bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Common Epitope in p53 and Tau Protein Aggregates
Authors: Lynch David , Bhatt Nemil , Samples Madison , Demny Madeline , Tamamis Phanourios , Kayed Rakez 
Published: January 2025

AbstractBackgroundThe oligomers and fibrils of tau are well known as an indicator of Alzheimer’s disease (AD). Recently, other protein aggregates have been shown to be potentially involved in the development of the disease.One of these proteins is p53, involved in DNA repair. Prior studies in our lab show that p53 will form oligomers and fibrils in AD cases but not healthy controls, and has even been observed as a co‐aggregate with tau protein. Owing to the importance of p53 in mitigating damage from diseased cells, it is possible that loss of function or even misfunction of p53 due to aggregation or mislocalisation could be an early contributing factor to AD, having been shown as a potential early biomarker for AD.Because of the co‐aggregation of p53 and tau, it is possible that aggregate‐specific antibodies will bind to both p53 and tau. Besides giving mechanistic insights into the proteins’ aggregation, this would also suggest that these antibodies could inhibit aggregation in vivo. This study examines this common epitope.Method• Using recombinant wild‐type and mutant p53 and tau proteins, the interaction of p53 and tau specific antibodies with each other was determined based around their immunoreactivity, and compared to amyloid‐β.• Co‐staining of AD mouse model and AD patient samples for both misfolded tau and p53 was used to determine if this conformation cross‐reactivity could also be observed in patient samples.ResultDespite the lack of sequence homology, an in‐house conformation and aggregation specific p53 antibody was found to be able to react with tau protein, and vice versa. It was also observed that the p53 mutant proteins had different reactions to these aggregate‐specific antibodies. As these antibodies are conformation‐specific, this provides information on the similar conformation both proteins must adopt in order to react with MDM2.ConclusionThe common epitope recognised by the p53 and tau antibodies suggests that this is a potential target for antibody therapy, as the ability to prevent the formation of the co‐aggregates may permit p53 to continue its role as the ‘guardian of the genome’, a role which, if inhibited, could be a contributing factor to AD.
Reduction of central arterial stiffness by senolytic quercetin improves age‐associated decline in cognitive function in a Dahl salt‐sensitive rat model of early vascular aging
Authors: Santos Carla Rocha Dos , Barnett Mackenzie J , McDevitt Ross A , Wei Wen , Zernetkina Valentina I , Juhasz Ondrej , Morrell Christopher H , Lakatta Edward G , Fedorova Olga V 
Published: January 2025

AbstractBackgroundEarly vascular aging (EVA), manifesting as increases in central arterial stiffness and BP, is associated with cognitive impairment in humans. EVA and cognitive impairment occurs in Dahl salt‐sensitive (DSS) rats consuming a normal salt (NS) diet with an advancing age. Quercetin (QRC), a flavonoid with anti‐oxidant, anti‐inflammatory and senolytic properties, previously shown to reduce salt‐sensitive hypertension in DSS. We hypothesized that QRC will not only reduce EVA but will also improve cognitive function in DSS consuming NS diet.MethodSix month old male DSS rats were assigned to two groups: a control group (n = 12) on a normal salt diet (0.5% NaCl) and an experimental group (n = 24) receiving the same diet supplemented with QRC (100 mg/kg BW/daily) for a 3‐month period. Systolic and diastolic blood pressure (SBP, DBP), pulse wave velocity (PWV, an index of CAS), echocardiography, and visuospatial attention test were assessed before and after QRC treatment or placebo.ResultBefore treatment, no differences existed between groups. From 6 to 9 months of age in the control group, SBP, DBP, and PWV increased, while heart rate (HR) and ejection fraction (EF) showed a borderline decrease, and attention behavior showed a borderline increase for 1.0s of stimulus duration and no change for shorter visual stimulus, 0.2s (Figure and Table). QRC treatment reduced SBP, PWV, and increased EF and attention. The QRC effect was to increase the number of correct responses for 0.2s of stimulus and was negatively correlated with PWV (Pearson r = ‐0.420, P = 0.02) but not with BP, indicating that CAS is linked to cognitive function.ConclusionQRC supplementation demonstrated the ability to reduce EVA and enhance cognition in DSS rats, as indicated by attention behavior. Despite BP and CAS reflecting EVA, the association between attention decline and PWV, but not BP, implies that CAS is linked to cognitive function through mechanisms not directly related to BP. Further exploration is required to understand the mechanistic basis of QRC effects on EVA in DSS rats.Supported by NIA/NIH/IRP
