bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of TDP‐43 in dysregulation of cholesterol metabolism and implications for AD
Authors: Kabra Khushbu , Bradshaw Elizabeth M 
Published: January 2025

AbstractBackgroundLipid dysregulation is a known feature of Alzheimer’s Disease. Importantly, alterations in lipids pathways affect immune responses in cells like microglia, which have been shown to accumulate cholesterol in both aging and neurodegeneration. Recently, the presence of TDP‐43 inclusions has been linked to increased severity of cognitive impairment in AD patients. While TDP‐43 inclusions are associated primarily with ALS, their presence has been observed in around 57% AD patients. The link between TDP‐43, cholesterol dyshomeostasis and defects in immune responses in the context of AD is yet to be uncovered.MethodMicroglia: Peripheral blood mononuclear cells (PBMCs) are isolated and microbead separation is used to further purify monocytes. These monocytes are cultured with a cytokine cocktail for 10‐14 days to induce differentiation into MDMi (monocyte derived microglia). N = 17 Knockdown screen: Lentivirus mediated shRNA knockdown is used to reduce expression of various genes implicated in AD and ALS, including TREM2, CD33 and TARDBP in MDMi. Functional assays: Cholesterol uptake is measured by using a fluorescence microplate reader and lipid droplets are stained using LipidTox. Gene expression is measured using Fluidigm.ResultTARDBP knockdown resulted in the most significant downregulation of several cholesterol metabolism associated genes, including ABCG1, NPC1, CYP27A1, LXR and SREBP1/2, which are involved in cholesterol uptake, storage and synthesis. The TARDBP knockdown MDMi also had reduced cholesterol uptake and lowered response to LPS stimulation, compared to other gene knockdowns.ConclusionTARDBP plays an important role in the regulation of cholesterol metabolism, specifically cholesterol uptake. The presence of TDP‐43 inclusions in AD may thus contribute to AD pathology through loss of function of TARDBP, causing defects in cholesterol homeostasis which lead to altered microglia function. This also has implications in better understanding Limbic‐predominant age‐related TDP‐43 encephalopathy (LATE), a recently characterized type of dementia associated with TDP‐43 proteinopathy.
Evaluating Congruence Between Clinical and Biological Staging Across The Alzheimer’s Disease Spectrum
Authors: Zalzale Hussein , Madeiros Marina Scop , Soares Carolina , Bauer‐Negrini Guilherme , Povala Guilherme , Ferreira Pamela C.L. , Amaral Livia , Lussier Firoza Z , Bellaver Bruna , Abbas Sarah , Rodrigues Matheus Scarpatto , Tudorascu Dana , Oliveira Markley , Felix Cynthia , Leffa Douglas Teixeira , Tissot Cécile , Aguzzoli Cristiano Schaffer , Ruppert Emma Patrice , Saha Pampa , Rahmouni Nesrine , Zetterberg Henrik , Blennow Kaj , Ashton Nicholas J. , Pascual Belen , Gordon Brian A. , Jagust William J. , Lowe Val J. , Karikari Thomas K , Oh Hwamee , Klunk William E , Soleimani‐Meigooni David N. , Rosa‐Neto Pedro , Baker Suzanne L. , Pascoal Tharick A. 
