bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the role of individual mTORC components on neuronal insulin signaling
Authors: Stahl Jack , Joji Aswathy , Khorkova Olga , Volmar Claude‐Henry , Wahlestedt Claes 
Published: January 2025

AbstractBackgroundRapamycin is currently in clinical trials for AD, yet numerous studies have suggested that rapamycin inhibits mTORC2 as well as mTORC1, which could be detrimental for AD pathology. Brain insulin resistance is a known aspect of AD pathology and mTORC2 inhibition reduces AKT phosphorylation, which is a main mediator of cellular insulin signaling, perpetuating insulin resistance and further worsening brain glucose metabolism. Here, we show that rapamycin prevents insulin‐induced AKT phosphorylation in human neurons and explore the differential effects of mTORC1 and mTORC2 on neuronal insulin sensitivity.MethodHuman neuronal cells were treated with 100nM rapamycin for 48 hours prior to collecting cellular protein for western blot analysis of S6 phosphorylation (mTORC1) and AKT phosphorylation (mTORC2). We then sought to specifically inhibit each complex by knocking down Raptor and Rictor, essential components for the formation of mTORC1 and mTORC2, respectively. Cells were transfected with siRNAs targeting Raptor or Rictor for 72 hours prior to collecting cellular protein for western blot analysis. For insulin experiments, cells were stimulated with 100nM insulin in serum‐free media for one hour prior to collecting protein for downstream analysis.ResultTreatment with 100nM rapamycin for 48 hours drastically decreased phosphorylation of ribosomal protein S6 (mTORC1) by 92% and phosphorylation of AKT (mTORC2) by 95%. While knocking down Rictor decreased mTORC2 activity by 71%, we were surprised to see that knocking down Raptor increased mTORC1 activity 2.1‐fold 72 hours post‐transfection. Treatment with 100nM rapamycin for 48 hours, which inhibits both mTORC1 and mTORC2, decreased total cellular protein and completely blocked insulin‐induced AKT phosphorylation at serine 473.ConclusionRapamycin has inhibitory effects on neuronal insulin signaling by inhibiting mTORC2, which can exacerbate AD pathology and symptoms. Our finding that knocking down Raptor increases mTORC1 activity contradicts the reduction in S6 phosphorylation seen with rapamycin treatment, a well‐established mTORC1 inhibitor, warranting further investigation into the role of individual mTORC components on neuronal metabolism. While mTORC1 inhibition has shown promise as a therapeutic strategy for AD, inhibition of mTORC2 can be detrimental for AD and elucidation of the metabolic role of each complex in the context of AD can guide future mTOR‐related therapeutic strategies.
Redundancy in systematic research of exercise interventions for older adults with cognitive impairment: Is more better?
Authors: Ries Julie D , De Santis Claudia , Ouabicha Kaoutar , Dagne Mahederemariam Bayleyegn , Sood Pallavi , Heyn Patricia C 
Published: January 2025

AbstractBackgroundExercise as an intervention to impact cognition in older adults with mild cognitive impairment and dementia is a well‐studied phenomenon. Recent proliferation of synthesis studies on this topic might be perceived as a positive contribution to the science of exercise as medicine, but research redundancy (defined here as multiple overlapping review studies utilizing the same randomized controlled trials [RCTs]) is not only unnecessary but can be harmful. Redundancy can create research waste and be detrimental to the ability to draw confident conclusions from the evidence. The purposes of this meta‐research are to (1) evaluate redundant representation of RCTs across published meta‐analyses (MAs) on the effects of exercise on older adults with cognitive impairment, and (2) discuss implications for interpretation of the evidence.MethodThis study was borne of a living evidence synthesis project, following standard synthesis methodology including PROSPERO registration, PRISMA guidelines, librarian‐assisted search strategy using multiple databases, and recurrent searches in 2015, 2018, 2020, and 2023.ResultThirty‐eight MAs met our inclusion criteria, referencing a total of 692 RCTs. Of the 692 studies cited in the MAs, only 267 (38.6%) are unique studies. One‐hundred‐forty‐nine of those unique studies were cited in only one MA, and 118 were cited in anywhere between 2‐17 different MAs. Thus, 425 (61.4%) of the total 692 RCTs recognized across the 38 MAs were redundant. Categorized by the number of MAs in which a study was represented, 37 RCTs (13.9%) were included in 2 MAs, 48 (18%) were represented in 3‐5 MAs, 26 (9.7%) were in 6‐10 MAs, and 7 of the unique studies (2.6%) were represented in 11‐17 MAs.ConclusionThe impact of exercise on cognition of older adults with cognitive impairment is an important topic being extensively researched. While replication is a common practice in research, excessive redundancy in research does not provide new contributions and may be wasteful. Additionally, there are negative implications for meaningful interpretation of evidence when there is significant redundancy across publications. Efforts to reduce research waste might include rigorous research protocol registration requirements and the use of artificial intelligence to aid in monitoring protocols and publications.
