bluuebunny/crossref_metadata_2025_split huggingface dataset:
FAD mutants decrease brain neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1/γ‐secretase
Authors: Robakis Nikolaos K. R K , Pandey Rukmani , Yoon Yonejung , Zarrouk Amira , Dey Poylomi , Georgakopoulos Anastasios 
Published: December 2023

AbstractBackgroundThe cerebrovascular system is central to neuronal survival and function and emerging evidence suggests that vascular brain abnormalities are involved in the development of neurodegenerative disorders such as Alzheimer’s disease (AD). Angiogenesis, the generation of new blood vessels from existing vasculature, is crucial throughout adult life for maintaining brain blood circulation and for reparative mechanisms of toxic insults such as ischemia. Angiogenesis is controlled by growth factors including the Vascular Endothelial Growth Factor (VEGF). By binding to its receptor (VEGFR2), VEGF regulates extension of new blood vessels in damaged areas and maintains blood supply to tissues and organs. FAD variants of Presenilin1 (PS1), the catalytic subunit of γ‐secretase induce Familial AD (FAD) and can serve as systems where mechanisms of AD‐like neurodegeneration can be studied.MethodsMouse brain endothelial cells (ECs) expressing knock‐in PS1 FAD mutants were isolated and cultured and effects of PS1/γ‐secretase on angiogenic functions and processing of VEGFR2 were performed as in literature. VEGF‐induced phosphorylation of kinases downstream of VEGFR2 were determined on WBs. Middle cerebral artery occlusion (MCAO) was performed in mice as in literature. Isolated brains were sectioned using a mouse brain matrix and slices were stained with TTC and fixed with 4% PFA to detect infarct area. Cerebral blood flow (CBF) was assessed using perfusion MRI (pMRI) as in literature. Neurons were stained with anti‐NeuN and positive neurons in lesioned and contralateral areas were countedResultsPS1/γ‐secretase process VEGFR2 and regulate crucial functions of the brain VEGF/VEGFR2 system including receptor dimerization, internalization and downstream angiogenic signaling. Importantly, PS1 FAD mutants decrease the VEGF‐induced activation and angiogenic signaling of VEGFR2 and reduce brain neovascularization suggesting mechanisms by which PS1 FAD mutants may cause neuronal dysfunction and death. In this presentation we discuss the importance of the PS1/γ‐secretase on the VEGFA/VEGFR2‐mediated angiogenenic signaling and brain neovascularization and test effects of PS1FAD mutants in brain neoangiogenesis and neuronal survival.ConclusionsThe PS1/γ‐secretase system regulates brain angiogenesis and neovascularization by activating properties of the VEGF/VEGFR2 system. PS1 FAD mutants decrease brain angiogenesis, neovascularization and neuronal survival by targeting angiogenic mechanisms of PS1 and γ‐secretase.
Utilization of the novel adeno‐associated virus PHP.eB serotype to modulate Intersectin 1 expression in the Ts65Dn mouse model of Down syndrome
Authors: Tallino Savannah L , Vural Austin , Espinosa Oscar Villareal , Velazquez Ramon 
Published: December 2023

