bluuebunny/crossref_metadata_2025_split huggingface dataset:
Neuroprotective effect of omega 3‐oil against aluminium chloride induced oxidative stress in the cerebellum of adult wistar rat
Authors: Tangban Cynthia Nyen 
Published: January 2025

AbstractBackgroundThe brain is a potential target for aluminium toxicity as it induces oxidative stress, strategies, rich in polyphenolic compound, containing flavonoid and possessing antioxidant property, found in natural plant products, to attenuate aluminium‐induced impairments could provide a potential therapeutic intervention and protection for aluminium neurotoxicity.MethodForty adult rats weighing between 160 – 165g was used. The rats were divided into four groups (n = 10). Group (I) received distilled water group (II) received 100mg/kg body weight of aluminum chloride, group (III) received 200mg/kg of omega‐3 oil orally and group (IV) received 200mg/kg of omega‐3 oil and 100mg/kg of aluminum chloride in an hour interval for 28 days. The initial and final body weights as well as neurobehavioural studies were done on day 27 before sacrifice on day 29. The brain of the rats in each group was dissected out. Some cerebellar were preserved in phosphate buffered saline at 4°C and pH, 7.2 for oxidative stress and antioxidant markers, while other cerebellar were fixed in 10% formol‐saline for histological and immunohistochemical studies. Data analyzed using one way analysis of variance (ANOVA) at p<0.05.ResultThe results showed normal activities in the control, omega‐3, aluminium+omega‐3 groups throughout the experimental periods while the group administered aluminium chloride showed general body weakness, decline in food and water intake, decrease body weight, alongside disturbance in the exploratory movement, anxiety, motor function and motor activity. Alcl3 induced oxidative stress by increasing lipid peroxidation and decreasing glutathione levels, glutathione peroxidase and catalase activities in the cerebellum compared with the control and other treated groups.histological observations showed distortion of the cytoarchitecture of the cerebellar cortex induced by aluminum which was evident by the severe loss of Purkinje cells and vacuolization of cells in the granular layer. Observations employing Glial Fibrillary Acidic Protein showed increased astrogliosis and apoptosis in the aluminum‐treated group compared with the other groups.ConclusionOmega‐3 fatty oil reversed the neurological deficits induced by aluminium chloride. From the study, omega‐3 fatty acid decreased the rate at which aluminium chloride induced oxidative stress in the cerebellum of Wistar rats by increasing the antioxidant capacity of the brain.
An Introduction to SORL1‐retromer Structure/Function and Its Role in Alzheimer’s Disease
Authors: Petsko Gregory A. 
Published: January 2025

AbstractSORL1 (SORLA, LR11) is a large (2214 residue), multi‐domain type 1 integral membrane protein that is the product of the SORL1 gene. In neurons, where it is highly expressed, SORL1 functions as both a substrate of and a cargo receptor for the retromer multi protein complex that is a master regulator of protein trafficking out of the early endosome. The SORL1‐Vps26b retromer, in particular, is dedicated to the recycling of cell surface proteins, including APP and AMPA receptor subunit GLUA1, back to the plasma membrane. Rare loss‐of‐function alleles of SORL1, both truncation and some missense variants are found only in familial Alzheimer’s patients and not in age‐matched normal controls, which has led to the suggestion that SORL1 is the fourth causal AD gene (after APP, PSEN1, and PSEN2). More than 500 other variants are known, many of which appear to be pathogenic, with varying penetrance. They encompass all 24 domains of the protein. A crystal structure exists for the VPS10‐10CC region of the protein, which binds peptide cargo such as the Abeta peptide. The extracellular (ectodomain) portion of SORL1 is sometimes shed from the surface of the cell by proteolysis. New data suggests that SORL1 has two potential dimer interfaces, one in the VPS10 domain and one in fibronectin type III (3Fn) region. A model of the entire ectodomain places these two potential interfaces on opposite sides of the protein, implying that if both are used, SORL1 can polymerize to form a network in the interior of the tubular endosome. Such a network would stabilize the tubule from inside, analogous to the way the polymer of retromer arches is thought to stabilize it from outside. Knowledge of the structure and function of SORL1 allows prediction of the possible reasons why certain variants may contribute to the development of Alzheimer’s disease.
