bluuebunny/crossref_metadata_2025 huggingface dataset:
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

Background

The 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.

Methods

Using 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.

Results

In 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).

Conclusions

Our 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

Background

Glutamatergic 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.

Method

We 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.

Result

The 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.

Conclusion

Our 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

Background

Alzheimer’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.

Method

5xFAD, 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.

Result

Mice 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.

Conclusion

It 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

Background

A 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.

Method

A 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.

Result

The 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.

Conclusion

The 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

Background

Alzheimer’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.

Method

We 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.

Result

MODEL‐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.

Conclusion

MODEL‐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

Background

In 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.

Method

For 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.

Result

Vorinostat 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.

Conclusion

Doses 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

Background

Variations 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.

Method

We 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.

Result

Patients 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.

Conclusion

The 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

Background

Alzheimer’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.

Method

Two 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.

Result

All 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.

Conclusion

These 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

Background

Longitudinal 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.

Method

To 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.

Result

Human 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.

Conclusion

Our data showed that MET treatment inhibits mTOR signaling and enhances the autophagy pathway in NS/PCs‐OE from non‐diabetic aged subjects.
Higher amyloid burden is associated with faster reduction in cerebral blood flow: a longitudinal study
Authors: Zhao Tianrui , Tang Jianing , Terner Jamie , Joe Elizabeth B , Braskie Meredith N , Chui Helena C , Marmarelis Vasilis , Yan Lirong
Published: January 2025

Background

Amyloid accumulation is one of the main pathophysiological hallmarks of Alzheimer’s disease (AD) and is closely associated with neuronal dysfunction and cognitive decline. Except for amyloid pathology, accumulating evidence has shown vascular dysfunctions, such as reduced cerebral blood flow (CBF), also contribute to AD pathophysiology. However, there remains limited research about the longitudinal changes between amyloid accumulation and CBF. The present study aims to address the gap through conducting both cross‐sectional and longitudinal studies to investigate the relationship between amyloid burden and CBF changes.

Method

168 participants (72.5 ± 8.5 years, 86 female) were enrolled in this study. CBF measurements were obtained from each participant using single‐delay pCASL. Among participants, 94 underwent amyloid PET scans. 72 out of them received a second pCASL MRI scan for one‐year follow‐up. Standardized update value ratio (SUVR) was calculated from PET data. A global SUVR of 1.08 was used to define amyloid positivity. Mean CBF and SUVR were extracted from gray matter and nine AD‐related brain regions.

Linear mixed effects model was employed to examine the association between baseline CBF and baseline SUVR with correcting for age and gender; A paired t‐test assessed CBF difference between the amyloid positive and negative groups; Multivariate linear regression was performed to investigate the association of baseline SUVR level with CBF changes by considering the follow‐up CBF as dependent variable and baseline CBF, SUVR level, time‐gap, age, and gender as independent variables.

Result

Baseline CBF showed significant correlations with age in gray matter and 8 AD‐related regions (Figure 1). Baseline CBF demonstrated a strong association with amyloid positivity in gray matter and 5 AD‐related regions (Figure 2). No significances were observed between baseline CBF values and SUVR levels in all 9 regions. However, baseline SUVR level was significantly associated with longitudinal CBF changes in 8 AD related regions (Figure 3). These results suggest a higher amyloid burden may predict faster CBF reduction during the progression of AD.

Conclusion

Our results demonstrate that longitudinal CBF changes are strongly associated with baseline SUVR levels both globally and regionally, suggesting that increased amyloid burden may affect neurological dysfunction leading to CBF reduction over time.
Shared and distinct molecular signatures of astrocyte subtypes across brain regions and neurodegenerative diseases
Authors: Saliu Ibrahim Olabayode , Zhao Guoyan
Published: January 2025

Background

Astrocytes are specialized glial cells that play crucial roles in the brain by providing metabolic and trophic support for the neurons. They become reactive (activated) and heterogeneously respond to neuropathology such as injuries and neurodegenerative diseases (NDs). High‐throughput single‐nucleus (snRNA‐seq) RNA sequencing has enabled a profound understanding of cell type heterogeneity. However, the number of astrocyte subpopulations in different regions of the brain, and the similarities and differences among these subpopulations in healthy and disease conditions are not clear.