Published: January 2025

AbstractBackgroundThe newly proposed criteria by the AA working group incorporates both biological and clinical stages to characterize the progression of AD. In this study, we aim to evaluate the agreement between these two complementary systems.MethodsUsing 188 participants from McGill TRIAD and 139 from the HEAD cohorts, we categorized participants into biological (0‐4) and clinical (0‐4) stages using amyloid PET, tau PET(MK‐6240), and clinical measures as described by the working group. Participants were then stratified into three categories: congruent (clinical = biological), higher in the biological stage (clinical < biological), and higher in the clinical stage (clinical > biological). In the TRIAD cohort, we further compared these groups for age, sex, years of education, vascular burden (WMH), microglial activation (PBR scan), Astrocyte reactivity (GFAP), amyloid load, tau load, and NPI‐Q scores using Welch two‐sided t‐test with FDR multiple comparison correction.ResultsIn the TRIAD cohort, 34% of participants were congruent, 24.5% had a higher clinical stage, and 41.5% had a higher biological stage. Meanwhile in the HEAD cohort 68.2% were congruent, 20.7% had a higher clinical stage, and 17% had a higher biological stage. TRIAD participants with a higher clinical stage had lower education (P = 0.02), more neuropsychiatric symptoms (P = 0.03), and a higher vascular burden (P = 0.03) (Table 1). As expected, people with higher biological stage had more amyloid(P<0.001), tau(P<0.001), and astrocyte reactivity(P<0.001) (Table 1, Figure 2).ConclusionsOur findings highlight important discordance between clinical and biological stages, which could be partially explained by cognitive reserve. This was supported by the protective effects of educational attainment in participants with a higher biological stage. Vascular burden played a major role in the cognitive impairment of individuals with higher clinical stages. Future studies should replicate these findings in larger more representative population‐based cohorts.
The Glutamatergic System in Alzheimer’s Disease: A Systematic Review with Meta‐analysis
Authors: Soares Carolina , Da Ros Lucas Uglione , Machado Luiza Santos , da Rocha Andreia Silva , Lazzarotto Gabriela , Carello‐Collar Giovanna , De Bastiani Marco , Ferrari‐Souza João Pedro , Lussier Firoza Z , Souza Diogo O. , Rosa‐Neto Pedro , Pascoal Tharick A. , Zimmer Eduardo R. 
Published: January 2025

AbstractBackgroundGlutamatergic neurotransmission system dysregulation may play an important role in the pathophysiology of Alzheimer’s disease (AD). However, reported results on glutamatergic components across brain regions are contradictory. Here, we conducted a systematic review with meta‐analysis to examine whether there are consistent glutamatergic abnormalities in the human AD brain.MethodWe searched PubMed and Web of Science(database origin‐October 2023) reports evaluating glutamate, glutamine, glutaminase, glutamine synthetase, glutamate reuptake, aspartate, excitatory amino acid transporters, vesicular glutamate transporters, glycine, D‐serine, metabotropic and ionotropic glutamate receptors in the AD human brain. The studies were synthesized by outcome and brain region. We included cortical regions, the whole brain(cortical and subcortical regions combined), the entorhinal cortex and the hippocampus. Pooled effect sizes were determined with standardized mean differences (SMD), random effects adjusted by false discovery rate, and heterogeneity was examined by I2statistics.ResultThe search retrieved 6 936 articles,63 meeting the inclusion criteria(N = 709CN/786AD;mean age 75/79). We showed that the brain of AD individuals presents decreased glutamate (SMD = ‐0.82;P<0.001) and aspartate levels (SMD = ‐0.64; I2 = 89.71%; P = 0.006), and reuptake (SMD = ‐0.75;P<0.001). We also found reduced AMPAR‐GluA2/3 levels(SMD = ‐0.63;P = 0.046), hypofunctional NMDAR (SMD = ‐0.60;P<0.001) and selective reduction of NMDAR‐GluN2B subunit levels(SMD = ‐1.07;P<0.001). Regional differences include lower glutamate levels in cortical areas and aspartate levels in cortical areas and in the hippocampus, reduced glutamate reuptake, reduced AMPAR‐GluA2/3 in the entorhinal cortex, hypofunction of NMDAR in cortical areas, and a decrease in NMDAR‐GluN2B subunit levels in the entorhinal cortex and hippocampus. Other parameters studied were not altered.ConclusionOur findings show depletion of the glutamatergic system and emphasize the importance of understanding glutamate‐mediated neurotoxicity in AD. This study has implications for the development of therapies and biomarkers in AD.
