bluuebunny/crossref_metadata_2025_split huggingface dataset:
Specifically targeting toxic forms of tau modulates AD pathologies and inflammageing in very old triple‐transgenic mice
Authors: Sciortino Alessia , Senapati Sudipta , Al‐Shaebi Fadhl , Samples Madison , Kayed Rakez 
Published: January 2025

AbstractBackgroundRodent models have been proved pivotal in Alzheimer’s disease (AD) research. Nevertheless, the use of models that only recapitulate one aspect of AD neuropathology, and of early time points that might be excluding important features such as age‐dependent inflammation and senescence, could hinder the development of effective AD therapeutics. Several tau immunotherapies are currently undergoing clinical trial. Misfolding and accumulation of tau have been shown to correlate with Alzheimer’s disease (AD) progression and dementia stage. Numerous studies showed that tau removal is able to slow down AD pathology propagation and cognitive deterioration in different animal models.MethodWe developed in‐house anti‐tau antibodies that target specific toxic tau conformations and evaluated immunotherapy impact on AD‐like pathology in very old triple‐transgenic AD mice (3xTg AD), in order to capture age‐dependent aspects often overlooked in other studies. Twenty‐three months old 3xTg AD mice, that reproduce both amyloid and tau pathology, and other cellular changes associated with AD, were injected in the tail vein with 120µg of anti‐toxic tau antibody or IgG isotype control. Behavioral tests to evaluate motor and cognitive performance were carried out one week post injection. Immunohistochemistry, immunofluorescence and western blot techniques were used to investigate brain neuropathology following toxic tau removal.ResultTreatment with conformational antibodies targeting toxic forms of tau modulated the extent of AD pathology, in the form of tau and amyloid deposition, in hippocampus and cortex. Furthermore, immunotherapy modified markers of age‐related pathology, suggesting an interplay of toxic tau with the ageing process i.e. inflammation and senescence.ConclusionOur study contributes to the investigation of selective tau immunotherapy approaches for AD and tauopathies. Our results suggest that specifically targeting toxic forms of tau modulates AD pathology beyond pathological protein aggregation and could have beneficial effects even at later disease stages.
MR1‐ and MAIT cell‐dependent pathology in a mouse model of AD
Authors: Brutkiewicz Randy R 
Published: January 2025

AbstractBackgroundWe have found that the MHC class I‐like MR1 molecule and the innate‐like T cells that recognize them (MAIT—mucosal‐associated invariant T cells) contribute to the development of pathology in Alzheimer’s disease (AD). Moreover, we find elevated levels of MR1 expression and increased numbers of MAIT cells in the brains of 5XFAD mice overtime; these MAIT cells express high surface levels of the T cell activation markers, CD25 and CD69. Here, we are focused on how these two phenomena are connected in AD pathology.MethodWe will analyze mice (MAITCAST) that have up to 20X the normal level of MAIT cells crossed onto the 5XFAD background and/or those expressing transgenes that encode GFP or YFP under the control of various cytokine promoters. Flow cytometry will allow us to determine the fraction of MAIT cells producing proinflammatory cytokines and their numbers, as well as their level of T cell activation markers as compared to conventional T cells, in both brain and peripheral immune organs.ResultIn normal 5XFAD mice, we found that, not only are MAIT cell higher in the brain, but also in the liver. Moreover, we have found that MAITCAST mice have up to 20X the normal level of MAIT cells in the brain, as well in peripheral tissue, such as the liver.ConclusionOur studies have identified an important role for the MR1/MAIT cell axis in AD pathology, and its potential utility as a novel therapeutic target for AD patients.
Microglia and extracellular vesicle‐mediated spread of Tau pathology
Authors: Ikezu Tsuneya 
Published: January 2025