Method

We performed uniform data analysis using the same algorithm and parameters on astrocytes from postmortem human brain single‐nucleus RNA‐sequencing (snRNA‐seq) data obtained from eight datasets with seven different brain regions of normal control subjects and subjects with different NDs including Alzheimer’s disease (AD), dementia with Lewy body disease (DLBD), Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD), Huntingtin disease (HD), or Nasu‐Hakola disease (NHD). We identified astrocyte subpopulations and systematically compared astrocyte subpopulations and defined their common marker gene set across seven brain regions in six disease conditions. We conducted functional enrichment pathway analysis on the marker genes to understand the putative contribution of these subpopulations to NDs including across different brain regions.

Result

We identified 3‐6 distinct astrocyte subpopulations by examining the expression of conserved marker genes across all the different datasets. Two subpopulations were shared across all the NDs and brain regions, representing homeostatic (Ast‐0) and activated transcriptional states (Ast‐1 and Ast‐2), while the other subpopulations are unique to different datasets. Functional enrichment analysis revealed distinct and shared pathways among astrocyte subpopulations across all brain regions.

Conclusion

We identified astrocyte subpopulations shared across all the brain regions and disease conditions with shared molecular marker genes but also regional‐ or disease‐specific gene expression features. We also observed disease‐ or brain region‐specific astrocyte subpopulations. These results suggest that regional differences in astrocyte subpopulations or gene expression could underly regional differences in brain susceptibility to different neurodegenerative diseases.
Efficacy of an inhibitor of GSK‐3β in an Alzheimer’s Disease Mouse Model
Authors: Ghuman Mobeena , Boutajangout Allal , Atta Abdurrahman , Kaddioui Rim El , Kozikowski Alan P , Wisniewski Thomas
Published: January 2025

Background

Neurofibrillary tangles (NFTs), one of the hallmarks of Alzheimer’s disease (AD), are composed of highly phosphorylated forms of the microtubule‐associated protein tau. Phosphorylation results from the activity of several threonine/serine kinases, and increased expression of glycogen synthase kinase‐3β (GSK‐3β). These are involved in the formation of paired helical filament (PHF)‐tau, which induces the formation of NFTs. Preclinical and clinical studies have supported that GSK‐3β inhibition may have therapeutic benefits for AD. We assessed the therapeutic effect of our novel GSK‐3β inhibitor, ING‐135, in an animal model of AD.

Method

hTau/PS1 mouse models were injected intraperitoneally with ING‐135 (30 mg/Kg; n = 15 per group) starting at 3 months of age, three times a week for three months, and control mice received saline only. Animals went through different behavioral tasks and brain tissue was subsequently harvested for analysis of treatment efficacy.

Result

Treated animals (n = 15) did not show significant differences when compared to controls on sensorimotor tasks (i.e., Traverse beam, Rotarod, and Locomotor activity). Significant behavioral improvement was noted in treated mice on three tasks using a closed field symmetrical maze (Day 1 one‐tailed t‐test p = 0.0036; Day 2 one‐tailed t‐test p = 0.0118; Day 3 one‐tailed t‐test p = 0.0002). Immunohistochemistry analysis was performed on brain sections of treated animals and controls, using monoclonal antibodies PHF1 and CP13. Histology analysis showed a reduction of tau pathology in the motor cortex and hippocampus of treated animals (one‐tailed t‐test p = 0.0001, p = 0.0002; respectively). No significant differences were observed between the two groups with GFAP, and Iba‐1 showed a reduction of microglia in the cortical area (p = 0.05). Results were not significantly different in the dentate gyrus. Further biochemical analyses are underway.