AbstractBackgroundDown Syndrome (DS) and Alzheimer’s disease (AD) include cholinergic neurodegeneration which parallels cognitive decline. Triplicated genes in DS are thought to play a role in basal forebrain cholinergic neuron (BFCN) pathology; one avenue to assess triplicated genes’ role is to normalize their expression in DS mouse models by stereotaxic injection of adeno‐associated viruses (AAVs) carrying silencing constructs such as single hairpin mRNA (shRNA). However, stereotaxic surgeries have drawbacks particularly when targeting areas lying deep within the brain. The introduction of the AAV‐PHP.eB serotype, which can cross the blood‐brain‐barrier when introduced into peripheral vasculature, has been shown to vary in efficiency depending on mouse background. Here, we investigated tropism of the AAV‐PHP.eB serotype in the Ts65Dn mouse, the most commonly used DS mouse model. We then used AAV‐PHP.eB to assess our ability to globally modulate expression of intersectin 1 (ITSN1), a protein triplicated in DS that may relate to BFCN dysfunction and memory impairments.MethodsWe retro‐orbitally injected N = 16 4‐4.5 month‐old male mice, (C57Bl, Ts65Dn trisomic and normosomic) with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA, to assess tropism and optimize virus concentration (2, 5, and 10µL). Four weeks post injection we imaged for GFP expression in 50µm coronal sections. To knock down ITSN1 globally, we injected N = 58 Ts65Dn mice (3 months, balanced by sex, genotype, virus) with either 5μl AAV‐PHP.eB‐U6‐scrmble‐GFP (control) or AAV‐PHP.eB‐U6‐shITSN1‐GFP (ITSN1); mice were behaviorally tested at 7 months and euthanized at 8 months followed by tissue collection.ResultsMice injected with AAV‐PHP.eB‐CamKII‐GFP‐scrmble‐shRNA showed GFP expression 4 weeks following injection, with robust expression visible with 5µL virus. Mice subsequently injected with control and ITSN1 AAVs showed significant effects of ITSN1 knockdown, including increased tremors, increased latency in the radial arm water maze – suggesting impaired spatial reference learning and memory – decreased brain weight, and altered weight change.ConclusionThe AAV‐PHP.eB serotype shows successful CNS tropism in the Ts65Dn mouse model, with 5µL of AAV providing the best efficiency throughout key brain regions affected in DS and AD. Furthermore, the AAV‐PHP.eB serotype can be used to modulate expression of genes triplicated in DS to investigate their mechanistic role in neurodegeneration both molecularly and behaviorally.
The Effects of 3‐month Aerobic‐Strength Training on Cognitive Functions and Adiponectin Levels in Cerebrospinal Fluid and Blood in the Elderly
Authors: Ukropcová Barbara , Tomkova Maria , Schön Martin , Slobodova Lucia , Straka Igor , Matejička Peter , Tsai Chia‐Liang , Bogner Wolfgang , Krssak Martin , Valkovič Peter , Ukropec Jozef 
Published: December 2023

AbstractBackgroundExercise improves physical fitness, cognitive functions & metabolism in the elderly. Evidence from animal models suggests the role for mediators from muscle or adipose tissue in the exercise‐induced brain plasticity (1). Knowledge on the regulation of these potentially neuroprotective molecules by exercise in humans is limited (2,3). We investigated effects of 3‐month supervised aerobic‐strength training on serum & cerebrospinal fluid/CSF adiponectin in the elderly, in association with cognitive functions & brain volumetry.MethodThe population consisted of sedentary elderly (n = 38, 10M/28F; 66.1±5.9yrs; BMI 26.3±3.7kg/m2). Body composition (MRI), physical fitness (Rockport test), muscle strength (dynamometry), motor tests (walking speed & chair stand tests), resting energy expenditure & substrate preference (REE, RQ, indirect calorimetry), insulin sensitivity & metabolic flexibility (euglycemic hyperinsulinemic clamp/EHC), cognitive functions (cognitive tests), brain volumetry (MRI), serum glucose & insulin were assessed.ResultTraining reduced BMI, blood pressure and insulinemia, while improving insulin sensitivity & metabolic flexibility (EHC), maximal aerobic capacity (VO2max), motor performance, and memory (ACE‐R). Improvements in cognitive functions were more pronounced in patients with MCI (p<0.05). Training led to a small but consistent increase of CSF adiponectin in cognitively healthy seniors (p<0.05), while no change was observed in MCI (p>0.1). CSF adiponectin was positively associated with psychomotor attention score (CogState), and it strongly correlated with the volume of corpus callosum normalized to intracranial volume. Training did not regulate serum adiponectin.ConclusionRelatively short‐term aerobic‐strength training can improve cognitive functions together with a spectrum of anthropometric, metabolic and fitness parameters, which may slow down the ageing‐related cognitive decline. Exercise modulated levels of adiponectin in CSF which correlated with cognitive functions and volume of specific brain areas. This might indirectly indicate the role for adiponectin in the exercise‐related brain plasticity in the elderly.
Funding: APVV 20‐0466, VEGA‐2/0076/22, COST DePASS, APVV 15‐0253
References
(1) Cooper, Moon, van Praag. Cold Spring Harb Perspect Med. 2018 Apr; https://doi.org/10.1101/cshperspect.a029736
(2) Effects of running on adiponectin, insulin & cytokines in CSF in healthy young individuals. M Schön, B Ukropcová et al. Sci Rep.2019Feb. https://doi.org/10.1038/s41598-018-38201-2.(3) CSF & plasma metabolomics of acute endurance exercise. Li, Schön, Ukropcová et al. FASEB 2022 Jul. https://doi.org/10.1096/fj.202200509R.
Chronic disease patterns and associated characteristics in an ADRC cohort: a latent class analysis
Authors: Choate Radmila , Kucharska‐Newton Anna M. , Jicha Gregory A , Abner Erin L 
Published: December 2023