Head‐to‐head evaluation of leading blood tests for amyloid pathology
Authors: Petersen Kellen K. , Schindler Suzanne E. , Tosun Duygu , Saef Benjamin A. , Shaw Leslie M. , Li Yan , Saad Ziad S. , Triana‐Baltzer Gallen , Baratta Michael , Rosenbaugh Erin G. , Bannon Anthony W. , Potter William Z. ,   the Alzheimer’s Disease Neuroimaging Initiative (ADNI), and the Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium Plasma Aβ and Phosphorylated Tau as Predictors of Amyloid and Tau Positivity in Alzheimer’s Disease Project Team
Published: January 2025

AbstractBackgroundBlood tests that accurately determine the presence of amyloid pathology are critically needed. Compared to amyloid PET and CSF tests, blood tests are less expensive, less invasive, more accessible, and highly scalable. The Foundation for the National Institutes of Health (FNIH) Biomarkers Consortium evaluated the accuracies of leading AD blood tests in classifying amyloid PET status.MethodAssays from C2N Diagnostics (Aβ42, Aβ40, p‐tau217, p‐tau217 ratio [phosphorylated to non‐phosphorylated tau at position 217]), Fujirebio Diagnostics (Aβ42, Aβ40, p‐tau217), ALZPath (p‐tau217), Janssen (p‐tau217), Roche Diagnostics (Aβ42, Aβ40, p‐tau181, GFAP, NfL), and Quanterix (Aβ42, Aβ40, p‐tau181, GFAP, NfL) were run on plasma samples from ADNI participants with corresponding florbetapir‐PET scans. Unadjusted logistic regression models were constructed for each measure or combination of measures from each assay platform. The classification accuracies of the plasma biomarker measures for amyloid PET status (Centiloids>20) were assessed with receiver operating characteristic area under the curve (AUC) analyses and compared using DeLong’s tests.ResultThe cohort included data from 392 individuals with a median age of 78.1 years; 193 (49.2%) were female; 132 (33.7%) were APOE ε4 carriers; 191 (48.7%) were amyloid PET positive; and 192 (49.0%) were cognitively impaired (Clinical Dementia Rating>0), (Table 1). Models with high classification accuracies for amyloid PET status included the C2N p‐tau217 ratio + Aβ42/Aβ40 (AUC 0.929 [95% confidence intervals 0.902‐0.956]) and Fujirebio p‐tau217 + Aβ42/Aβ40 (0.911 [0.882‐0.940]), (Table 2). The AlzPath p‐tau217 (0.885 [0.851‐0.920]), Janssen p‐tau217 (0.882 [0.848‐0.916]), Roche p‐tau181 + Aβ42/Aβ40 + GFAP + NfL (0.873 [0.838‐0.909]), and Quanterix p‐tau181 + Aβ42/Aβ40 + GFAP + NfL (0.808 [0.763‐0.854]) models had lower accuracies than the C2N p‐tau217 ratio + Aβ42/Aβ40 model (p = 0.0006, 0.0006, 0.0006, and <0.0001, respectively), (Figure 1). In 122 individuals with CSF Roche Elecsys p‐tau181/Aβ42 data, the classification accuracy for amyloid PET status was 0.915 (0.864‐0.967).ConclusionIn this head‐to‐head study, logistic regression models of C2N p‐tau217 ratio + Aβ42/Aβ40 and Fujirebio p‐tau217 + Aβ42/Aβ40 were among the most accurate in classifying amyloid PET status. The classification accuracies of the blood tests for tau PET status, brain atrophy status, and clinical dementia symptoms will also be assessed.