Conclusion

Our novel inhibitor of GSK‐3β (ING‐135), improves cognitive decline (long‐term memory) and decreases tau phosphorylation in treated animals versus controls, in the absence of toxicity.
The role of manganese over‐exposure in glutamate dysregulation and EEG outcomes in a mouse model of Alzheimer’s disease
Authors: Buchanan Rebecca A. , Harrison Fiona E.
Published: January 2025

Background

Manganese (Mn) is an essential metal that serves as a cofactor for metalloenzymes important in moderating the glutamate/glutamine cycle and other oxidative stress pathways. Typically, Mn is acquired through the diet, however, Mn overexposure can arise through drinking inadequately treated well water or inhalation of Mn‐containing industrial byproducts. Mn toxicity disrupts dopaminergic neurotransmission resulting in a Parkinsonian disorder referred to as manganism. More recently, increased focus has been given to the role Mn toxicity in the progression of other neurodegenerative diseases including Alzheimer’s Disease (AD). Excess Mn may contribute to dysregulation of astrocytic glutamatergic transport, leading to elevated extracellular glutamate, excitotoxicity, and ultimately cell death, which are all key features of early AD pathology. We hypothesized that Mn toxicity drives glutamatergic signaling dysfunction to exacerbate pathology seen in AD including excitotoxicity and epileptiform activity.

Method

APPswe/PSEN1dE9 mice, a mouse model of AD, and wild‐type littermates of both sexes were exposed to 50mg/kg MnCl2·4H2O or the vehicle subcutaneously three times over the course of a week as an acute high dose exposure of Mn. Increased seizure susceptibility in response to manganese and kainic acid (kainate receptor agonist) exposure was analyzed through surface cortical electroencephalogram recordings. Changes in glutamate reuptake transporter protein and mRNA expression from cortical and hippocampal tissue were quantified using western blot and qPCR.

Result

APPswe/PSEN1dE9 mice have more cortical spiking activity over the course of exposure compared to WT mice. Effects of kainic acid were quantified over four hours and we found that Mn‐exposed mice have significantly decreased spiking over the first hour compared to vehicle treated mice. However, spiking activity increased over time in Mn‐treated mice, while spiking activity decreased in vehicle treated mice resulting in a significant reaction between treatment and time. There was no difference in spiking at the end of the four‐hour observation period.

Conclusion

Dynamic responses to kainic acid and changes in glutamate reuptake transporter expression are consistent with glutamatergic changes that can contribute to excitotoxicity. Taken together, these findings support the hypothesis that manganese acutely interferes with glutamate functioning and could exacerbate phenotypes observed in AD.
Subjective and objective memory among older adults: Examining the intersecting role of depression and locus of control in the ACTIVE study
Authors: Weigand Alexandra J. , Clark Alexandra L. , Garcia Mary Ellen , Parisi Jeanine M , Zahodne Laura B. , McDonough Ian M , Marsiske Michael , Thomas Kelsey R.
Published: January 2025

Background

Subjective memory concerns (SMC) may be a sensitive marker of future cognitive declines. However, there are multiple factors that can impact the predictive utility of SMC. Prior studies have demonstrated the effect of depression on SMC. Further, perceived control over one’s situation as measured by locus of control (LOC) has been linked to both depression and SMC. Therefore, the current study examined the moderating effect of depressive symptoms on the association between SMC and memory decline and further investigated whether this interaction varied as a function of internal LOC.

Method

This study included 2721 older adults without dementia from the Advanced Cognitive Training for Independent and Vital Elderly (ACTIVE) study. Predictors of interest included SMC, depressive symptom severity, and internal LOC. Multilevel mixed models examined the 4‐way interaction between internal LOC, depressive symptoms, SMC, and time on 10‐year rate of change on an objective memory factor score.

Result

There were significant independent effects of SMC (t = ‐2.40, p = .02) and depressive symptoms (t = ‐3.48, p < .001) on 10‐year memory trajectories, but no significant interaction between SMC and depressive symptoms (t = 1.45, p = .15). However, there was a significant interaction between internal LOC, depressive symptoms, and SMC on memory trajectories (t = ‐3.52, p < .001). Specifically, in the context of lower internal LOC, depressive symptoms strengthened the association between SMC and objective memory trajectories, whereas depression was not a significant moderator among individuals with higher LOC.