Known disease‐causing variants in homologous proteins help predict pathogenicity of SORL1 variants in Alzheimer’s disease
Authors: Andersen Olav M. , Monti Giulia , Jensen Anne Mette Gissel , de Waal Matthijs W J , Hulsman Marc , Olsen Johan G , Holstege Henne 
Published: January 2025

AbstractBackgroundSORL1 encodes the retromer‐associated receptor SORLA that functions in endosomal recycling. Rare variants in SORL1 have been associated with Alzheimer’s disease (AD) and rare pathogenic variants are estimated to occur in up to 2.75% of early onset AD patients and in 1.5% of unrelated late onset AD patients. While truncation mutations are observed almost exclusively in AD patients, it is currently unknown which among the hundreds of rare missense variants identified in SORL1, are pathogenic.MethodHere we address this question by relying on SORLA’s distinct molecular architecture. First, we completed a structure‐guided sequence alignment for all the protein domains. Next, we identified proteins that contain domains homologous to those of SORLA, which include pathogenic variants for monogenic diseases.ResultWe identified the analogous domain positions of these variants in the SORLA protein sequence and showed that variants in these positions similarly impair SORL1, and lead to AD. Together, our findings represent a comprehensive study on SORLA protein variation and functional effects, which allowed us to prioritize SORL1 genetic variants into high or moderate priority mutations.ConclusionWe envision that our findings will be used by clinical geneticists for assessing variants they identify in patients, allowing further development of diagnostic procedures and patient counseling strategies. Ultimately, the identification of the most pathogenic variants will inform investigations into the molecular mechanisms of endosomal recycling which will support the development of therapeutic treatment strategies for SORL1 variant‐carrying patients.
The effect of specific SORL1 variants on Alzheimer’s Disease risk supports the existence of highly penetrant SORL1 variants
Authors: Holstege Henne , de Waal Matthijs W J , Tesi Niccoló , van der Lee Sven J , Vogel Maartje , van Spaendonk Rosalina M.L. , Hulsman Marc , Andersen Olav M ,   ADES‐consortium, ADSP consortium, StEP‐AD consortium, Knight‐ADRC, UCSF/NYGC/UAB
Published: January 2025

AbstractBackgroundThe sortilin‐related receptor 1 protein, SORL1, interacts with retromer to regulate trafficking of cargo out of the early endosome. Genetic variants in SORL1 that lead to a premature protein truncation (PTVs) are observed almost exclusively in Alzheimer’s disease (AD) patients, suggesting SORL1’s haploinsufficiency may be causal for AD. However, the large majority of SORL1 variants are rare missense variants which affect diverse structural domains, some of which may be causative for disease or (strongly) risk‐increasing, while others are (likely) benign.MethodsWe prioritized functionally relevant SORL1 protein‐residues by domain‐mapping of disease mutations, DMDM, (Figure A). We evaluated the effect of prioritized genetic SORL1‐variants identified in 18,959 AD cases and 21,893 non‐demented controls, on age at onset and on disease risk. Second, since functional SORLA is cleaved at the neuronal membrane into soluble SORLA (sSORLA) we used Western Blot and proteomics to test whether SORL1 variants affected the level of sSORLA in CSF.ResultsPrioritized missense variants (PMVs) associated with a 10.5‐fold increased risk of early onset AD (p = 3.0 × 10‐29) and a 4.5‐fold increased risk of late onset AD (p = 4.9 × 10‐11). The distribution of the ages at onset of PMV‐ and PTV‐carriers overlapped (Figure B), which was on average >8‐years earlier than carriers of wild‐type SORL1, regardless of APOE genotype. Variants affecting the ‘YWTD‐motif’ or ‘calcium cage’ residues (Figure A) were observed only in AD cases. Carriers of such variants had an earlier age at onset compared to carriers of PTVs, indicative of a dominant negative effect, while other variants had a milder effect than losing a copy (Figure C). Using WB, we found that sSORLA levels in carriers of specific PMVs were reduced to ∼50% relative to carriers of benign SORL1 variants, while levels of PTVs were reduced to ∼65%.DiscussionSpecific SORL1 variants occur only in AD cases and have an early age at onset, and some may have a dominant negative effect, independent of APOE background. Carriers of these variants might be identified by a very low level of CSF sSORLA. Such variants might be grouped with pathogenic variants in the three autosomal dominant AD genes PSEN1/2 and APP.