Immature and mature pathological tau forms in the retina of MCI and AD patients correlate with brain tauopathy
Authors: Fuchs Dieu‐Trang , Shi Haoshen , Mirzaei Nazanin , Koronyo Yosef , Davis Miyah R , Robinson Edward K , Rentsendorj Altan , Schneider Lon S. S. , Hawes Debra , Schneider Julie A. , Black Keith L , Kayed Rakez , Selenica Maj‐Linda B , Lee Daniel C , Koronyo‐Hamaoui Maya 
Published: January 2025

AbstractBackgroundThis study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer’s disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post‐translational modifications, including hyperphosphorylation (p‐tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs). Previously, increased p‐tau and other abnormal forms were detected in postmortem retinas of AD patients; however, their presence and levels at earlier stages – in mild cognitively impaired (MCI due to AD) patients – and their association with brain pathology remain undefined.MethodIn this study, we acquired 75 postmortem human eyes and 39 paired brains. Retinal cross‐sections in predefined geometric regions were prepared from 34 AD and 11 MCI patients, and 30 age‐ and sex‐matched cognitively normal controls. Histological analyses involved Bielschowsky silver staining and immunostaining of brains and retinas with antibodies for tau (pS396, AT8, AT100, CitR209, T22, PHF‐1, and MC‐1). Stereological examination and quantification were conducted, and correlations were determined with brain pathology and cognition. P‐tau forms were also determined by NanoString GeoMx digital spatial profiling.ResultOur immunohistochemical examination revealed significant upregulation of immature hyper‐citrullinated (CitR209) and p‐tau forms, propagating tau oligomers, as well as mature PHF‐tau and NFT forms in the retinas of patients with early‐AD (MCI due to AD) and AD‐dementia stages. Interestingly, retinal PHF‐tau accumulated only in the AD‐dementia stage. GeoMx spatial profiling analyses revealed site‐specific increases in various p‐tau epitopes in AD, particularly at the early MCI stage. Tau oligomers had the largest accumulations in MCI and, moreover, AD retinas, showing a strong correlation to Braak staging, representing the spread of tauopathy across brain regions during disease progression. Strong correlations were also found between retinal tauopathy and brain NFTs, ABC, and MMSE severity scores.ConclusionOur data demonstrate that most forms of retinal tauopathy are increased in early AD and correlate with one or more AD neuropathology and cognitive parameters, encouraging the development of retinal tauopathy imaging for AD detection and monitoring disease progression.
Genomic Approaches to Study Alzheimer’s Disease Immunity
Authors: Gate David 
Published: January 2025

AbstractBackgroundMuch attention has been paid to the role of the perenchymal brain immune response in Alzheimer’s disease (AD). Yet, the peripheral immune system in AD has not been thoroughly studied with modern sequencing methods.MethodHere, we used a combination of single‐cell sequencing strategies, including assay for transposase‐accessible chromatin and RNA sequencing, to investigate the epigenetic and transcriptional alterations to the AD peripheral immune system.ResultWe reveal a striking amount of open chromatin in peripheral immune cells in AD. In CD8 T cells, we uncover a cis‐regulatory DNA element co‐accessible with the CXC motif chemokine receptor 3 gene promoter. In monocytes, we identify a novel RELA transcription factor binding site adjacent to an open chromatin region in the nuclear factor kappa B subunit 2 gene. We also demonstrate apolipoprotein E genotype‐dependent epigenetic changes that correspond to altered cytokine gene expression in monocytes. Surprisingly, we also identify differentially accessible chromatin regions in genes associated with sporadic AD. Finally, we provide an online data portal resource to explore gene expression in the AD immune system.ConclusionOur findings provide novel insights into the complex relationship between epigenetics and genetic risk factors in the AD peripheral immune system.