Conclusion

Findings demonstrate the complexities of SMC in predicting memory decline and highlight intersecting individual‐level factors that may influence the predictive utility of SMC among older adults. Specifically, we found that in individuals with lower internal LOC (e.g., less belief they can control their own cognitive aging), the strength of association between SMC and memory decline was strengthened by depressive symptoms. Future research will examine additional interacting factors (e.g., demographics, sociocontextual variables) to help provide a nuanced understanding of when SMC are most prognostically useful.
Targeting and reducing neuronal ceramide overaccumulation in 5xFAD mice improves AD pathologies and cognitive function
Authors: Wilkerson Joseph L , Chaix Amandine , Summers Scott A , Holland William L
Published: January 2025

Background

Neurodegenerative disorders such as Alzheimer’s Disease (AD) are increasingly associated with irregular lipid accumulation. Dysfunction in the catabolism of sphingolipids leads to many neurodegenerative disorders but has only recently garnered interest in AD. Excess ceramide deposition has been observed in Aβ‐plaques, plasma, and cerebrospinal fluid in AD patients and AD mouse models. Ceramide‐lowering strategies have been underexplored as a treatment for AD and may prove to be a beneficial target in mitigating the disease.

Method

We have used both pharmaceutical and genetic approaches to target ceramide accumulation in the 5xFAD mouse model of AD. Myriocin was used block ceramide de novo synthesis. The drug was administered in mice on a normal chow diet and an obesogenic pro‐ceramide high‐fat diet. As a genetic approach, we developed an inducible loss‐of‐ceramides model by overexpressing Asah1, the gene encoding the ceramide degrading enzyme acid ceramidase specifically in neurons. We assessed the loss of ceramides as a preventative treatment (overexpression beginning at 6‐weeks) or mature disease treatment (overexpression beginning at 30 weeks). We assessed Aβ plaques and the activation and quantity of glia by immunohistochemistry. Cognitive behavior was assessed using the Barnes maze and fear conditioning chambers. Frailty index scores were generated through clinically equivalent tests.

Result

Myriocin treatment reduced ceramide accumulation in the hippocampus of 5xFAD mice. Vehicle‐treated 5xFAD mice had significant memory deficits compared to myriocin‐treated mice. The myriocin‐treated mice had smaller and fewer Aβ plaques, fewer hippocampal microglia, and a reduction in astrocyte arborization and numbers in hippocampus and cortex. Early overexpression of Asah1 in neurons improved memory loss in fear conditioning chambers. Plaque size and number remained unchanged. However, IBA1+ microglia/monocyte and GFAP+ astrocyte activation and migration were eliminated in neuronal Asah1 overexpressing mice. Plaques in these mice had no associated glia and glia morphology resembled wild‐type mice. Late overexpression of Asah1 in neurons led to improved frailty index scores compared to 5xFAD mice at one year of age.

Conclusion

Pharmaceutical inhibition of ceramide synthesis improved cognitive outcomes and reduced AD pathologies in 5xFAD mice. Reducing ceramides specifically in neurons in 5xFAD mice eliminated gliosis and improved cognitive function.
Isolation of single neuronal nuclei by phospho‐tau accumulation in Alzheimer’s disease brain
Authors: Jin Bowen , Naik Samuel , Kirkham Samantha L , Qian Xuyu , Zhou Zinan , Oakley Derek , Frosch Matt P. , Hyman Bradley T. T , Huang August Yue , Miller Michael B
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the deposition of amyloid‐beta and hyperphosphorylated tau (P‐tau) proteins in the brain. P‐tau accumulates in neurons and is strongly associated with AD severity and affected brain regions. However, only a subset of neurons in AD exhibit tau pathology. The molecular mechanisms behind heterogeneous tau pathology and how it contributes to AD are not well understood.

Method

We developed a fluorescence‐activated nuclear sorting (FANS) method to separate P‐tau+ neuronal nuclei from P‐tau‐ neuronal nuclei from the same brain tissue. To validate the specificity of P‐tau+ neurons, we mixed non‐AD control tissue with AD tissue and examined the origin of neuronal nuclei based on their genotype. We also subjected nuclei with P‐tau signal from FANS to immunofluorescence microscopy to examine the morphology and localization of P‐tau aggregates.