Optimization of the object recognition assay to test mouse cognition
Authors: Sambamurti Kumar , Crowder Dallas , Pappolla Miguel A , Shah Suhua , Fan Hongkuan , Lahiri Debomoy K. , Greig Nigel H , Kanthasamy Anumantha 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) has traditionally been recognized as progressive dementia with brain deposits of amyloid (Aβ) and Tau (MAPT) proteins starting 20 and 10 years before the onset of clinical symptoms. Aggregation and deposition of Aβ and Tau proteins have been successfully studied in vitro, cell cultures, and animal models, but clinical deficits have been more difficult to assess. Behavior in mice is a complex phenomenon and subject to variation based on mouse interest, moods, stress‐induced distraction, and other undefined parameters. We have attempted to optimize the novel and displaced object assays to improve behavior studies to evaluate animal models of neurodegeneration.Method5xFAD, hTau, and related mice were habituated in the field for 15 minutes twice on day‐1, followed by familiarization with two identical objects twice for 15 minutes on day‐2. The final testing on day‐3 started with novel followed by displaced object analysis. We compared three opaque arenas –rectangular (34 × 24 cm), large square (40 cm), and small square (25 cm) and objects of several heights and types. We also assessed handling mice by cupping to make them more interactive and relaxed for the study.ResultMice tend to jump over the arena walls and escape when handled by their tail but are contained when handled by cupping through a cylinder. All the systems were equally able to discriminate between novel and familiar objects. However, we could only distinguish between the familiar and displaced objects in the smaller 25 cm square arena. Also, object interaction time was longer in the smaller field.ConclusionIt is critical to handle mice by cupping to ensure reduced stress and optimum object interaction. A smaller arena may promote object interaction; taller objects reduce detection artifacts. NIH grants supported the study.
Targeting Alzheimer’s disease with a Geroscience approach
Authors: Darvas Martin 
Published: January 2025

AbstractBackgroundA drug cocktail targeting different processes of aging was tested in an aging mouse model of Alzheimer’s disease (AD) neuropathologic change as an intervention to improve behaviors corresponding to cognitive dysfunction in AD.MethodA cocktail of acarbose/rapamycin/phenylbutyrate or a control treatment was administered (medicated vs. non‐medicated chow) chronically to 22 months‐old mice that received viral vector injections to induce amyloid and tau pathology in the hippocampus at 24 months of age. At 27 months of age motor, anxiety and cognitive behaviors were measured using open field, y‐maze and contextual‐fear conditioning tests.ResultThe percentage of spontaneous alternations in the y‐maze of mice with hippocampal injection of viral vectors to induce amyloid and tau pathology (amyloid‐tau group) was significantly reduced when compared to mice that received hippocampal injection of control viral vectors (sham group). Further, the percent of time spent freezing in the fear‐conditioning apparatus of mice from the amyloid‐tau group was significantly reduced when compared to sham‐control mice. Treatment with the drug cocktail improved both spontaneous alternations in the y‐maze and time spent freezing in the fear‐conditioning apparatus in mice from the amyloid‐tau group.ConclusionThe drug cocktail of acarbose/rapamycin/phenylbutyrate reduced the negative effects of hippocampal amyloid and tau pathology on two measures of cognitive function.