AbstractBackgroundAbout 70% of American older adults report multiple chronic conditions (CC). The disease combinations are complex and often lead to adverse health outcomes, reduced quality of life, and require tailored treatment plans. Our study aimed to identify patterns of chronic diseases, define disease clusters and evaluate associated participant characteristics.MethodIncluded in these analyses were adults ≥50 years with normal cognition at baseline and available history of 11 measured CC, demographic, and quality of life data from the University of Kentucky Alzheimer’s Disease Research Center cohort, a convenience sample of community‐based older adults followed longitudinally until death. Persons not reporting any of the 11 measured CC were assigned to a separate class. A latent class analysis (LCA) among those with ≥1 measured CC was used to identify subgroups of individuals with distinct patterns of CC. A series of LCA models with 2‐7 latent classes were assessed, and the best‐fitting model was selected based on the lowest adjusted BIC, highest entropy, and plausible clinical interpretation. Demographic and clinical characteristics of each of the latent classes were evaluated.ResultThe 772 participants were mean age 73.1±6.7 years, 66.6% female, 89.0% white, mean CDR Sum of boxes score was 0.04±0.2, and MMSE score 29.0±1.2. N = 99 (12.8%) reported none of the measured 11 CC (class 0). LCA identified 4 latent disease patterns among those with ≥1 measured CC: class 1‐prevalent hypertension, hypercholesterolemia, and diabetes; class 2‐prevalent thyroid disease; class 3‐low/moderate complexity; and class 4‐high complexity/cardiovascular and cerebrovascular conditions. Item‐response probability plots are displayed in Figure 1. Class‐specific probabilities of reporting each of the 11 CC for the 4‐class model are shown in Figure 2. On average, participants in class 4 had 5.3±1.0 CC, were older, more likely to be male, and had poorer physical quality of life than other classes (Table 1).ConclusionFour clusters of CC were identified in this cohort of elderly adults with normal cognition. Latent class analysis can provide additional insights into the complex relations across CC, in addition to a widely used count of comorbidities. Future longitudinal studies are needed to evaluate health outcomes in individuals assigned to the identified disease clusters.
Anti‐inflammatory biochemical mechanisms of lithium in hippocampal tissue of triple transgenic animals for Alzheimer’s disease
Authors: Wagner Carlos , Couto Caíque de Oliveira Portugal , Forlenza Orestes Vicente , De‐Paula Vanessa V.J. 
Published: December 2023

AbstractBackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative disorder of multifactorial etiology. The toxicity of senile plaques and neurofibrillary tangles are associated with structural changes that lead to brain tissue atrophy. Pro‐inflammatory cytokines are present in abnormal amounts and this accelerates the progression of the disease. Our objective is to determine the proteins of the ontological pathways, identified in the proteome, altered in the hippocampus of 3xTg‐AD animals chronically treated with lithium at therapeutic and subtherapeutic doses.Method48 (3xTg‐AD;Tg) will be used. The animals received lily for 8 months of treatment and were divided into 3 groups (control, Li 1mM and Li2 mM). The hippocampal tissue was subjected to the proteome. The inflammatory pathways of the identified proteins will be compared by Gene Ontology, using the ClueGO software. Ethics Committee (1876/2022).ResultThe genes of the Toll‐Likes receptor family was analyzed into the STRING bioinformatics program, in order to study the ontological pathways and molecular function. As parameters, we set the significance at 0.7 with the limitation of 50 interactions per gene. Thus, the results demonstrate that the ontological alterations are: immune response‐activating signal transduction, activation of immune response, regulation of defense response, positive regulation of immune response, regulation of response to stress, immune response, positive regulation of response to stimulus and immune system processConclusionThe results seem promising for understanding the inflammatory pathways related to toll‐likes. However, the results with the hippocampus tissues are under analysis.
Mitochondrial calcium function is altered by lithium in hippocampal cell culture and triple transgenic for Alzheimer’s disease
Authors: De‐Paula Vanessa V.J. , Forlenza Orestes Vicente 
Published: December 2023