IGFBP‐5 Potentially Mediates the Association of Brain Insulin Signaling with Late‐Life Cognitive Decline
Authors: Tong Han , Capuano Ana W. , Bennett David A. , Ahima Rexford S. , Arnold Steven E. , Arvanitakis Zoe 
Published: January 2025

AbstractBackgroundAbnormal brain insulin signaling has been associated with Alzheimer’s disease pathology and a faster rate of late‐life cognitive decline. However, the underlying mechanisms remain unclear. In this study, we examined whether AD‐related cortical proteins identified using targeted‐proteomics play a role in the association of brain insulin signaling and cognitive decline.MethodAmong the Religious Orders Study participants who underwent annual clinical and comprehensive neuropsychological testing (summarized as global and domain‐specific cognitive measures), 118 deceased and autopsied older individuals (59 with diabetes matched to 59 without, by age at death, sex, and education) had both brain (prefrontal cortex) insulin signaling (by ELISA and immunohistochemistry, including RAC‐alpha serine/threonine‐protein kinase or AKT1) and AD‐related cortical protein measurements. Levels of five cortical proteins including insulin‐like growth factor‐binding protein‐5 (IGFBP‐5), inositol‐tetrakisphosphate 1‐kinase (ITPK1), heat shock protein B2 (HSPB2), adenylate kinase 4 (AK4), and plexin B1(PLXNB1) were measured using selection reaction monitoring quantitative proteomics. We conducted linear mixed‐effect model analyses adjusted for age at death, sex, and education to examine associations of cortical proteins and insulin signaling measures with longitudinally assessed cognitive function.ResultA higher level of IGFBP‐5 (estimate = 0.260, SE = 0.092, p = 0.005) and a lower level of ITPK1 (estimate = ‐0.278, SE = 0.092, p = 0.003) were each associated with a higher level of pT308AKT1 /total AKT1. In addition, a higher level of pT308AKT1 /total AKT1 was associated with a faster rate of decline in global cognition (estimate = ‐0.035, SE = 0.013, p = 0.007), and most cognitive domains including episodic memory (estimate = ‐0.039, SE = 0.014, p = 0.005), working memory (estimate = ‐0.031, SE = 0.009, p = 0.001), perceptual speed (estimate = ‐0.026, SE = 0.011, p = 0.015), and visuospatial abilities (estimate = ‐0.017, SE = 0.007, p = 0.019). Yet, when the level of IGFBP‐5 and its interaction with time were added to the models as covariates, the level of pT308AKT1 /total AKT1 was no longer associated with the decline rate of global cognition (estimate = ‐0.023, SE = 0.012, p = 0.067) and cognitive domains including perceptual speed (estimate = ‐0.018, SE = 0.010, p = 0.082) and visual spatial abilities (estimate = ‐0.014, SE = 0.007, p = 0.052).ConclusionAD‐related cortical proteins IGFBP‐5 and ITPK1 are each associated with insulin signaling AKT1 phosphorylation in postmortem human brain. Further, IGFBP‐5 potentially mediates the association of AKT1 phosphorylation with late‐life cognitive decline.
Chlamydia pneumoniae infection and inflammasome activation in Alzheimer’s retina: Correlations with disease status
Authors: Gaire Bhakta Prasad , Koronyo Yosef , Subedi Lalita , Rentsendorj Altan , Fuchs Dieu‐Trang , Swerdlow Natalie , Black Keith L , Arditi Moshe , Crother Timothy R , Koronyo‐Hamaoui Maya 
Published: January 2025

AbstractBackgroundAn emerging theory suggests a link between Alzheimer’s disease (AD) and microbial infection. Notably, various microbes have been detected in the post‐mortem brains of AD patients and murine models. However, there exists a gap in research concerning the presence and role of microbial infection in the AD retina, which shares common pathogenesis with the brain. Focusing on Chlamydia pneumoniae (Cp), a gram‐negative respiratory pathogen, we assessed the presence and severity of infection and inflammasome activation in retinas and paired brains from individuals with mild cognitive impairment (MCI) or AD, comparing them to age‐ and sex‐matched counterparts with normal cognition (NC). This investigation provides critical insights into the potential microbial involvement in AD pathology.MethodEmploying diverse histological and biochemical techniques, we identified and quantified Cp and related biomarkers in retinas and brains of MCI and AD patients vs NC controls. We determined the relationships between retinal and brain Cp infection and gliosis, inflammasome activation, pyroptosis, and disease status.ResultCp inclusions were identified in the postmortem retina of individuals with MCI and AD, correlating with Cp burden in the corresponding brain tissues. Notably, a threefold increase in retinal and brain Cp infection was observed in AD, not in MCI, compared to NC, suggesting a predilection of Cp infection at later AD stages. Live Cp was successfully isolated from AD retinal lysates, confirming active Cp infection. Retinal Cp infection correlated with retinal amyloidosis and synaptic damage, but not with brain amyloidosis. Additionally, it was associated with brain tauopathy markers as well as the cognitive status. Cp‐infected cells were engulfed by retinal microglia. Furthermore, Cp infection triggered NLRP3‐inflammasome activation, gliosis, pyroptosis, and apoptosis. While retinal NLRP3 inflammasome increased earlier in MCI, Cp‐induced retinal ASC, Capase‐1 and ‐3, and cleaved‐GSDMD rose later in AD‐dementia stage. These findings unveil the intricate relationship between Cp infection, retinal pathology, and AD progression.ConclusionOur findings reveal Cp infection in both AD retina and brain, coupled with inflammasome markers. This highlights a potential link to neurodegeneration in AD, offering avenues for therapeutic exploration, involving early antibiotic treatment or inflammasome attenuation.
