bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of bone morphogenetic protein signaling prevents tau pathology
Authors: Affaneh Amira , Linden Anne K , Tunc‐Ozcan Elif , Tsai Yung‐Hsu , Peng Chian‐Yu , Kessler John A 
Published: January 2025

AbstractBackgroundAging is the most significant risk factor for neurodegenerative tauopathies, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), and others. However, no specific age‐related molecular change in the brain has been identified that leads to disease onset and progression. We have found age‐related increases in bone morphogenic protein (BMP) signaling in both human and mouse brains. Inhibition of BMP signaling in mice improves cognitive performance and age‐related molecular changes in the brain. Therefore, we hypothesized a potential link between the age‐related increase in BMP signaling and the onset and progression of neurodegenerative pathology.MethodNeurons differentiated from iPSC‐derived (iNs) from AD individuals were used to investigate the effects of BMP signaling on tau phosphorylation and release and the mechanisms underlying these effects. Using mouse models, we overexpressed of BMP4 in wild‐type (WT) mice and inhibition of BMP signaling in the P301S (PS19) tauopathy mouse model were used to understand the effects of BMP signaling on cognition and pathology.ResultBMP signaling increased levels of phospho‐tau (p‐tau) expression and release in healthy control and AD iNs, and treatment with the BMP inhibitor, noggin, reduced p‐tau levels. The effects of BMP signaling on tau phosphorylation were mediated by increased non‐canonical p38 mitogen‐activated protein kinase signaling. APOE4 iNs have increased cellular and secreted p‐tau compared to isogenic cells that express APOE3, and the APOE4‐associated increase in p‐tau is further exacerbated by BMP4 treatment. However, noggin treatment reduced p‐tau in APOE4 cells to levels comparable to those in isogenic APOE3 cells. BMP4 overexpression in the brain increased p‐tau in WT mice in vivo. Remarkably, noggin overexpression prevented tau hyperphosphorylation, neuropathological changes, and behavioral abnormalities in the widely studied PS19 tauopathy mouse model.ConclusionEvidence from mouse models and iPSC‐derived human neurons strongly supports the hypothesis that increased BMP signaling is part of aging‐related changes predisposing to tauopathies. Further, interactions between BMP signaling and genetic factors such as APOE4 act synergistically to increase tau phosphorylation and release. These observations suggest therapeutic interventions that reduce BMP signaling in the aging brain could potentially slow or prevent disease development.
Hyperhomocysteinemia and hypertension exacerbate cerebrovascular dysfunction and Alzheimer’s Disease pathology in the Tg2576 mouse model of amyloidosis
Authors: Carey Ashley M , Fossati Silvia 
Published: January 2025

AbstractBackgroundRecent evidence suggests that cerebrovascular dysfunction may precede and contribute to amyloid beta‐(Aβ)‐mediated pathology in Alzheimer’s Disease (AD), particularly promoting endothelial cell damage and stress, causing the cerebral blood flow impairments, cerebral hypoperfusion, and blood brain barrier (BBB) permeability that are pathologically characteristic in AD. Studies have emerged suggesting a link between cardiovascular diseases and AD pathology, showing that cerebrovascular/cardiovascular risk factors (CVRFs), including hyperhomocysteinemia (Hhcy) and hypertension (HTN), and the cerebral consequences of these CVRFs, such as cerebral hypoperfusion, contribute to AD pathology and risk. Despite this, the underlying molecular mechanisms for these associations remain unclear. Previously, our lab has demonstrated that combined exposure of human cerebral microvascular endothelial cells (HCMECs) to Aβ40‐Q22 (vasculotropic Dutch mutant) and homocysteine resulted in potentiated increases in apoptosis and decreases in barrier integrity and angiogenic capabilities. Additionally, we have demonstrated that Aβ in combination with oxygen glucose deprivation exacerbates HCMEC cell death, barrier dysfunction, and angiogenic impairment. We tested the hypothesis that Tg2576 AD mice with hyperhomocysteinemia and/or hypertension will demonstrate exacerbated vascular cell death, BBB dysfunction, angiogenic defects and worsened AD pathology.MethodWT and Tg2576 AD mice (Swedish APP mutation) were fed with a hyperhomocysteinemia‐inducing diet, HTN‐inducing water (L‐NAME), or both starting at 5 months. Mice were sacrificed at 13‐14 months and tissue was harvested. Apoptotic mediator expression and vascular caspase‐3 activation were measured to assess apoptosis. BBB‐associated tight junction protein expression, GFAP/IBA1 expression and morphology (neuroinflammation), and microhemorrhages were measured to assess BBB integrity. Angiogenic mediator expression and CD31+ microvessel density were utilized to measure cerebral angiogenesis. Soluble and insoluble Aβ42 and Aβ40 were measured to assess AD pathology progression.ResultTg2576 mice with CVRFs revealed exacerbated cerebral caspase‐3 activation and apoptosis as well as potentiated BBB and angiogenesis impairment versus WT mice and Tg2576 mice without CVRFs. Additionally, Tg2576 CVRF mice trended towards potentiated increases in cerebral soluble Aβ40 and fibrillar Aβ42.ConclusionCVRFs potentiate increases in specific cerebrovascular and angiogenic deficits in Tg2576 mice. This study revealed new molecular mechanisms and druggable targets through which amyloidosis, Hhcy and HTN additively act to produce vascular damage and dysfunction in AD.