Spermidine Attenuated Brain pathology and Learning Deficit in Estrogen‐deprived Condition
Authors: Pratchayasakul Wasana , Arunsak Busarin , Kaorop Wichida , Maneechote Chayadom , Donchada Suriphan , Kongkaew Aphisek , Chunchai Titikorn , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundAn increase in the development of learning deficit occurred during estrogen‐deprived periods via the increment of systemic and brain oxidative stress, brain apoptosis, and synaptic dysplasticity. Although estrogen supplementation has been shown to improve the brain function in estrogen‐deprived conditions, it can lead to several adverse effects. Therefore, the novel therapeutic approach with minimal side effects to protect brain function in estrogen‐deprived conditions should be further investigated. Spermidine is a natural polyamine, which can be obtained orally from diet. In the brain, spermidine attenuated age‐induced memory impairment and age‐related locomotor activity loss via the modulation of autophagic process. However, the effects of spermidine on brain function in estrogen‐deprived conditions have never been investigated.MethodEighteen female rats were assigned to sham‐operated (Sham; n = 6), or estrogen‐deprived group by ovariectomy (OVX; n = 12). Twelve weeks after surgery period, sham was received vehicle (normal saline; SV; n = 6) for additional 8 weeks. OVX groups were divided into two subgroups to receive either vehicle (normal saline; OV; n = 6) or spermidine (20 mg/kg/day; OS; n = 6) for an additional 8 weeks. At the end of the experimental period, all animals were taken to test the learning process with a novel objective location test. After that, blood and brain were collected to determine systemic and brain parameters.ResultOvariectomized rats showed the characteristic of estrogen deprivation, as indicated by decreased estradiol level when compared with those of sham rats (p<0.05, Figure 1). Spermidine did not increase the estradiol level of ovariectomized rats. Furthermore, systemic oxidative stress, hippocampal ROS production, hippocampal apoptosis, hippocampal autophagic imbalance, dendritic spine loss, synaptic dysplasticity, and learning deficit were observed in ovariectomized rats (p<0.05, Figure 1). Interestingly, spermidine attenuated these systemic and brain pathologies, which lead to improved learning process in ovariectomized rats (p<0.05, Figure 1).ConclusionThese findings suggest that spermidine may be another therapeutic approach for improving systemic and brain functions in the case of estrogen deprivation.
Genetic factors affect tau deposition in entorhinal cortex and neocortex
Authors: Giorgio Joseph , Solsberg Caroline Warly , Wang Yilin , Yokoyama Jennifer S. , Wang Jingshen , Jagust William J. 
Published: January 2025

AbstractBackgroundThe amyloid cascade hypothesis posits a sequence of events proceeding from amyloid‐β (Aβ) deposition to entorhinal cortical (EC) tau to neocortical (meta‐temporal) tau. This study examined how genetics may modify relationships between these variables on the AD pathway.MethodsWe used causal path analyses to model effects of sex, APOE‐ε4 (0,1,2 alleles), and genetic risk for neuroinflammation on Aβ, EC tau and meta temporal tau. We modelled main effects and pairwise interactions between genetic profiles and earlier pathology on downstream pathologies, accounting for the full mediation path from Aβ→ EC tau → meta‐temporal tau (Figure 1.). Participants were 628 individuals from ADNI and A4 with whole genome sequencing, Aβ‐PET (Centiloids, CL) and [18F]flortaucipir (FTP)‐PET SUVR. Neuroinflammation gene burden (1/0) was defined as one or more rare polymorphisms on the coding region of the TREM2 gene that have been previously associated with AD (Table 1.).ResultsWe observed interactions between Aβ and APOE‐ε4(2‐alleles) (β = 0.002, P = 0.002), and Aβ and sex(F) (β = 0.0008, p = 0.032) on EC tau: higher Aβ was associated with more EC tau in APOE‐ε4 homozygotes and females (Figure 2ab.). Next, we observed interactions between EC tau and APOE‐ε4(2‐alleles) (β = 0.364, P<0.001), and EC tau and TREM2(1) (β = 0.309, P<0.001) on the spread of tau to meta‐temporal regions: both APOE‐ε4 homozygotes and individuals with a TREM2 risk allele had greater downstream meta‐temporal tau burden for a given level of EC tau (Figure 2cd). A significant interaction between APOE‐ε4 and TREM2 (β = 0.0186, p = 0.0168) indicated highest risk in those with a TREM2 risk allele and 1 or 2 ε4 alleles (Figure 2e.).ConclusionGenetic factors affect tau pathological burden above and beyond the effects of Aβ. Both females and APOE‐ε4 homozygotes express tau deposition in the EC at lower Aβ CL than males and non‐homozygotes. Neocortical tau deposition is related to EC tau and is greater in APOE‐ε4 homozygotes and individuals with a genetic risk for impaired neuroinflammatory responses. These findings may explain variable effects of anti‐amyloid treatments and provide insights into the potential biological drivers of tau spread.