To study the correlation between cognitive decline and Parkinson’s disease with sarcopenia in Qinghai‐Tibet Plateau
Authors: Zhu Aiqin , Liu Jiangang 
Published: January 2025

AbstractBackgroundTo investigate the correlation between cognitive decline and gait speed and grip strength in patients with Parkinson’s disease (PD) and sarcopenia in the hypoxic environment.MethodFrom October 2022 to December 2023, a cross‐sectional study was conducted to collect 134 patients (65 males and 69 females) of Parkinson’s disease (age 68.59±10.20 years), who had lived in a Qinghai‐Tibet Plateau area (Qinghai province, an average altitude of 2,500m) for more than 30 years. Skeletal muscle mass index (SMI) was measured using InBody S10 Biospace device from Korea. Grip strength(GS) and six‐meter gait speed test(GST) were measured by JAMAR handgrip dynamometer and Tsinghua Tongfang 6‐meter walking test instrument. PD related scales were used to assess motor and cognitive function.ResultThe prevalence of PD with sarcopenia was 32.8%, including 59.1% (female) and 40.9% (male). Compared with the PD without sarcopenia group, the PD with sarcopenia group showed an increased in age(65.17±8.80 vs 75.50±9.36 years), MDS Unified‐Parkinson Disease Rating Scale‐III (MDS‐UPDRS III) and Hoehn‐Yahr stage (H‐Y) grading (which were used to assess the severity of PD), while Body Mass Index (BMI), GST, SMI, GS, Mini‐mental state Examination (MMSE) and Montreal Cognitive Assessment (MOCA) scores were significantly decreased (P < 0.001). Correlation analysis showed that the GS and GST of PD patients were negatively correlated with UPDRS III (r = ‐0.461; r = ‐0.410), H‐Y grading (r = ‐0.347, r = ‐0.399), and Activities of Daily Living (ADL) (r = ‐0.558, r = ‐0.344) (P<0.001), and positively correlated with MMSE (r = 0.452, r = 0.506), MOCA (r = 0.267, r = 0.453) (P <0.001), and language ability (r = 0.177, r = 0.208; P <0.05). GS was positively correlated with orientation (r = 0.302), attention and calculation (r = 0.262)(P<0.002). Binary regression analysis showed that BMI (OR = 0.682,95%CI: 0.495‐0.940, P<0.05) and MMSE (OR = 0.695,95%CI: 0.557‐0.866, P < 0.001) were protective factors for PD with sarcopenia. H‐Y stage (OR = 4.942,95%CI: 1.567‐15.896, P < 0.006) was a risk factor for PD with sarcopenia.ConclusionCognitive decline is the main risk factor for Parkinson’s disease with sarcopenia in the Qinghai Tibet Plateau region. It may be related to slow gait speed and decreased grip strength. The processing speed and executive dysfunction are mainly related to weak grip strength.