Results

We observed disease‐specific P‐tau signal for nuclei in advanced AD (Braak stage V‐VI) cases. These P‐tau+ nuclei are highly distinguished from the P‐tau‐free nuclei. Confocal immunofluorescence microscopy showed P‐tau adherent to the outside of nuclei that exhibited P‐tau signal by FANS. We demonstrated that the nuclei sorting method based on P‐tau levels can highly enrich for P‐tau+ nuclei (>380 fold) and has a high accuracy of 98% based on the mixing experiments. In addition, we were able to obtain high‐quality single‐cell genome amplification for P‐tau‐sorted nuclei using primary template‐directed amplification (PTA), permitting single‐nucleus genome interrogation.

Conclusion

We developed a highly efficient method using fluorescence‐activated nuclear sorting (FANS) to separate the population of P‐tau+ neuronal nuclei in AD brains. This method allows interrogation of human neuronal nuclei based on single‐cell tau pathology and enables single‐cell genomic studies of heterogeneous tau pathology in AD, toward insight into disease pathogenesis and therapeutic targets.
Sensitivity of Remote App‐Based Assessment of Cognition to Sleep‐Mediated Differences in Cognitive Functioning Among Older Adults
Authors: Rovere Rachel , Liebenberg Erin , Halberstadter Kimberly , Wolk David A , Mechanic‐Hamilton Dawn
Published: January 2025

Background

This study assesses the sensitivity of the mobile cognitive app performance platform (mCAPP), a mobile and engaging cognitive assessment tool, to participant sleep duration.

Method

The mCAPP includes three gamified tasks: a memory task (“Concentration”), a stroop‐like task (“Brick Drop”), and a digit‐symbol coding‐like task (“Space Imposters”). For all games, shorter reaction times and fewer guesses indicates better performance. The cohort included 50 participants (72% female; age = 71.9±4.5; education = 16.8±2.3; 51% white; 49% Black/African American) without cognitive impairment who are enrolled in the Penn ADRC cohort. Sleep data was collected via actigraphy (Fitbit). Game performance and overnight sleep prior to gameplay were analyzed as a whole and grouped by fewer (quartile 1; Q1) and higher (quartile 4; Q4) minutes of sleep.

Result

The average number of minutes of sleep was 378.0±96.5. Overall, minutes of sleep showed a significant negative correlation with reaction time on Space Imposters (ρ = 0.001). Participants with the fewest minutes of nighttime sleep performed slower than those with the most sleep on Space Imposters (Q1 M = 2.73; Q4 M = 2.40; p<.001), Brick Drop (Q1 M = 1.58; Q4 M = 1.31; p = .004), and Concentration (Q1 M = 5.25; Q4 M = 5.02; p = .006). There was not a significant difference in number of errors on Space Imposters (p = 0.53) or Brick Drop (p = 0.45) when comparing performance of participants with lower and higher quartiles of sleep, but there was a significant difference in the number of guesses on Concentration (Q1 M = 14.91; Q4 M = 12.80; p = 0.01).

Conclusion

The mCAPP can remotely detect differences in cognitive performance related to nighttime sleep prior to gameplay. Future studies will examine differences in performance related to the time‐of‐day gameplay occurs (how long after overnight sleep) and whether performance is affected by daytime napping. A larger data set will also be used to fully determine the sensitivity of mCAPP to participant sleep duration and examine within‐participant effects.
Investigating the effects of increasing O‐GlcNacylation in Alzheimer’s disease in the TgF344‐AD rat model
Authors: Garcia Melissa L , McMahon Lori L , Jackson Nateka L
Published: January 2025

Background

Alzheimer’s disease (AD) pathology can start accumulating 20‐30 years before cognitive symptoms occur, with increases in inflammation, amyloid‐β (Aβ), and hyperphosphorylated Tau during this time. Previous studies have shown that the post‐translational modification of a single N‐acetylglucosamine moiety to serine or threonine residues to cytosolic or nuclear proteins, known as O‐GlcNAcylation, can modify a plethora of cellular processes, including the processing of the amyloid precursor protein, competing with phosphorylation on tau, as well as having anti‐inflammatory effects. This study is designed to evaluate how increasing O‐GlcNAcylation is impacting AD pathology in the most comprehensive AD rat model to date, the TgF344‐AD rat model.