Ingestion of Ubiquitous Environmental Metal‐Metalloid Neurotoxicants Lead, Cadmium, or Arsenic in Drinking Water Results in Brain Accumulation And Alters the Alzheimer’s Disease Exposome
Authors: Goldstein Lee E , Kotredes Kevin P , Minaeva Olga , Moncaster Juliet A , Lupoli Nicola , Howell Gareth R 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) and AD‐related dementias (ADRD) are modulated by gene‐environment (GxE) interactions across the lifespan. Variants of specific genes increase AD risk and synergize with lifetime exposure to environmental toxicants (“exposome”), including neurotoxic metals (lead, Pb; cadmium, Cd) and metalloid (As). These metal/metalloid toxicants readily enter the body (e.g., via contaminated drinking water), transit in blood, cross the blood‐brain barrier (BBB), and distribute in the brain. Pb, Cd, and As are potent neurotoxicants and suspected modifiers of AD pathobiology. The mechanisms underpinning AD‐related GxE interactions specific to Pb, Cd, As exposures are largely unknown and potentially modifiable. Hypothesis: Pb, Cd, As exposures alter expression of AD‐linked genes and potentiate AD pathogenesis in a toxicant‐specific, neurodevelopment‐sensitive, biomarker‐responsive, and age‐dependent manner.MethodWe exposed mice expressing humanized AD gene variants (hAPOE, hMAPT, hAβ; NIA MODEL‐AD) to Pb, Cd, As in drinking water at human‐relevant toxicant levels (Pb: 200 ppm; Cd: 5, 50 ppm; As: 20 ppm) vs unspiked drinking water (control). Exposures were carried out for 30 days. Mice were sacrificed, blood collected by cardiac puncture, and cerebrovasculature cleared by transcardiac saline perfusion. Harvested brains were analyzed by ICP‐MS solution analysis, high‐resolution laser ablation metallomic imaging ICP‐MS mapping), transcriptomics, biochemistry, other assays.ResultMODEL‐AD mice exposed to Pb, Cd, As in drinking water increased levels of metal/metalloid toxicant in blood and brain and altered expression of human AD genes in a toxicant‐specific manner: decreased ↓VGF (Pb, As), increased ↑APP (Cd). Both ↓VGF and ↑APP are associated with increased AD risk. Pb distribution in brain showed striking regional variation. Significant associations (FDR<0.05; LOAD GO terms): Pb (600 genes): chaperone‐dependent protein refolding (FDR = 0.02), glutamate signaling (FDR = 0.009), cognition (FDR = 0.003), synaptic transmission (FDR = 0.01); As (201 genes): synaptic plasticity (FDR = 0.02) and organization (FDR = 0.04), unfolded protein response (FDR = 0.008); Cd (348 genes): protein localization (FDR = 0.03), protein metabolism (FDR = 0.05), sensory perception (FDR = 0.001). No group differences noted in water intake or daily weight.ConclusionMODEL‐AD mice exposed to Pb, Cd, or As accumulate metal/metalloid toxicants in blood and brain and showed toxicant‐specific alterations in AD‐relevant gene expression and gene module profiles.
Vitamin A and Histone Deacetylases in Alzheimer’s disease: The Good, the bad and the ugly
Authors: Bose Chhanda , Hindle Ashly X , Baker Adam X , Smith Shane , Strickland Jake , Guzman Isabel , Singh Sharda P , Lawrence J. Josh 
Published: January 2025

AbstractBackgroundIn Alzheimer’s disease (AD), histone acetylation is disrupted, suggesting loss of transcriptional control. Moreover, converging evidence suggests an age‐ and AD‐dependent loss of transcription controlled by all‐trans‐retinoic acid (ATRA), the bioactive metabolite of vitamin A (VA). Antioxidant depletion causes oxidative stress (OS). Nrf2‐mediated antioxidant defenses are triggered by OS. Here, we investigated roles of VA, histone acetylation, Nrf2, and OS in vitro. Finally, we established a dietary dose of vorinostat that crosses the blood brain barrier and promotes histone acetylation in AD mouse brain.MethodFor in vitro studies, mouse HT22 cells were treated with vorinostat (up to 40 µM), ATRA, and/or H2O2. MTT and lipid peroxidation assays were performed. Acetylated histone H3 and Nrf2 expression were examined via western blot (WB) and immunocytochemistry (ICC). For in vivo studies, the hAb‐KI AD mice were treated with 0.18 or 0.36 mg vorinostat/gram of diet (125 or 250 mg/kg/week for 2 weeks). HDAC activity in brain tissue was examined via histone H3 acetylation and enzyme activity via WB and colorimetric ELISA.ResultVorinostat and ATRA treatment (up to 20 μM) had no significant cytotoxic effects on HT22 cells. H2O2 alone (25‐50 µM) caused ∼30‐40% cell death (p<0.0001). ATRA (5 µM), in combination with vorinostat (0.5 µM), protected against H2O2 up to 150 µM. Vorinostat caused gradual and significant (p<0.001) induction in acetylation of histone H3 with 0.5‐3.0 µM treatment for 24h, with no change in total histone H3 levels. ROS was significantly reduced. Nuclear translocation of Nrf2 was induced by H202 and reduced after ATRA and vorinostat treatment. For 0.18 or 0.36 mg vorinostat/gram doses in vivo, histone H3 acetylation was increased, HDAC activity was inhibited (p<0.001 and 0.05, respectively), and peroxidation was reduced.ConclusionDoses of vorinostat used in vitro and in vivo increased histone acetylation without cytotoxicity/toxicity. In vivo, we established that 125 mg/kg/week in diet is an optimal tolerable dose. VA, alone and in combination with vorinostat, may exhibit synergistic effects in protecting neuronal cells from oxidative stress. Together, our study provides a possible link between oxidative stress, Nrf2 and HDACs as potential contributors to Alzheimer’s disease progression.