AbstractBackgroundExtracellular vesicles (EVs) carry pathogenic molecules and play a role in the disease spread, including aggregated tau proteins. The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is responsible for the biogenesis of small EVs (exosomes), thus targeting critical ESCRT molecules can disrupt EV synthesis. We hypothesize that microglia‐specific targeting of ESCRT‐I molecule Tsg101 suppresses microglia‐derived EV‐mediated propagation of tau pathology, leading to amelioration of the disease phenotype of the tauopathy mouse model.MethodsPS19 tau transgenic mouse line was crossed with Cx3cr1CreERT2/+:Tsg101fl/fl lines for tamoxifen‐inducible Cx3cr1‐specific deletion of Tsg101 (Tsg101 cKO) in PS19 mice to generate WT, Tsg101 cKO, PS19, and PS19:Tsg101cKO groups. The animals were treated with tamoxifen or corn oil at 2 months of age and subjected to comprehensive behavioral, neuropathological, biochemical, and molecular biological assessments at 6‐7 months of age. The microglia isolated from Cx3cr1CreERT2/+:Tsg101fl/fl pups were subjected to in vitro synaptosome uptake analysis with or without 4‐Hydroxytamoxifen treatment.ResultsPS19 mice develop cognitive impairment as determined by Y‐maze, forced alternation, novel object recognition and fear conditioning, which are reversed in PS19:Tsg101cKO mice. This is correlated with reduced Alz50+ tau accumulation, neurodegenerative microglial activation, neuroinflammation and complement pathway activation as determined by bulk RNA sequencing, ELISA and neuropathology. Primary cultured Cx3cr1CreERT2/+:Tsg101fl/fl microglia with 4‐Hydroxytamoxifen treatment show reduced phagocytosis of E. coli particles and synaptosome in C1q dependent manner. Tsg101 cKO microglia show reduced expression of C3aR1 and CD68, and secretion of total and Tau+ EVs in vivo.ConclusionMicroglia‐specific targeting of Tsg101 show beneficial effect for ameliorating the disease progression of tauopathy mouse model via suppression of EV secretion, microglial activation, tau accumulation and complement‐dependent synaptic pruning. Microglial Tsg101 is a potential therapeutic target of Alzheimer’s disease and related tauopathy.
Validation of an AAV gene therapy designed to complement the loss of TDP‐43 splicing repression for ALS‐FTD
Authors: Mallika Aswathy Peethambaran , Wong Philip C 
Published: January 2025

AbstractBackgroundEmerging evidence support the notion that loss of splicing repression by TDP‐43, an RNA binding protein that was first implicated in ALS‐FTD, underlies their pathogenesis. Previously, we showed that delivery of an AAV9 vector at early postnatal day expressing a fusion protein, termed CTR comprised of the N‐terminal region of TDP‐43 and an unrelated splicing repressor termed RAVER1 complemented the loss of TDP‐43 in mice lacking TDP‐43 in spinal motor neurons (ChAT‐IRES‐Cre;tardbpF/F mice). To translate this potential therapeutic strategy to the clinic, it will be important to demonstrate benefit of such AAV delivery of CTR to motor neurons in adult mice. Here we validate a therapeutic approach using a recently developed AAV.PHP.eB vector that enables efficient transduction in central neurons, including motor neurons by an intra‐venous (IV) administrative route.MethodIntra‐venous injection of AAV.PHP.eB.RAV1‐3’UTR (ChAT‐IRES‐Cre;TardbpF/F, n = 12 and ChAT‐IRES‐Cre;TardbpF/+, n = 8) and AAV.PHP.eB.GFP (ChAT‐IRES‐Cre;TardbpF/F, n = 10 and ChAT‐IRES‐Cre;TardbpF/+, n = 8) was carried out in 6 weeks old littermate animals. Histology and immunohistochemistry to show the infectivity, RT‐PCR and RNA in situ hybridization to show the rescue of splicing repression and the grip strength analysis to measure the motor strength were performed.ResultWe show that IV delivery of AAV.PHP.eB.RAV1‐3’UTR to adult ChAT‐IRES‐Cre;TardbpF/F mice efficiently transduced spinal motor neurons, repressed cryptic exon inclusion and attenuated muscle weakness.ConclusionThese data support validation of our AAV gene therapeutic strategy to attenuate motor neuron disease, including ALS and potentially extended to other human disorders harboring TDP‐43 pathology. Other relevant results, including rescue of motor neurons and extension of life span will be presented.
Effects of APOE ε2 on different cognitive domains in the PUMCH dementia cohort
Authors: Shang Li , Dong Liling , Mao Chenhui , Huang Xinying , Chu Shanshan , Jin Wei , Wang Tianyi , LI Bo , Bao Jialu , Qiu Yuyue , Jiang Yuhan , Huang Yixuan , Gao Jing 
Published: January 2025