Exploring the Relationship Between Brain Structural and Antipsychotic Drug Dosage in BPSD
Authors: Hong Bo , Tao Tianli , Zhang Han , Li Xia , Chen Jianhua , Yue Ling 
Published: January 2025

AbstractBackgroundPsychotropic medications are commonly prescribed for behavioral and psychological symptoms of dementia (BPSD). However, the safety of antipsychotic drugs has always been a concern. The study aims to investigate the relationship between brain structural and the effective dosage of antipsychotic drugs.MethodAll the subjects were from Shanghai Mental Health Center. On baseline, the BPSD patients completed a 3D T1 MRI scan and evaluated by MMSE and Neuropsychiatric Inventory (NPI). Patients who underwent standardized clinical treatment were followed up until BPSD remission. Drug treatment procedures were recorded, with the antipsychotic drugs being converted using a defined daily doses (DDDs) method to obtain the final daily doses. We divided the patients into three groups: DDDs = 0, 0<DDDs<0.3, and DDDs≥0.3, representing a non‐antipsychotic group (NAP), a low‐dose group (LAP), and a high‐dose group (HAP). The relationship between the altered brain regions and the DDDs were investigated.ResultA total of 86 BPSD patients were enrolled (NAP = 28, LAP = 26, HAP = 32). Among the three groups, NAP group showed less NPI score, while no difference was observed in age, gender, education level, and MMSE (Tab. 1). ANCOVA analysis showed significant differences in the cortical thickness of pars orbitalis on the left (F = 3.277, p = 0.003) and the volume of thalamus on the left (F = 4.279, p<0.001) among three groups. Post hoc analysis indicated that HAP group had thinner cortex in the left pars orbitalis compared to NAP group (Fig. 1). Ordinal logistic regression analysis revealed that NPI (p = 0.014) and cortical thickness at the left pars orbitalis (p = 0.037) were independent predictors of DDDs. Further association analysis revealed a significant negative correlation between cortical thickness of left pars orbitalis and DDDs (r = ‐0.229, p = 0.04), even after adjusting for gender, age, education, MMSE, and NPI. (Fig. 2).ConclusionThis study provides the first‐ever evidence that brain anatomical changes may serve as valuable biomarkers in the prediction of antipsychotic drug dosage for BPSD. The result has significant implications for optimizing clinical management strategies and offers insights into the intricate neuropathological mechanisms of BPSD.
Effects of Memantine on okadaic acid induced neurotoxicity at the systemic and molecular level in rats
Authors: Rusadze Khatuna , CHIGHLADZE MARIAM , Dashniani Manana , Burjanadze Maia , Chkhikvishvili Nino , Beselia Gela 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) is a neurodegenerative disease that causes progressive cognitive decline over age 65. Individuals suffering from this disease suffer memory loss, and histological examination of the brains. Okadaic acid (OA), is a potent and selective inhibitor of protein phosphatases 1 and 2A. Intracerebroventricular (ICV) administration of OA can produce an Alzheimer‐like hyperphosphorylation of tau protein. Therefore, it was suggested that intracerebral injection of OA can affect the activity of neurotransmitters and their receptors in brain areas. Central cholinergic and glutamatergic activity together are known to be crucial for the acquisition and consolidation performance of a variety of learned behaviors. The present study was designed to investigate the effects of okadaic acid (OA) intracerebroventricular (ICV) injection on memory function and expression level of α7 subunit of nicotinic acetylcholine receptor (nAChR) and NR2B subunit of NMDA glutamate receptors in the hippocampus, as well as effect of the antidementic drug memantine on OA induced changes at systemic and molecular level in rats.MethodOA was dissolved in artificial cerebrospinal fluid (aCSF) and injected ICV 200 ng/10 μl. Vehicle control received 10 μl of aCSF ICV. Control and OA injected rats were divided into 2 subgroups: treated i.p. with saline or memantine (5 mg/kg daily for 13 days starting from the day of OA injection). Rats were trained in the dual‐solution plus‐maze task that can be solved by using place or response strategies. The Western immunoblotting was used to determine relative amount of hippocampal receptors protein levels.ResultObtained data revealed that OA ICV injected rats were severely impaired at acquiring the place version of the maze accompanied by significant decline in hippocampal α7 subunit of nACh receptors protein levels. Memantine treatment can prevent OA induced impairment of hippocampal‐dependent spatial memory and accompanied by modulation of the expression level of α7 subunit of nACh and NR2B subunit of NMDA receptors in the hippocampus.ConclusionThus, our results support the presumption that α7 nACh receptors may play an important role in the cognitive enhancer effects of memantine and emphasize the role of cholinergic‐glutamatergic interactions in memory.