Use of melatonin in mild cognitive impairment: a retrospective study
Authors: Olivar Natividad , Brusco Luis Ignacio , Cardinali Daniel Pedro 
Published: January 2025

AbstractBackgroundVariations in the circadian rhythm in older adults can negatively affect brain and cardiovascular health. As a consequence, poor cognitive functioning, an increase in the inflammatory response, alterations in sleep patterns, changes in mood and a decrease in motivation, energy and initiative are observed.MethodWe retrospectively examined the initial and final neuropsychological assessment of 250 MCI outpatients, 125 of whom had received daily 3‐9 mg of a fast‐release melatonin preparation p.o. at bedtime for 12 months. Melatonin was given in addition to the standard medication prescribed by the attending psychiatrist.ResultPatients treated with melatonin showed significantly better performance in Mini Mental State Examination and the cognitive subscale of the Alzheimer’s Disease Assessment Scale. After application of a battery of neuropsychological tests including Mattis test, Digit‐symbol test, Trail A and B tasks and the Rey’s verbal test, better performance was found in melatonin‐treated patients, except for the Digit‐symbol test score which remained unchanged. Abnormally high Beck Depression Inventory scores decreased in melatonin‐treated patients, concomitantly with an improvement in wakefulness and sleep quality.ConclusionThe results suggest that melatonin can be a useful add‐on drug for treating MCI in a clinical setting.
Aging x Environment x genetic risk for late onset Alzheimer’s disease results in alterations in cognitive function in mice independent of amyloid and tau pathology
Authors: Williams Sean‐Paul Gerard , Santos Diogo Francisco Silva , Haynes Kathryn A , Heaton Nicholas , Hart Jason T , Kotredes Kevin P , Pandey Ravi S , Persohn Scott C , Eldridge Kierra , Ingraham Cynthia M , Lloyd Christopher D , Wang Nian , Sasner Michael , Carter Gregory W , Territo Paul R , Lamb Bruce T. , Howell Gareth R , Oblak Adrian L , Rizzo Stacey J Sukoff 
Published: January 2025

AbstractBackgroundAlzheimer’s disease (AD) research has been historically dominated with studies in mouse models expressing familial AD mutations; however, the majority of AD patients have the sporadic, late‐onset form of AD (LOAD). To address this gap, the IU/JAX/PITT MODEL‐AD Consortium has focused on development of mouse models that recapitulate LOAD by combining genetic risk variants with environmental risk factors and aging to enable more precise models to evaluate potential therapeutics. The present studies were undertaken to characterize cognitive and neurophysiological phenotypes in LOAD mice.MethodTwo genetic risk factors, APOE4 and Trem2*R47H, were incorporated into C57BL/6J mice with humanized amyloid‐beta to produce the LOAD2 model (JAX# 030670). Male and female LOAD2 and WT mice were exposed to ad libitum 45% high‐fat diet from 2‐months of age (LOAD2+HFD or WT+HFD, respectively) throughout their lifespan and compared to LOAD2 and WT mice on control diet (+CD). Cognitive training began at 14‐months of age using a touchscreen testing battery, similar to previously described methods (Oomen et al 2013). At the conclusion of touchscreen testing, subjects were implanted with wireless telemetry devices (DSI) for evaluation of electroencephalography (EEG) signatures.ResultAll subjects met the touch‐reward association criteria. During task acquisition LOAD2+CD mice demonstrated impaired acquisition relative to WT+CD, while both LOAD2+HFD and WT+HFD failed to learn