Mortality and Its Predictors Amongst Patients With Advanced Dementia Receiving Psychiatric Inpatient Care
Authors: Marguet Oriane E , Chen Shanquan , Sidhom Emad , Wolverson Emma , Russell Gregor , Crowther George , White Simon R , Dunning Rebecca , Shahrin Hasan , Underwood Benjamin R , Lewis Jonathan 
Published: January 2025

AbstractBackgroundPeople with dementia frequently develop behavioural and psychological symptoms, sometimes necessitating care in specialist dementia mental health wards. There has been little research on their life expectancy following admission or need for palliative care. The work presented here explores the mortality of these patients and whether this can be predicted at their time of admission to the ward.MethodWe conducted a retrospective analysis of 576 patients admitted to the Cambridgeshire and Peterborough NHS Foundation Trust dementia mental health wards in the United Kingdom, and built a Kaplan‐Meier survival curve as well as machine learning models. Next, to examine changes in deaths occurring over time, a retrospective service evaluation was conducted involving four mental health wards for people with dementia in the United Kingdom, encompassing a further 1,976 patients.ResultThe median survival length post‐admission was 1201 days. Clinical data collected on admission did not predict mortality in machine learning models at a level of accuracy likely to have clinical utility. Data from four different wards show that the number of patients dying in dementia mental health wards has increased over time.ConclusionOur cohort had a high mortality, although with a wide range of survival times. We suggest all people admitted to these units should have discussions and access to high‐quality end‐of‐life care.
The association between the age and the rate of tau accumulation and spreading in different sexes
Authors: Zhu Zeyu , Dehsarvi Amir , Roemer Sebastian Niclas , Steward Anna , Dewenter Anna , Gross Mattes , Wagner Fabian , Ewers Michael , Brendel Matthias , Franzmeier Nicolai ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: January 2025

AbstractBackgroundNeuroimaging studies have revealed age and sex‐specific differences in Alzheimer’s disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid‐beta (Aβ)‐induced accumulation and spreading of tau pathology from local epicenters across connected brain regions.MethodWe included 313 ADNI participants (female/male, n = 167/146), i.e. 110 cognitively normal (CN) Aβ‐negative, and 203 Aβ‐positive subjects across the AD spectrum (i.e. CN/MCI/Dementia, n = 98/70/35) with baseline amyloid‐PET and longitudinal Flortaucipir tau‐PET. Annual tau‐PET change rates for 200 cortical regions of the Schaefer atlas were calculated. Sex‐specific resting‐state fMRI‐connectivity templates across the 200 Schaefer regions were determined in independent Aβ‐negative controls (female/male, n = 118/82) to determine the connectivity of tau epicenters to the rest of the brain. Using linear regression, we investigated interactions between age, sex and Aβ on tau accumulation and spread, controlling for APOE4‐status and diagnosis.ResultHigher Aβ (i.e. centiloid) predicted faster tau accumulation, where this association was pronounced in younger individuals (i.e. age x centiloid interaction, b = ‐3.64, p<0.001, Fig. 1A). This age x centiloid interaction was stronger in men (b = ‐4.82, p<0.001, Fig. 1B) vs. women (b = ‐1.67, p = 0.029, Fig. 1C), suggesting that younger age promotes Aβ‐related tau accumulation predominantly in men. Bootstrapping analysis further confirmed this effect (Fig. 1D). In Aβ+, epicenters with highest baseline tau‐PET showed a similar temporal‐lobe distribution in men and women (Fig. 2A&B), yet epicenter connectivity to the rest of the brain was stronger in men vs. women (Fig. 2C). Stronger connectivity of tau epicenters to the rest of the brain was linked to faster tau accumulation especially in younger Aβ+ subjects (i.e. interaction age x epicenter connectivity, b = 4.41, p<0.001, Fig. 3A). However, this effect was clearly driven by men (b = 6.13, p<0.001, Fig. 3B) and not observed when tested in women only (b = 1.55, p = 0.252, Fig. 3C).ConclusionAβ drives faster tau accumulation and this effect is particularly strong at younger age and even further pronounced in men, whose tau epicenters are more densely interconnected with the rest of the brain. Together, age and sex have clear modulating effects on tau spreading, and heterogeneous AD trajectories may be partly arisen due to sex‐specific differences in brain network architecture.