Inhibition of Smad4 improves the cognitive function of APP/PS1 mice by targeting the level of c1qa
Authors: Ge Jianwei , Luo Benyan 
Published: January 2025

AbstractBackgroundSynaptic plasticity impairment plays a critical role in the pathogenesis of Alzheimer’s disease (AD), Smad4, a central intracellular signal transmission mediator of transmission of transforming growth factor‐β (TGF‐β) signaling, plays a pivotal role in many biological processes, including cell differentiation, migration, apoptosis and tumorigenesis. Emerging evidence has demonstrated that Smad4 is also involved in the pathogenesis of AD. Once TGF‐β signaling is stimulated, Smad4 interaction with Sp1 and Smad3 induces the transcriptional activation of APP. Smad4 physically binds with TGF‐β1‐induced anti‐apoptotic factor (TIAF1) and prevents TIAF1 self‐aggregation, which reduces production of Aβ and amyloid fibrils.MethodThe adeno‐associated virus knocking down Smad4 (AAV‐sh‐Smad4) and the corresponding control were respectively injected into the bilateral hippocampus of 6‐month‐old APP/PS1 mice using a stereotaxic apparatus. Open filed tests, novel object recognition tests, Morris water maze (MWM) tests and contextual fear conditioning tests were applied to test the cognitive function of APP/PS1 mice. Real‐time quantitative PCR and western blot was used to measure the expression of Smad4. Patch clamp technique was used to record the LTP and fEPSP of the hippocampal CA1 slices. Golgi staining and transmission electron microscope were applied to evaluate the number and structure of synapses. Luciferase activity assay, cleavage under targets and tagmentation assay and chromatin immunoprecipitation were applied to discover and verify the potential target c1qa of Smad4.ResultThe level of Smad4 was significantly increased in the hippocampus of APP/PS1 mice. Smad4 inhibition alleviates memory deficits in 6‐month‐old APP/PS1 mice. Smad4 inhibition significantly increased the number of synapses and thickness of PSD in APP/PS1 mice. Furthermore, Smad4 inhibition increased the dendritic spine density and the percentage of mushroom spines in APP/PS1 mice as demonstrated by Golgi staining. Cut&Tag assay was performed to explore the potential targets of Smad4, and it showed that Smad4 negatively affected the expression of c1qa by directly binding to the ‐1049 to ‐776bp of the c1qa promoter with CHIP and Luciferase activity assay. Immunofluorescence showed inhibition of Smad4 effectively reduce the phagocytosis of synapses by microglia.ConclusionInhibition of Smad4 improves the cognitive function and synaptic plasticity of APP/PS1 mice by targeting the level of c1qa.
Unraveling the molecular mechanisms underlying neocortical tau propagation in Alzheimer’s disease to reveal novel insights into clinical heterogeneity
Authors: Chongtham Anjalika , Farinas Marissa , Broekaart Diede , Seo Joon Ho , Ramakrishnan Aarthi , Zhu Carolyn W. , Sano Mary , Shen Li , Pereira Ana C. 