AbstractBackgroundPrevious studies on APOE have mostly focused on APOE ε4, while less attention has been paid to APOE ε2. The aim of this study was to clarify the effect of APOE ε2 on different cognitive domains in dementia patients.MethodAll subjects were from the Peking Union Medical College Hospital (PUMCH) dementia cohort and included clinical diagnoses of AD, VaD, FTLD, and LBD. All included individuals had completed the neuropsychological assessment. Genotypes were used to bin participants into five groups based on carrier status: ε2 carriers (ε2/ε2 or ε2/ε3), ε2/ε4 carriers, ε3/ε3 carriers, ε3/ε4 carriers, and ε4/ε4 carriers. The effect of APOE ε2 on different cognitive domains of the patients with dementia was assessed by using multivariate regression models.ResultA total of 348 dementia patients were included in this study, with a mean age of 68.4± 9.8 years, 69.3% with AD, 14.4% with VaD, 10.1% with FTLD, and 6.3% with DLB. 19.5% were ε2 carriers, 3.4% were ε2/ε4 carriers, 30.7% were ε3/ε3 carriers, 32.3% were ε3/ε4 carriers, and 14.1% were ε4/ε4 carriers. Compared to ε3/ε3 carriers, ε2 carriers were more successful in MOCA (β = 1.93, P = 0.016), trail making test part A (β = 1.18, P = 0.025), nonverbal memory (β = 1.08, P = 0.003), AVLT 5 (β = 0.27, P = 0.039), episodic memory (β = 0.41, P = 0.005), calculation (β = 1.05, P = 0.045) and word fluency (β = 1.82, P = 0.03). Compared to ε4/ε4 carriers, ε2 carriers performed better in nonverbal memory (β = 1.59, P<0.001), AVLT 4 (β = 0.68, P<0.001), AVLT 5 (β = 0.62, P<0.001), associative learning test (β = 0.57, P<0.001), episodic memory (β = 0.46, P = 0.007) performed better. When adjusted for clinical diagnosis, the above significant differences remained statistically significant. While ε2/ε4 carriers performed better in associative learning (β = 1.38, P<0.001) compared to ε3/ε3, visuospatial (β = ‐1.94, P = 0.020) function was worse than ε3/ε3 carriers. Compared to ε4/ε4, ε2/ε4 carriers performed worse in similarity test and visuospatial function, while in verbal memory performed betterConclusionThe present study found complex effects of APOE ε2 and APOE ε2/ε4 on cognitive domains that varied according to the selected control group, whereas different clinical diagnoses did not seem to influence their effects.
Mapping of Cognitive Pathways in Indian Ageing Population
Authors: Kushwaha Suman , Talwar Puneet , Agarwal Rachna , Sharma Vibha , Anthony Aldrin , Dhamija Rajinder 
Published: January 2025

AbstractBackgroundCognitive Reserve(CR) a concept based on the brain plasticity, is a mechanism that delays or minimizes clinical manifestations of brain changes due to aging. Prospective epidemiologic studies non‐demented individuals have shown that education, occupational duration and complexity, and greater lifetime engagement in cognitively stimulating activities are associated with a reduced risk of dementia. We study the cognitive reserve and its neuroimaging correlate.MethodsProspective cross‐sectional study. 500 subjects were screened, Recruitment of subjects with inclusion criteria of age 40‐80 yr without neurodegenerative or psychiatric disorder. Clinical History and presence of CVD risk factors were investigated. MMSE, MOCA, Selected neuropsychology tests were done to evaluate cognitive status, CR assessed by CRIq scale. Biochemical and MRI(volumetry) and DTI(FA, Diffusivity.Result252 pts were recruited, Mean age ‐53 yrs. 33% female. Diabetes(17%) and hypertension(24%). Mean MOCA score 24.CRIq was high in 10 subjects and majority had medium score. Significant association was found between Verbal and Category fluency with low CRIq and Serum ferritin with brain volume. Fractional isotropy(FA) values were reduced in central part of corpous callosum corelated with verbal fluency.ConclusionCognitive reserve can play a significant modifiable risk factor for cognitive decline. Neuroimaging can play an important biomarker to diagnose and in prognosis of cognitive impairment.
Influence of liver function on Alzheimer’s brain pathologies: A longitudinal study
Authors: Kim Jee Wook , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Kang Koung Mi , Sohn Chul‐Ho , Lee Yun‐Sang , Kim Yu Kyeong , Lee Dong Young ,   KBASE Research Group
Published: January 2025