Disruption of Arc‐NMDAR‐p55PIK‐AKT pathway increases Aß42 and Aβ plaque deposition, and reduces CA3 neuron counts in APPswe/PS1∆E9 mouse model
Authors: Gladulich Luis , Cuoco Camila , Worley Paul F 
Published: January 2025

AbstractBackgroundArc is a synaptic immediate early gene that mediates two distinct pathways at excitatory synapses. Canonically, Arc accelerates endocytosis of AMPA receptors by direct binding to TARPgs and endocytic machinery and thereby contributes to mGluR‐LTD. Arc also acts at recently potentiated synapses, where it is phosphorylated by CaMKII and binds NMDAR subunits NR2A and NR2B and recruits the PI3K adaptor p55PIK to assemble a signaling complex that activates AKT and inhibits GSK3β. This Arc‐NMDAR‐p55PIK‐AKT signaling mediates metaplasticity that prevents depotentiation of recently potentiated synapses and is important for memory updating (Arc‐LTP pathway). Arc‐NMDAR‐p55PIK‐AKT signaling contributes significantly to total AKT activity, which is a pro‐growth/pro‐survival signal, and can be selectively disrupted by conditional deletion of p55PIK. The Arc‐LTD pathway has previously been shown to enhance APP processing to generate Aß by recruiting g‐secretase to endosomes. Here, we examine the role of the Arc‐LTP pathway in Aß amyloidosis, and cell viability using the APPswe/PS1∆E9 mouse model.MethodWe bred p55PIK floxed(p55PIKflox/flox) mice with APPswe/PS1∆E9(APP/PS1) mice and Nestin‐Cre to generate APP/PS1+ mice that were also conditional knock‐outs for p55PIK. p55PIKflox/flox; APP/PS1+ mice without Cre were examined as controls. Mice were examined at 6 m. Aβ40/42 were measured via ELISA and IF staining. Cell count was done via NeuN co‐staining. Comparisons used Prism 10 software and student’s T‐test for comparison and considered statistically significant if p<0.05.ResultCompared to APP/PS1, APP/PS1;p55PIK KO mouse forebrain exhibited roughly two‐fold increase in Aβ42 in both the PBS and formic‐acid soluble fractions and a corresponding increase in both number and size of Aβ plaques. Aß40 levels were not significantly increased. Neuronal cell counts in the hippocampus suggested ∼20% reduction in the CA3 region without changes in other regions.ConclusionPreliminary studies suggest a role for Arc‐NMDAR‐p55PIK‐AKT signaling in APP processing. The prominent increase of Aß42 and plaque area are consistent with a role in effective g‐secretase processing of APP while the reduction of CA3 cell counts suggests a role in neuron viability. Arc acting at potentiated synapses appears to have a protective effect. Ongoing studies are examining larger cohorts of both genders at 6m and 12m
Pharmacological reacidification of lysosomes attenuates intraneuronal amyloidosis, early neuron death, and amyloid plaque formation in 5xFAD mice
Authors: Malampati Sandeep , Stavrides Philip , Im Eunju , Goulbourne Chris N. , Mohan Panaiyur S. , Das Bhaskar C. , LEE Ju‐Hyun , Nixon Ralph A. , Stavrides Philip , Im Eunju , Goulbourne Chris N. , Mohan Paniyur S. , Das Bhaskar C. , Lee Ju‐Hyun , Nixon Ralph A. 
Published: January 2025

AbstractBackgroundAutophagy‐lysosomal pathway (ALP) dysfunction emerges early in Alzheimer’s disease(AD). In mouse AD models, lysosomal acidification deficits impair ALP in neurons, in some inducing massive autolysosome accumulations, intraneuronal amyloid plaque, and early neuronal death yielding an extracellular amyloid plaque. This distinctive neurodegenerative pattern (PANTHOS) emerges in early‐stage AD and is recapitulated in human late‐onset AD (accompanying poster). Restoring lysosomal acidity via β2‐adrenergic receptor (β2‐AR) activation with Isoproterenol (ISO) reverses ALP dysfunction in PSEN1‐FAD patient fibroblasts.MethodTo reverse autolysosomal acidification deficits in vivo, we engineered 33 derivatives using ISO pharmacophore. Candidate compounds compared to ISO underwent screening in AD model cell lines and PSEN1‐FAD fibroblasts. After toxicity and PK/PD studies in vivo, a lead compound achieving an effective 11.63 micromolar brain concentration was administered IP for 2 or 4 months in 2‐month 5xFAD mice expressing a ratiometric autophagy/pH LC3 probe (5xFAD/TRGL) or in 2‐month 5xFAD versus vehicle‐treated 5xFAD/TRGL or 5xFAD controls respectively. Effective ISO sustained release pellets were implanted SC in the matched cohorts for 2 months. Outcomes were assessed using multiplex immunocytochemistry, computer‐aided ALP and pH analysis, EM, and behavioral tests (fear conditioning, novel object recognition).ResultIncubating AD cell lines with the lead compound, restoring lysosome pH by acting through β2‐AR mediated, PKA‐dependent pathway, efficiently rescued autophagy. 