. Additionally, plaque‐associated insoluble Aβ40 deposits in T2D‐induced APPxhQC mice were significantly higher compared to the control group.ConclusionPresence of Aβ deposits surrounding blood vessels accompanied by intense gliosis seems common in APPxhQC mice and might indicate a CAA‐like pathology specific to this AD model.
Instruments used to assess language in low‐educated individuals with mild cognitive impairment: a systematic review
Authors: Alves Emily Viega , Beber Bárbara Costa , Castilhos Raphael Machado 
Published: January 2025

AbstractBackgroundMild Cognitive Impairment (MCI) is a cognitive decline that is greater than expected for an individual’s age and level of education, but which does not interfere with functionality. It may be divided into amnestic (when it predominantly affects memory) and non‐amnestic (other cognitive domains). One of the cognitive functions that may be affected by MCI is language. As this is a function closely linked to education, it is essential to understand how it is assessed in people with low levels of schooling in different populations, such as those with cognitive impairment. Therefore, this study aimed to perform a systematic review of measures of language in low‐educated individuals with MCI.MethodThis is a systematic review of the literature. The search was performed in four databases: PubMed, Embase, LILACS, and Scielo, using MeSH descriptors related to MCI with low education and in which there was a description of tests used. We included papers that assessed language domain in individuals with MCI. The PRISMA guideline was adopted to better conduct the review.ResultsThe search strategy initially resulted in 2978 articles. After excluding duplicates and applying the eligibility criteria, 23 papers were selected for full‐text reading and 8 were included for analysis. The tools used for language assessment were not standardized, ranging from isolated tasks to subtests of larger instruments and complete batteries. The most common instrument was the Boston Diagnostic Aphasia Examination (25%), which was applied completely in one study and partially in another. The most commonly tested language skills were verbal fluency assessed in 75% of the works and naming, present in 50% of the studies. Skills such as reading and writing were little explored, possibly because educational issues impact on the possibility of reliably assessing these abilities.ConclusionThere is no consensus and no specific instruments for assessing language in low‐educated individuals with MCI. In addition, few language skills are tested in this population, which means there is a need to create better‐validated tests designed for this public.