AbstractBackgroundNumerous studies have demonstrated an association between altered liver function and Alzheimer’s disease (AD) or related dementia. Nevertheless, the neuropathological substrates underlying the association remains unclear. Our aim was to investigate the association between liver function markers and the longitudinal changes of in vivo AD pathologies.MethodsWe utilized a longitudinal study designs using data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort study that began in 2014. Total 347 older adults between 55 and 90 years of age assessed at both baseline and 2‐year follow‐up were included in community and memory clinic setting. We used four liver function markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], AST to ALT ratio, and total bilirubin) as exposure variables. Participants underwent comprehensive clinical assessments and multimodal brain imaging, including Pittsburgh compound‐B positron emission tomography (PET), AV‐1451 PET, fluorodeoxyglucose (FDG)‐PET, and MRI at both baseline and the 2‐year follow‐up.ResultsA higher ALT level and lower AST to ALT ratio at baseline were associated with greater amyloid deposition over a 2‐year period (ALT: β, 0.151 [95% CI, 0.007 to 0.033], P = 0.004; AST to ALT ratio: β, ‐0.153 [95% CI, ‐0.050 to ‐0.010], P = 0.004), but not with the change of other neuroimaging markers. A lower total bilirubin level was associated with greater tau deposition over a 2‐year period (β, ‐0.442 [95% CI, ‐0.385 to ‐0.106], P < 0.001), but not with the change of other neuroimaging markers. In contrast, AST alone was not associated with any neuroimaging marker change.ConclusionsThe present findings, based on longitudinal observation for older adults, suggest that lower liver function may accelerate the accumulation of AD pathology in the brain. These results also support the possibility that the liver‐brain axis could be a potential target for therapeutic or preventive strategies against AD.
Associations between AD polygenic risk scores and global amyloid deposition in the European AMYPAD consortium
Authors: Luckett Emma S. , Abakkouy Yasmina , Collij Lyduine E. , García David Vállez , Alves Isadora Lopes , Lorenzini Luigi , Gispert Juan Domingo , Visser Pieter Jelle , den Braber Anouk , Ritchie Craig W , Vandenberghe Rik , Wolz Robin , Shekari Mahnaz , Vilor‐Tejedor Natalia , Farrar Gill , Barkhof Frederik , Cleynen Isabelle ,   the AMYPAD consortium
Published: January 2025

AbstractBackgroundPublished data have highlighted associations between Alzheimer’s disease (AD) susceptibility loci and AD‐related brain changes. The amyloid imaging to prevent AD (AMYPAD) consortium is a European collaboration consisting of several parent cohorts, four of which had raw genotype array data available. We sought to integrate and harmonise the genetic data, calculate AD polygenic risk scores (PRS), and investigate their association with global amyloid deposition.MethodRaw genetic data (GRCh37) was available for 753 non‐demented participants, which underwent standard pre‐imputation quality control (QC) using PLINK. Imputation was performed using the Michigan Imputation server and HRC reference panel, and standard post‐imputation QC was done prior to the final merging of cohorts. PRSice was used for PRS calculations with Stage 1 summary statistics from Kunkle et al. (2019) as base file and European individuals from 1000 Genomes as reference for clumping. We calculated several builds of PRS at three p‐value thresholds for SNP inclusion: 5 × 10‐8, 1 × 10‐5, and 0.1. These included PRSall, PRSAPOEonly (Chr19:45‐48.8Mb), APOEε2+
ε4 (the weighted sum of the two major APOE SNPs rs429358 and rs7412), PRSnoAPOE (all SNPs excluding Chr19:45‐48.8Mb), and a composite PRSnoAPOE+APOEε2+
ε4. All were corrected for genetic principal components 1‐5 and standardised against 1000 Genomes. Cross‐sectional global amyloid burden (expressed in Centiloids) was available for everyone. Linear regression models determined if PRS were associated with amyloid deposition (age, sex, and education as covariates). Significance was based on an uncorrected p<0.05 divided by the number of SNP inclusion thresholds (N = 3).ResultParticipants were 66.9±7.6 years, 58.6% female, and 207 (27%) considered amyloid positive (CL>21). In this preliminary analysis, we found that most PRS builds were significantly associated with amyloid at all SNP inclusion thresholds assessed (Table 1, representative plots Fig. 1A,1B), except for PRSnoAPOE (Table 1, representative plot Fig. 1C).ConclusionWe highlight the significant influence of APOE in determining AD genetic predisposition, and that AD PRS are associated with amyloid deposition. Our results show that AMYPAD is a suitable cohort for studying genetic factors driving amyloid deposition before clinical onset, which we aim to extend with the inclusion of more parent cohorts, and regional and longitudinal amyloid data.
Reduced plasma nicotinamide level and altered NAD+ metabolism in glial cells surrounding Aβ plaques in the mouse model of Alzheimer’s disease
Authors: Sekiya Michiko , Sakakibara Yasufumi , Hirota Yu , Ito Naoki , Takei Kimi , Chikamatsu Sachie , Nishijima Risa , Iijima Koichi M. 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Accumulation of amyloid‐β (Aβ) in the brains causes chronic neuroinflammation, synaptic loss, and neurovascular damage, which is thought to initiate decades‐long AD pathogenesis. Recent clinical trials for anti‐Aβ immunotherapy highlights the utility of biomarkers that faithfully reflect Aβ‐related brain pathology to diagnose AD at the preclinical stage, to predict the onset and progression of the disease, and to assess the therapeutic efficacy of drugs.MethodTo search for plasma metabolites reflecting neuroinflammation due to Aβ accumulation, we conducted untargeted metabolomics in plasma and analyzed potential roles of metabolic changes in neuroinflammatory response in brains using Appknock‐in (AppNLGF) mouse model of brain parenchymal Aβ amyloidosis.ResultThe capillary electrophoresis‐time‐of‐flight mass spectrometry analysis on plasma samples from wild‐type and AppNLGF mice revealed that plasma nicotinamide levels were significantly reduced in AppNLGF mice, and “nicotinate and nicotinamide metabolism” was the most enriched pathway of altered metabolite profiles. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+). In AppNLGF mouse brains, while NAD+ levels were unaltered, mRNA levels of NAD+‐synthesizing and NAD+‐degrading genes were increased, and these enzymes were expressed in reactive astrocytes and microglia surrounding Aβ plaques.ConclusionThis study suggests that alterations in plasma nicotinamide levels may be a potential biomarker to assess neuroinflammatory response against Aβ pathology and “nicotinate and nicotinamide metabolism” may be a potential therapeutic target to prevent the onset of AD by targeting both neuroinflammation and neuroprotection.
Lewy body pathology in autosomal dominant and sporadic Alzheimer’s disease – neuropathological distribution patterns and associated survival and genetic findings
Authors: Vöglein Jonathan , Ryan Natalie S , Cruchaga Carlos , Gorijala Priyanka , Bateman Randall J. , McDade Eric , Paumier Katrina L. , Cairns Nigel J , Franklin Erin E. , Xiong Chengjie , Jucker Mathias , Lashley Tammaryn , Arzberger Thomas , Herms Jochen , Perrin Richard J. , Danek Adrian , Höglinger Günter , Morris John C. , Fox Nick C , Levin Johannes 
Published: January 2025