5xFAD mice treatment with compound or isoproterenol restored neuronal lysosomal acidification and markedly attenuated ALP deficits. Lysosomal re‐acidification strikingly reduced ALP‐related intracellular amyloid/APP‐βCTF/Aβ (PANTHOS) and death of these neurons. Moreover, extracellular plaque burden reduction (>50%) commensurate with reduced neuronal death frequency. Notably, compound induced pH restoration alleviated memory impairments in 5xFAD mice.ConclusionThese studies establish that lysosomal acidification deficit in the 5xFAD mouse is upstream of, and the likely basis for ALP failure, neuronal death, and amyloid pathology, consistent with the pathological sequence previously documented in multiple mouse AD models. The mechanism of action of β2‐AR activators via correcting PKA‐regulated Cl− and H+ flux in vATPase‐deficient lysosomes as established in PSEN1‐FAD fibroblasts, likely accounts for autolysosome pH correction in 5xFAD neurons. These findings demonstrate the potential of lysosomal remediation as a therapeutic approach for AD. Grant support: NIA P01AG017617, R01AG062376.
Deciphering the Relationship Between Astrocyte Calcium Signaling, Neurovascular Coupling, and Cerebrovascular Function in Alzheimer’s Disease
Authors: Weiss Blaine E. , Gant John C , Lin Ruei‐Lung , Kraner Susan D , Thibault Olivier , Sompol Pradoldej , Norris Christopher M. 
Published: January 2025

AbstractBackgroundAstrocytes are a glial cell type responsible for many protective functions in the brain. While they are primarily recognized for regulating synaptic activity, they’re also essential for maintaining the neurovascular unit, and cerebral hyperperfusion during metabolic demand. Calcium signaling has been identified as a regulatory process for these functions. Amyloid Beta deposits (Aβ) are a primary diagnostic marker of Alzheimer’s disease, and are linked to synaptic degeneration, astrocyte reactivity, and cognitive decline. Alzheimer’s disease also frequently presents with vascular damage and hypoperfusion, suggesting impaired astrocyte function. We investigated the impact of amyloid burden on stimulation‐evoked vasoreactivity and astrocyte calcium signaling to determine potential patterns of physiological impairment that may contribute to Alzheimer’s disease pathology.MethodsSix‐month‐old 5XFAD and littermate control mice were injected with AAV2/5‐Gfa104‐jGCaMP8f into barrel cortex and imaged three weeks later, while awake, using two‐photon microscopy. Neurovascular coupling experiments were conducted using timed air puff stimulation of whiskers, and calcium signals were recorded from activated astrocytes. Calcium transient properties were analyzed over different cellular compartments by custom developed Matlab applications. Vascular tone in response to stimulation was also measured, and correlations calculated with endfeet signaling.ResultsAstrocytes from 5XFAD mice showed a significant reduction in calcium signaling amplitudes, (F(1,53) = 8.735, p = 0.0047, n = 25,32) compared to wild type controls with a significant deficit in female 5XFAD mice. Correlations between other signaling properties such as rise/decay kinetics, and network connectivity were also characterized between the 5XFAD and control mice. Astrocyte endfoot compartments also showed reduced transient amplitudes. (F(1,30) = 3.226, p = 0.033, n = 17,15) Neurovascular coupling in the 5XFAD mice was reduced (F(1,39) = 2.511, p = 0.015, n = 20,19) despite no changes in arteriole elasticity. A correlation between astrocyte calcium signaling and the magnitude of stimulation‐induced vasodilation was observed in wild‐type mice but not in the 5XFAD group.ConclusionAmyloid induced pathology impairs the brain’s adaptivity to neuronal stimuli at the neurovascular unit. The uncoupling between vasoreactivity and astrocyte signaling processes implies that amyloid accumulation may render the brain vulnerable to conditions of neuronal hyperexcitability and metabolic dysregulation observed in Alzheimer’s disease.