Method

For these experiments, we used 6‐month‐old TgF344‐AD (Tg) rats and non‐transgenic (nTg) littermates injected with 10mg/kg of thiamet‐G (TMG), an inhibitor of O‐GlcNAcase, (nTg‐TMG or Tg‐TMG) or saline (nTg‐S or Tg‐S) as a control, 3 times a week from 6‐9 months. We then sacrificed the animals via cardiac perfusion with oxygenated artificial cerebrospinal fluid before splitting the brain in half; one hemisphere to be drop fixed in PFA for immunohistochemistry and half to be sub dissected and flash frozen for protein analysis.

Result

We have preliminary results that confirm significant increases in GFAP, Iba1 and Amyloid‐β in Tg‐S rats compared to nTg‐S rats, however GFAP and Iba1 protein levels in Tg‐TMG rats are no longer significantly different from nTg‐S rats after 3 months of TMG injections to increase O‐GlcNAcylation. We have also evaluated noradrenergic innervation into the dentate gyrus using anti‐tyrosine hydroxylase (TH) immunohistochemistry and confocal imaging to evaluate if increasing O‐GlcNAc protects against loss of TH innervation of the dentate gyrus, and have so far confirmed our previous results at this time point; TMG treated animals are not significantly different from their saline controls.

Conclusion

We report that increasing O‐GlcNAcylation from 6‐9 months in the TgF344‐AD rats is reducing reactive astrocytes. While this could be beneficial to preserving their function and neuronal health, this work is still ongoing. We are working to increase our sample size, and to examine the locus coeruleus for changes in hyperphosphorylated tau and other biomarkers.
Advancements in High‐Resolution MRI Postmortem brain imaging: Histological examination on cells exclusively exhibiting White Matter Hyperintensities made possible using a novel, 3D printed, reusable, imaging container and cutting guide
Authors: Berardinelli Jacob , Li Jinghang , Farhat Nadim , Liou Jr‐Jiun , Sajewski Andrea , Santini Tales , Wu Minjie , Mettenburg Joseph , Aizenstein Howard J , Ikonomovic Milos D , Kofler Julia , Ibrahim Tamer S
Published: January 2025

Background

Employing a custom 60‐channel single‐transmit/32‐channel receive Tic‐Tac‐Toe (TTT) coil in 7T MRI imaging has enhanced the resolution and contrast for identifying White Matter Hyperintensities (WMHs), which are critical markers in Alzheimer’s disease and related dementias (AD/ADRD).

Method

The method involves resecting the left hemisphere of the brain, excluding the cerebellum, followed by embalming in 10% formalin. 1.5% agar and 30% sucrose by weight are heated and mixed for embedding in the container. The brain is positioned in the cutting guide and inserted into the base (Figure 1). Agar is meticulously poured ensuring minimal air bubble formation in the sulci and ventricles with additional agar pipetted as needed. The lid is then attached, more agar is added until the container is filled, and the cap is secured. The container is sealed in plastic to safeguard the coil from potential liquid damage and isolate the tissue/formalin while scanning. The imaging protocol includes a B1+ map at 3.2mm, MP2RAGE at 0.4mm, GRE at .37mm, and T2‐SPACE at .36mm all isotropic resolutions. The high‐resolution T2‐weighted SPACE is used for WMH segmentation and quantification. The MP2RAGE provides a T1‐weighted image for further data analysis registration to gross anatomy as well as in vivo scans.

Result

This protocol has been applied to 120 brain specimens to date, with representative MR images in Figure 2. The techniques afford pathologists flexibility in slicing the brain into coronal or axial parallel 5 mm slabs at various angles. See Figure 3 for a visual representation of the progression of the container design and of the cutting process.

Conclusion

This innovative combination of the cutting guide, container, and the custom 7T TTT coil is reusable and reliable. It accommodates various brain sizes, offers precise cutting options, ensures fast and accurate image registration to in vivo and gross anatomy, and achieves homogeneous B1 fields, culminating in superior research data. The described method is subject to ongoing refinement for enhanced efficiency, with iterative optimization of the container’s shape, size, and function through 3D printing.

This work was supported by the National Institutes of Health under award numbers R01MH111265, R01AG063525, T32MH119168, and U19AG068054.