Published: January 2025

AbstractBackgroundHeterogeneity in the progression of clinical dementia poses a significant challenge, impeding the effectiveness of current therapies for Alzheimer’s disease (AD). To decipher the molecular mechanisms governing heterogeneity in AD progression that remains a critical knowledge gap precluding rational therapeutic design, we investigated the biochemical and biophysical properties of tau present in the inferior temporal gyrus (ITG) and prefrontal cortex (PFC) brain regions of AD patients who had varying disease progression rates. To explore gene expression changes in the ITG which are associated with tau pathology and cognitive decline, we used RNA sequencing for molecular characterization of patients displaying tau and clinical heterogeneity.MethodPostmortem brain samples from the ITG and PFC of AD (n = 20) and control (n = 8) subjects were used to evaluate the biochemical features of abnormal tau species, specifically those that may influence its propagation and best predict AD progression. Further, we investigated molecular heterogeneity in AD with RNA‐seq analyses of ITG tissues with differential seeding potential. The present study integrates tau biochemistry with transcriptional alterations to elucidate the molecular mechanisms of cognitive decline in AD, which is critical for advancing future therapeutic interventions and development of personalized treatments.ResultBiochemical analysis of human postmortem ITG and PFC tissues revealed individual variability in tau seeding, which correlated with cognitive decline, particularly in the ITG, a region known for promoting accelerated tau propagation. Specific hyperphosphorylated high and, intriguingly, low‐molecular‐weight tau (p‐T217, T231, S396 and S396/S404‐tau) and their isoforms (3R and 4R‐tau) are likely mediators of seeding and cognitive decline. Additionally, RNA‐seq transcriptomic analyses showed that cognitive decline during AD progression could be related to tau‐mediated failure of neural mechanisms in the ITG, particularly a loss of neural and synaptic plasticity and increased neuroinflammation.ConclusionThese findings provide further insights into multiple molecular mechanisms potentially involved in disease progression, highlight targets for early intervention, and improve patient subtyping, which is critical for developing precision medicines.
Mdivi‐1 Mitigated Excessive Brain Mitochondrial Fission and Brain Mitophagy, Consequently Restoring Spatial Memory in Rats Under Iron‐overloaded Condition
Authors: Sripetchwandee Jirapas , Kongkaew Aphisek , Kumfu Sirinart , Chattipakorn Nipon , Chattipakorn Siriporn C 
Published: January 2025

AbstractBackgroundOur studies suggest that iron‐overloaded rats developed neurotoxicity and cognitive impairment (1,2). An increase in brain mitochondrial fission and brain mitophagy have been considered as one of underlying mechanisms in brain with iron‐overloaded condition (3,4). Hence, a pharmacological intervention focused on preventing brain mitochondrial pathologies is required. The mitochondrial fission inhibitor, Mdivi‐1, has recently gained attention because of its beneficial effects on several neuropathological conditions including traumatic brain injury and intracerebral hemorrhage (5,6). However, the effectiveness of Mdivi‐1, particularly regarding brain mitochondrial parameters and cognitive function in iron‐overloaded condition, has not been investigated.MethodsTwenty‐four male adult Wistar rats were divided into 2 groups to receive an intraperitoneal injection with 10% dextrose in normal saline solution (NSS) as a control group (n = 6) or 100 mg/kg iron dextran as an iron‐overloaded group (n = 18). After 4 weeks of injection, the iron‐overloaded group was subdivided into 3 subgroups (n = 6/subgroup) to subcutaneously receive pharmacological interventions either 1) vehicle (10% DMSO in NSS), 2) deferoxamine (25 mg/kg), or 3) Mdivi‐1 (2 mg/kg). The control rats were also given a vehicle. All rats were received the assigned treatment for further 2 weeks. Behavioral tests including open field test (locomotor activities) and the Morris water maze test (spatial memory test) were evaluated. At the end of experiments, rats were euthanized, and serum samples were collected to assess serum iron level. Furthermore, brain tissues were preserved for the assessment of blood‐brain tight junction protein, brain iron level, and the protein expression related to brain mitochondrial fission and brain mitophagy.ResultsIron dextran‐injected rats demonstrated an increase in serum/brain iron levels, called as “iron‐overloaded condition”, blood‐brain barrier disruption, and increased brain mitochondrial fission and brain mitophagy, resulting in a decline in spatial memory. The administration of deferoxamine alleviated brain pathologies and partially mitigated the impaired spatial memory test in iron‐treated rats. Interestingly, the Mdivi‐1 exhibited greater neuroprotective effects than deferoxamine by attenuating brain mitophagy and restoring spatial memory (Figure 1).ConclusionMdivi‐1 potentially exerted neuroprotective effects and cognitive restoration in iron‐overloaded rats, suggesting a novel therapeutic strategy using mitochondrial fission inhibitor in the brain following iron‐overloaded condition.