AbstractBackgroundCalcium (Ca2+) regulate many functions in neuronal and glial cells. The Mitochondrial Calcium Uniporter (Mcu) complex is thought to be the primary pathway for Ca2+ entry into mitochondria. The Mcu protein has an important role in regulating mitochondrial Ca2+ homeostasis. Dysregulation of mitochondrial Ca2+ homeostasis has been implicated in various pathological conditions, such as Alzheimer disease. AD pathology is characterized by the progressive accumulation of amyloid β‐peptide and neurofibrillary tangles. In AD patients a significant increase in an oxidative damage and decrease in energy metabolism resulting in a mitochondrial calcium disbalance. Lithium has been used for decades to treat neurodegenerative diseases, as it has an action on several intracellular organelles, including mitochondria. The lithium regulates calcium channels, decreases oxidative stress and increases autophagic processes. Therefore, we aim to analyze whether chronic treatment with lithium in primary cultures of hippocampal neurons and in the hippocampus of triple transgenic animals for Alzheimer’s disease (3xtgAD).MethodThe cultures were treated for 7 days (dose of 0.02; 0.2 and 2mM) and 3xtgAD for 8 months (doses of 1mM and 2mM). The hippocampus were analysed by proteomic and transcriptomics.ResultOur results showed that lithium increases Mcu and Micu 3 proteins, showing that lithium has an effect on the modulation of mitochondrial calcium channels that should be explored.ConclusionMitochondrial calcium is an important mechanism for understanding neurodegenerative diseases and lithium can reverse Alzheimer’s disease‐related dysfunction.
A core outcome set (COS) for dementia with Lewy bodies
Authors: Leroi Iracema 
Published: December 2023

AbstractBackgroundMethodological heterogeneity in the outcome measurements adopted in DLB trials impedes effective evidence synthesis, rigorous meta‐analysis, and clinical translation. We aimed to develop a Core Outcome Set (COS), an agreed standardised set of outcomes that should be measured and reported, as a minimum, in all clinical DLB trials.MethodWe adopted a multi‐faceted approach to COS development, adopting the principles of the Core Outcome Measures in Effectiveness Trials (COMET) initiative. We conducted systematic reviews of outcomes used in intervention trials, qualitative studies, and health economic studies in DLB. A resulting shortlist of outcome measures formed the basis of an e‐Delphi consensus process, piloted among members of the study group, before it was administered in two rounds to clinicians, scientists, policy and third sector leads. Lay stakeholders, including people with DLB and their caregivers, also contributed to the e‐Delphi process. Consensus on inclusion was determined by at least 70% of respondents grading an outcome measure as “critical for inclusion” and less than 15% grading as “not important”. After appraisal of each outcome using Consensus‐based Standards for the selection of health Measurement Instruments (COSMIN) guidelines, a consensus meeting was conducted, in which all participants were invited to agree on final outcomes and rate each outcome on impact, relevance and clinical feasibility.ResultsThrough validated mechanisms we constructed a COS including measurements of motor, cognitive, neuropsychiatric, autonomic, health economic, health provision, and quality of life. A diverse group of international and intersectional stakeholders have lent approval to its use.ConclusionWe propose a COS; a benchmark which all DLB trials should meet. This standardised approach will could optimise research resources, facilitate multicentre collaboration, and minimize methodological bias.
Highly specific gene therapy in a rat model of sporadic Alzheimer’s disease: use of adeno‐associated viral vectors to overexpress IGF1 in hippocampal astrocytes
Authors: Peralta Facundo , Escobedo Ana Abril Vidal , Hanotte Juliette López , Villar Maria Florencia Zappa , Reggiani Paula Cecilia , Pardo Joaquín 
Published: December 2023