Iron–induced, sex‐specific alterations of mitochondrial bioenergetic function and increased amyloid beta plaque size in 5xFAD mice
Authors: Peng Wilson , Osabutey Mark , Okoye Chidozie N , Chung Kaitlin , Trojanczyk Lee , Le Linh , Selim Nada Ahmed , Milliken Alex S , Al‐Qazzaz Ali , Majewska Ania K , Wojtovich Andrew P , Dirksen Robert T , O'Banion M. Kerry , Onukwufor John O 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disease characterized by neuronal dysfunction leading to decreased memory and cognitive function. AD research has largely focused on the potential pathogenic role of two disease hallmarks: amyloid beta and phosphorylated tau. However, pharmacological interventions targeting these disease hallmarks have met with limited clinical trial success. Thus, other variables may initiate disease etiology prior or contribute to the development of tau and amyloid pathologies. Iron is essential for brain function where its tight regulation aids in neurotransmitter biosynthesis and energy homeostasis. AD patients exhibit high levels of iron in their brain relative to age‐matched, non‐AD patients. However, the potential role of high brain iron levels in AD pathogenesis is unclear.MethodEight‐week‐old male and female C57BL/6 and 5xFAD mice were exposed to standard chow or iron 8 g/kg chow for 8 weeks. Half of the brain from each mouse was used to assess mitochondrial bioenergetic function, with the remaining half quantified for amyloid beta plaque number and size.ResultIron treatment significantly enhanced state 3 (maximum) respiration in male 5xFAD mice, but not in female 5xFAD mice. In contrast, iron treatment increased state 4 respiration in both male and female 5xFAD mice, though the effect in female mice was greater. As a result, mitochondrial respiratory control ratio was greatly impaired in both sexes. Furthermore, iron treatment significantly increased average plaque size in female 5xFAD mice with no effect on male 5xFAD mice, while the total number of plaques were not different in either sex.ConclusionOur data suggest that iron treatment induced sex‐specific alterations of mitochondrial bioenergetic function and amyloid beta plaque size in 5xFAD mice. Future studies will assess the underlying molecular mechanisms driving sex‐specific differences in iron‐induced AD pathology.