AbstractBackgroundLewy body pathology (LBP) is common in autosomal dominant (ADAD) or sporadic Alzheimer disease (sAD). LBP seems to be the most frequent co‐pathology in sAD and even in the relatively young ADAD population, where other co‐pathologies are rare. Knowledge of neuropathological distribution patterns of LBP and associated survival and genetic characteristics in both AD variants is incomplete.MethodsData from the National Alzheimer’s Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were used to correlate widespread (neocortical, limbic) and focal (amygdala‐predominant, brainstem‐predominant, olfactory system‐predominant) LBP distribution patterns with survival (time from symptom onset to death) and genetic findings in individuals with ADAD or neuropathologically diagnosed sAD. T‐test or chi‐squared test were used for comparison of continuous or categorical variables.ResultsIn 134 ADAD cases, widespread LBP was found in 20.9% and focal LBP in 41.0%. LBP was absent in 38.1%. In 3706 sAD cases, widespread LBP was present in 14.0% and focal LBP in 11.2%. The remaining 74.9% had no LBP. In both AD variants individuals with focal LBP survived longer compared to individuals without LBP, whereas no differences in survival were observed when comparing patients with widespread and no LBP. In both AD forms both focal and widespread distribution patterns were associated with APOE4 positivity. While there was no difference in Parkinson’s disease polygenic risk scores (PD‐PRS) between ADAD LBP distribution groups, PD‐PRS were statistically significantly higher in individuals with sAD with widespread LBP, both compared to sAD with focal LBP and to sAD without LBP (Table).ConclusionDistribution of LBP is focal in two‐thirds of ADAD with LBP and a little less than half of sAD patients with LBP. The longer survival in ADAD and sAD patients with focal but not widespread LBP may suggest that spreading of LBP in AD does not follow the same spatial evolution as described by Braak stages, but exhibits a unique, AD‐specific pattern. The association of APOE4 positivity with both focal and widespread LBP in AD and of PD‐PRS with widespread LBP in sAD indicates a genetic component that influences occurrence and distribution of LBP in AD.