the task as indicated by accuracy less than chance (<50%); which was confirmed in a separate cohort. LOAD2+HFD mice demonstrated increased spikewave events as measured by EEG, relative to LOAD2+CD. At 18‐months of age +CD mice that met acquisition criteria were evaluated in a location discrimination task with LOAD2+CD mice demonstrating modest impairments in pattern separation relative to age‐matched WT+CD.ConclusionThese data are the first reports of cognitive deficits and neurophysiological alterations in mice with environmental x genetic risk for LOAD, independent of amyloid and tau pathology. Importantly, the present findings demonstrate the sensitivity of the translational touchscreen testing battery for detecting mild cognitive impairment in LOAD mice with corresponding neurophysiologic alterations, and extend previous characterization data for the LOAD2 model and its utility for the study of the biology of LOAD.
Modulation of Autophagy and mTOR pathways by Metformin in Olfactory Neuroepithelial Cells Across Different Age Groups: Insights into Pharmacological Implications for Neurodegeneration
Authors: Cardenas‐Aguayo Maria‐del‐Carmen , Gomez‐Virgilio Laura , Lora‐Marin Obed‐Ricardo , Silva‐Lucero Maria‐del‐Carmen 
Published: January 2025

AbstractBackgroundLongitudinal population‐based studies have consistently revealed an expedited cognitive decline in the elderly population with type 2 diabetes mellitus (DM2). Additionally, there is a documented increased risk of developing vascular dementia and Alzheimer’s disease in individuals with DM2. Conversely, recent research has pointed to metformin (MET), a widely prescribed medication for type 2 diabetes mellitus (T2DM), potentially mitigating age‐related cognitive dysfunction (Madhu et al., 2022). To explore this further, we utilized Neural Stem/Progenitor Cells derived from the Olfactory Epithelium (NS/PCs‐OE) obtained from healthy subjects across different age groups. The primary objective is to assess MET’s effectiveness in modulating mTOR signaling and enhancing autophagy, which likely could contribute to its observed positive effects on cognitive function.MethodTo collect NS/PCs‐OE, volunteers were exfoliated from the anterior region of the medial‐lateral turbinate nasal regions, using a specific brush and circular movements. This study was authorized by the UNAM School of Medicine’s Ethical Committee (FMED/CEI/PMSS/074/2021). Participants gave written informed consent before nasal exfoliation. Immunodetection has been used to characterize those cell cultures. The cells were collected in DMEM/F‐12 supplemented with 4 mM L‐glutamine, 100 g/ml streptomycin, 100 IU/ml penicillin, and 10% fetal bovine serum. Cells from passages 5 through 10 from young and adult normal subjects were used in all experiments. We assessed the expression of p62, LC3, Lamp2a, Beclin‐1, and pmTOR with or without MET treatment by Western blotting. We also evaluate the expression of neuronal markers. Finally.ResultHuman NS/PCs‐OE express proliferation (Ki67) and neural precursor (Nestin) markers. These cells also expressed βIII‐tubulin, but they did not express markers of mature neurons or glial markers. Moreover, human NS/PCs‐OE isolated from aged subjects show decreased autophagy and increased mTOR signaling in comparison with younger subjects. MET treatment enhanced the expression of autophagy markers. In addition, MET suppressed mTOR signaling.ConclusionOur data showed that MET treatment inhibits mTOR signaling and enhances the autophagy pathway in NS/PCs‐OE from non‐diabetic aged subjects.