Behavioral and Molecular Consequences of Pathogenic Tau Expression in Mouse Locus Coeruleus
Authors: Korukonda Anuradha , Atallah Jake , Tish Margaret M , Weinshenker David 
Published: January 2025

AbstractBackgroundEarly stages of Alzheimer’s disease (AD) are characterized by neuropsychiatric symptoms such as anxiety, apathy, compulsivity, and sleep disturbances, which manifest years before cognitive deficits. It has been hypothesized that dysregulation of the locus coeruleus‐norepinephrine (LC‐NE) system contributes to these symptoms because (1) the LC is the first site where hyperphosphorylated ‘pretangle’ tau can be detected in the human brain and (2) NE influences physiological processes such as mood, stress responses, and arousal. To investigate causal relationships between LC tau pathology and neuropsychiatric symptoms, we developed a translationally‐relevant model where pathogenic tau is exclusively expressed in mouse LC to recapitulate the ‘LC‐first’ phenomenon.MethodAdult male and female tyrosine hydroxylase (TH)‐Cre mice aged 2‐3 months received intra‐LC infusions with a Cre‐dependent adeno‐associated virus expressing either EYFP or P301S mutant human tau (n = 10/group). Three months following infusions, mice were tested in a panel of behaviors encompassing neuropsychiatric and cognitive domains. Following behavioral testing, brain sections containing the LC and projection regions such as dentate gyrus and prefrontal cortex were immunostained for human tau and phospho‐tau (AT8) to verify hyperphosphorylated tau expression, TH to evaluate LC integrity, NE transporter (NET) to assess NE innervation, and the neuroinflammatory markers GFAP and Iba‐1.ResultP301S human tau‐expressing mice displayed significantly lower latency to fall asleep after gentle handling, indicating hypersomnia. Additionally, they showed increased latency to eat a food pellet in a novel arena, reflecting anxiety‐like behavior, and stress‐induced compulsivity in nestlet shredding compared to EYFP‐expressing mice. In the fear conditioning paradigm, mice associated tone with foot shock across both treatment groups during training, and exhibited normal context and cued memory of the shocks as assessed by time spent freezing. AT8 staining indicated hyperphosphorylated tau accumulation in cell bodies and somatodendritic compartments of TH+ neurons. However, tau pathology did not affect LC cell body integrity (TH and NET immunoreactivity) but triggered astrocytic (GFAP) and microglial (Iba‐1) reactivity compared to EYFP controls.ConclusionAt 3 months, anxiety‐ and compulsive‐like behaviors and hypersomnia phenotypes suggest dysregulation of LC‐NE transmission. Further studies are ongoing to assess the cellular and molecular mechanisms governing these behavioral symptoms in early AD.
APOE4 to APOE2 ‘Switching’ in Astrocytes Alters the Cerebral Transcriptome and Decreases AD Neuropathology at Different Points on the AD Pathophysiological Timeline
Authors: Golden Lesley R , Stephens Isaiah O , Siano Dahlia , MacLean Steven M , Pandya Kumar , Gordon Scott , Morganti Josh M. , Johnson Lance A 
Published: January 2025

AbstractBackgroundCompared to the ‘neutral’ E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15‐fold increase in Alzheimer’s Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. Here, we aimed to assess the therapeutic potential of cell‐type specific allelic ‘switching’ by investigating the physiological and neuropathological changes associated with an inducible, in vivo APOE4 to APOE2 transition in astrocytes using a novel transgenic mouse modelMethodThe APOE “switch mouse” (APOE4s2) uses the Cre‐loxP system to allow for inducible APOE allele switching from E4 to E2. These mice express a floxed human APOE4 coding region followed by the human APOE2 coding region. Allelic discrimination (RT‐PCR) and mass spec‐based proteomic analyses were employed to validate the E4 to E2 transition. Single‐cell RNAseq and Xenium In Situ were used to measure transcriptomic changes following the astrocytic E4 to E2 allele switch. Behavioral measures and neuropathological analyses were applied to assess the effects of an early‐life vs. mid‐life allelic switch on AD pathology.ResultmRNA and protein analyses confirm that APOE4s2 mice synthesize full‐length human APOE4 pre‐switch, and that tamoxifen induces an efficient recombination and expression of human APOE2 in target tissues. Single‐cell RNAseq and Xenium reveal that, genetic replacement of astrocytic APOE4 with APOE2 results in distinct alterations to glial cell transcriptomes affecting pathways involved with metabolism, inflammation, and amyloid beta. Neuropathological analyses show that an astrocyte‐specific E4 to E2 ‘switch’ significantly decreases total amyloid burden, even once severe amyloidosis has already begun (mid‐life ‘switch’), and that the astrocytic E4 to E2 transition improves cognition. Additionally, amyloid‐associated astro‐ and micro‐gliosis are decreased, and mice with E2‐expressing astrocytes had less MHCII expressing microglia and a decrease in plaque‐associated ApoE.ConclusionTogether, these data suggest that a successful transition from E4 to E2 in astrocytes has broad impact on the cerebral transcriptome and that an astrocyte‐specific E4 to E2 ‘switch’ improves multiple AD‐associated pathologies at different points across the AD pathophysiological timeline.