AbstractBackgroundSporadic Alzheimer’s disease (sAD) is the most prevalent neurodegenerative disease. The cerebral histopathological study shows that the hippocampus (Hc) is severely affected and presents marked astroglial reactivity and in consequence, neuronal trophic support decreases. We set out to develop an astrocyte‐targeted therapy that prevents the detrimental actions of reactive astrocytes, enhance their neuroprotection, and restore their modulatory properties in our sAD rat model mediated by the intracerebroventricular (icv) injection of streptozotocin (STZ).Method
AAV generation: Bicistronic serotype 9 adeno‐associated viruses (AAVs) driven by the gfaABC1D promoter (astrocyte specific) [Lee et al 2008. https://doi.org/10.1002/glia.20622] were generated by the 3‐plasmid system. Two vectors harbouring the cassettes gfaABC1D‐IGF1‐ires‐tdTomato (AAV‐IGF1) and gfaABC1D‐GFP‐ires‐tdTomato (AAV‐GFP) were constructed. AAVs characterization was performed by RT‐qPCR and immunohistochemistry (IHC). Gene therapy in Hc with AAV‐IGF1: Young male rats were used and divided into 3 groups: SHAM, GFP and IGF1. On Experimental Day (ED) ‐28, animals received bilateral injections of artificial cerebrospinal fluid (aCSF) (SHAM) or AAV‐GFP/IGF1(GFP/IGF1). At ED 0, animals received icv aCSF (SHAM) or STZ (GFP/IGF1) (3mg/kg) bilaterally. Among the ED +17/+26 behavioural tests were performed (Open Field Test, Novel Object Recognition Test, and Barnes Maze).ResultTransgenes overexpression was confirmed by RT‐qPCR and IHC. Vectors specificity was determined since 100% of the cells with red fluorescence (tdTomato+) were GFAP+. We also observed that a single injection of the vector is sufficient to transduce Hc throughout its rostro caudal extension. Animals belonging to the AAV‐GFP+STZ group showed a significant deterioration in the behavioural tests, while AAV‐IGF1+STZ animals did not show significant differences compared with the SHAM control in tested behaviours.ConclusionWe explored a targeted therapeutic approach with high specificity to hippocampal astrocytes, which allowed us to modulate astrocyte IGF1 expression, thus promoting neuroprotective effects and preventing behavioural decline in animals with sAD. Consequently, our results are encouraging and suggest that astrocyte manipulation can be approached as a promising therapeutic means.*PCR and JP have equal contribution in this work
Differences in Functional Connectivity between Normal Controls and Mild Cognitive Impairment in Motion Detection Tasks
Authors: Gu Ming , Deng Jinxian , Sun Boxin , Kavcic Voyko , Giordani Bruno , Li Tongtong 
Published: December 2023

AbstractBackgroundIt has long been observed that the abnormal brain functions in Alzheimer’s disease (AD) and mild cognitive impairment (MCI) are closely related to the weakening or loss of functional connectivity across certain brain regions. At the same time, the decreased cross‐connectivity is often accompanied by increased connectivity between some other regions, and this was considered to reflect the compensatory mechanisms of the brain. In this research, we investigate the differences in time‐varying functional connectivity between normal controls (NC) and MCI patients in motion detection tasks.MethodOur research is based on task‐based EEG (64‐channel), where the participants were asked to perform a motion direction discrimination task. The current dataset includes 60 consensus‐diagnosed, community‐dwelling African Americans (ages 60‐90 years, 30 NC and 30 MCI) recruited through the Wayne State Institute of Gerontology Healthy Black Elders Center and the Michigan Alzheimer’s Disease Research Center with subjective cognitive complaints.We evaluated the time‐varying functional connectivity at different time periods of the motion‐detection task across all the possible EEG region pairs, in terms of the Pearson correlation vector of the current source density. For each task trial, the successive time periods being examined included: stimulus onset to Go/NoGo indication, Go/NoGo indication to motion‐stop, and the button‐press period. For each subject, we calculated the mean, maximum and minimum of the Pearson correlation vector for each EEG region pair and each time period as features, and then selected the features where NC and MCI show a significant difference (p‐value<0.05 in the t‐test).ResultOur analysis indicated that NC shows significantly higher connectivity across EEG region pairs Right Frontal‐Left Central (through most periods), Left Temporal‐Medial Central and Left Temporal‐Occipital (in button‐press period). On the other hand, MCI shows signigicantly high connectivity across Medial Parietal‐Occipital (through all the periods), which may reflect the compensatory mechanisms of the brain.ConclusionHC and MCI do show significant difference in functional connectivity during the motion detection task, and the EEG regions pairs Medial Parietal‐Occipital, and Right Frontal‐Left Central shown to be excellent choices for biomarker development for the discrimination of NC and MCI.Funding: NSF‐2032709/Li; NIH‐ P30AG05376004/Paulson; NIH‐1R21AG046637‐01A1/Kavcic and NIH‐1R01AG054484‐01A1/Kavcic;