Exploring Alzheimer’s disease progression through the lens of genetics and sleep disturbances
Authors: Fernandez‐Moguel Leticia , Gobdon Ifrah , Seixas Azizi A , Çöltekin Arzu , Dedic David , Ramos Alberto R 
Published: January 2025

AbstractBackgroundT/S ratio represents the average telomere length per genome, and has been previously linked to Alzheimer’s Disease (AD) and biological sex [1], but there is a gap in our understanding of its interactions with sleep patterns. Towards filling this gap, we present a preliminary analysis exploring correlations between age, biological sex, T/S ratio and presence of a sleep disorder for patients with mild cognitive impairment (MCI) and AD against a “cognitively normal” (NL) baseline.MethodExpanding on our previous work [2] we include the T/S ratio and the biological sex variables from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset (n = 1409). We split biological age in decades, and create a binary variable for reported sleep disturbance, i.e., No = 0, Yes = 1, in either Neuropsychiatric Inventory Questionnaire (NPIK) or Obstructive sleep apnea (OSA). We then examine correlations between the studied variables in NL/MCI/AD groups. Table 1(a) shows the sample distribution.ResultThe T/S ratio decreases with increasing age, and it is statistically significantly lower for men than women on average (Figure 1, Table 1(b)), converging around age 90. In the group without sleep disturbances, no significant differences were observed for men, whereas for women, the groups (61‐70, MCI/AD) and (71‐80, NL/MCI) showed significant differences (Figure 2 & Table 1(b)). People with sleep issues exhibit erratic T/S ratio changes and more statistically significant differences depending on the cognitive state of the patient (Figure 2).ConclusionThe T/S ratio decreases with age, and is lower for males than females. Importantly, the erratic T/S ratio pattern for people with sleep issues, especially in MCI and AD groups, suggest potential new hypotheses on genetics and epigenetics. Further research and refinement of these models may contribute towards early detection and intervention strategies for Alzheimer’s disease.References[1] Nudelman, KNH, et al. “Telomere shortening in the Alzheimer’s disease neuroimaging initiative cohort.” Journal of Alzheimer’s disease 71.1 (2019): 33‐43.[2] Bonfa, A, et al. “Exploring the relationship between sleep disturbances and Alzheimer’s disease using machine learning.” Sleep 46. Supplement_1 (2023): A370‐A370.
Investigating Granulovacuolar Degeneration in Alzheimer’s Disease and Other Tauopathy Models
Authors: Dai Daniel S , Chio Tak Ian , Lee Virginia M.‐Y. 
Published: January 2025

AbstractBackgroundGranulovacuolar degeneration (GVD) is a common feature in Alzheimer’s disease (AD) and other tauopathies such as corticobasal degeneration (CBD), progressive supranuclear palsy (PSP), and Pick’s disease (PiD). Despite its prevalence, much remains unknown about the role of GVD in the pathobiology of these diseases. Morphologically, GVD is characterized by intraneuronal membrane‐bound vacuoles, also known as GVD bodies (GVBs). Previously, it has been observed that in vitro and in vivo mouse models of tauopathy can also induce GVB formation. Nevertheless, the in vivo models in particular remain poorly characterized. Herein, we provide a more systematic characterization of GVD in the in vivo mouse models to better enable elucidation of GVD and its relation to tau pathology and neurodegeneration.MethodBrain sections were retrieved from various tauopathy mouse models. GVB distribution was characterized via immunohistochemistry using CK1δ as the primary GVB marker. Co‐staining with a phospho‐tau antibody (AT8) confirmed the presence of tau pathology in all of our models.ResultsCK1δ+ GVBs were detected in multiple tauopathy mouse models, including PS19 as well as AD‐tau‐injected wild type, 5xFAD, and 6hTau mice. The level of GVBs differ between mouse models and correlate with the level of tau pathology that was developed in these mice. In particular for the 6hTau mice, where the amount of GVBs was the most robust, temporal characterization of GVB formation shows the most significant increase in the number of GVB+ neurons from 1 to 3 months post‐AD‐tau injection. At the single cell level, the number of CK1δ+ puncta also increased over time. By 3 mpi, GVBs were detected beyond the hippocampus (site of injection) and in the cortical regions where tau pathology was also present. Finally, 6hTau mice injected with CBD‐, PSP‐, and PiD‐tau all developed GVBs, albeit at variable levels that parallel the extent of tau pathology.ConclusionsGVB development tracks with tau pathology development in our in vivo mouse models. The increase in GVBs within a cell over time suggests that GVBs continue to form as tau pathology matures. This induction of GVBs by tau pathology is irrespective of the different tau strains from different tauopathies.