Topographic relationship between tau and TDP‐43 in the combined Alzheimer’s disease and Limbic‐predominant Age‐related TDP‐43 Encephalopathy Neuropathologic Changes
Authors: Oh Jae Won , Agrawal Sonal , Yu Lei , Sperling Reisa A , Bennett David A. , Schneider Julie A. , Yang Hyun‐Sik 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is highly comorbid with Limbic‐predominant age‐related TDP‐43 encephalopathy neuropathological change (LATE‐NC), and the combined AD+LATE‐NC is more common than either pathology alone. However, the topographic relationship between tau and TDP‐43 in AD+LATE‐NC remains unclear.MethodWe analyzed the data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) participants. Quantitative amyloid‐β (Aβ) and tau burden were assessed in 8 brain regions using immunohistochemistry; global Aβ burden, mesial temporal tau (mtTau), and neocortical tau (nTau) burdens were calculated. Semiquantitative global TDP‐43 burden was measured with immunohistochemistry in 6 brain regions. We assessed the Aβ–TDP‐43 association with linear regression, adjusting for APOE ε4 count, age at death, and sex. Then, we additionally included nTau and mtTau as predictors in this linear model. We performed mediation analysis to test whether nTau mediates Aβ–TDP‐43 association. We examined the contributions of Aβ, mtTau, nTau, and TDP‐43 on cognitive decline (random slope of change in annual global cognition after controlling age, sex, and education) using a linear model.ResultWe analyzed n = 1,428 deceased ROSMAP participants (Table 1). Global Aβ was positively associated with global TDP‐43 (B = 0.13, p = 2.9×10‐8). However, this association was no longer present after including nTau and mtTau in the model; nTau was positively associated with TDP‐43 (B = 0.34, p<2.0×10‐16), while mtTau was negatively associated with TDP‐43 (B = ‐0.12, p = 3.6×10‐11; Table 2). The negative mtTau–TDP‐43 association was significantly attenuated after excluding participants with hippocampal sclerosis (B = ‐0.038, p = 0.02; Table 2), suggesting that hippocampal sclerosis in advanced LATE‐NC drove this negative association. In a subsequent mediation analysis, nTau completely mediated the Aβ–TDP‐43 association (Proportion mediated: 92.6%, Mediated effect: p<2.2×10‐16, Direct effect: p = 0.48). In a multivariable linear model, TDP‐43 and nTau were independently associated with faster cognitive decline, while mtTau and Aβ were not (Table 3).ConclusionOur large human neuropathology study supports that, in AD+LATE‐NC, TDP‐43 accumulation might be a downstream consequence of nTau, which fully mediated the Aβ–TDP‐43 association. Both TDP‐43 and nTau exacerbate cognitive decline in AD+LATE. Interventions targeting AD pathophysiology might also delay the progression of comorbid LATE‐NC.
Transcriptomic Analysis in Alzheimer’s Disease Brain During Systemic Infection
Authors: Pegoraro Giulia , Smith Rebecca G. , MacBean Lachlan Ford , Smith Adam , Boche Delphine , Pishva Ehsan , Lunnon Katie 
Published: January 2025

AbstractBackgroundThe onset and progression of Alzheimer’s disease (AD) has been widely linked with inflammation both in the periphery and within the brain. Indeed, infections during life can increase the risk of developing dementia and the rate of cognitive decline in AD patients, with many AD sufferers ultimately dying with a systemic infection. One of the aims of this study is to investigate the molecular mechanisms involved in the brain’s response to systemic infections in AD through the analysis of gene expression changes.MethodThe cohort of patients selected for the study is composed of 204 post‐mortem prefrontal cortex brain samples. The cohort is divided as follows: 58 samples affected by AD and 33 controls, all of whom died with a respiratory infection, and 60 AD patients and 53 controls who did not have an infection at the time of the death. Following RNA sequencing; differential expression analysis, weighted gene correlation network analysis (WGCNA) as well as cell‐type and pathway enrichment analysis were performed.ResultThe results of the differential expression analysis indicate that 1185 genes were differentially expressed. The cell‐type enrichment analysis revealed a significant enrichment in microglia, fundamental cells in brain immune response. Pathway enrichment analysis on the differentially expressed genes reported that the top ten enriched pathways were all associated with immune response; examples include “regulation of myeloid leukocytes mediated immunity.” A module from WGCNA also exhibited a correlation with both AD and infection. The cell‐enrichment analysis on the genes in this module demonstrated enrichment in oligodendrocytes and astrocytes, which are reported to be involved in immune response.ConclusionThis analysis laid the foundations for further investigations into gene expression changes associated with AD and infection. Future work will include combining this data with miRNA sequencing, DNA methylation and genotyping data from the same individuals to gain a comprehensive overview of the underlying biological mechanisms.