bluuebunny/crossref_metadata_2025 huggingface dataset:
Timed “ Up and Go” test in single and dual‐task conditions in older people with and without cognitive impairment according to Verbal Fluency Screening
Authors: Baccani Beatriz S. E. , Borges Sheila de Melo
Published: January 2025

Background

Motor performance is related to executive function, especially in dual tasks conditions. Thus, the aim of this study was to compare the results of Timed “Up and Go” test with and without dual task in older people with and without cognitive impairment according to verbal fluency test.

Method

A cross‐sectional study was carried out in 291 elderly people attended by the Basic Health Unit of the city of Santos, São Paulo, Brazil. These elderly patients were divided in two groups, according to the presence of cognitive impairment (SG; n = 106) and the group without cognitive impairment (CG; n = 185) using Verbal Fluency (VF) test – animals category. The Timed “up and go” (TUG) test was evaluated under three experimental conditions: TUG‐simple (TUG alone); TUG‐cognitive (TUG with animal fluency task); and, TUG‐manual (TUG while carrying a full cup of water). The Mann‐Whitney test was used to compare TUG test between the groups (SG and CG) and ANCOVA for adjustment of the variable (age). The numerical data was presented with mean [minimum‐maximum] between groups.

Result

The results showed a significant difference between groups on the development of TUG simple (SG = 11.17[6.63‐33.26] seconds, and CG = 9.79[5.0‐17.25] seconds ‐ p<0.001), TUG‐cognitive (SG = 13.29[6.07‐60.02] seconds, and CG = 11.76[4.15‐28.88] seconds ‐ p<0.001); and, TUG‐manual (SG = 12.29[7,13‐38,70] seconds, and CG = 10.5[4.75‐19.85] seconds ‐p<0.001) and this values remained significant after ANCOVA for adjustment of age (p<0.001).

Conclusion

Older adults with cognitive impairment evaluated by VF test presented worse motor performance in both, with and without dual‐task conditions as compared to older person without cognitive impairment.
Overview and Application of Intrasubject Variability in ADRD Research
Authors: Malek‐Ahmadi Michael H.
Published: January 2025

Intrasubject variability is an important, but often overlooked, measure that has shown to be predictive of important clinical outcomes in ADRD research. Intrasubject variability is often quantified using the intrasubject standard deviation (ISD) that is derived from longitudinal measures or cross‐sectional observations from similarly scaled variables. This talk will begin with an overview of ISD and its application in both longitudinal and cross‐sectional analyses. For longitudinal analyses, ISD can be an important measure of normative performance variability on cognitive measures which can better inform clinicians on what normative trajectories for cognitive tests might be. An example using longitudinal data for the Montreal Cognitive Assessment (MoCA) will demonstrate how the ISD can be used quantify normative variability of longitudinal cognitive performance. The second part of this talk will discuss how ISD is used in cross‐sectional analyses of neuropsychological data. Specifically, how ISD is used to characterize the concept of dispersion which quantifies the inconsistency of between‐domain cognitive performance. Several studies have indicated that cognitive dispersion predicts incident cognitive decline and is associated with AD pathology which highlight the utility ISD may have in characterizing preclinical AD. An additional example using data from a complex motor task will show how the ISD of repeated task trials can differentiate cognitively unimpaired (CU), mild cognitive impairment (MCI) and AD cases. The conceptualization and application of ISD in this talk will set the stage for the other talks in this session that will demonstrate in greater detail how ISD can be used across the AD spectrum.
Mild inhibition of mitochondrial complex I reduces Tau pathology and improves energy homeostasis and synaptic function in human‐derived neurons of LOAD patients
Authors: Nguyen Thi Kim Oanh , Hasan Md Fayad , Trushina Eugenia
Published: January 2025

Background

Despite recent FDA approvement of disease‐modifying treatments that reduce Aβ, the identification of novel therapeutic strategies that could delay the Alzheimer’s disease (AD) development are needed. We identified and developed novel small molecule compounds that mildly inhibit mitochondrial complex I (MCI). Chronic treatment with a tool compound CP2 in 4 mouse models of familial AD was efficacious protecting against synaptic dysfunction and memory impairment, improving brain energetics and cognitive performance, reducing levels of human pTau and Ab. The objective of this study was to validate efficacy of this approach in a human brain‐like environment to support its translation into clinical trials. Human induced pluripotent stem cells (hiPSC) retain the host’s endogenous AD‐associated genetic alterations and recapitulate multiple hallmarks of late‐onset Alzheimer’s disease (LOAD).

Method

Using pure human induced neurons (iNs) from ApoE4/4‐carrying LOAD patients, we evaluated mitochondrial bioenergetics and morphology using a Seahorse XFe96 flux analyzer and electron microscopy. Axonal trafficking was assessed using MitoTracker Red and live confocal imaging. Immunohistochemistry, quantitative‐PCR, and western blot were carried out to assess changes in the expression of genes and proteins, and cell viability assays were used to perform H2O2 challenge.

Results

Cultures of hiPSC‐derived neurons were established using a lentiviral delivery for tetracycline‐inducible expression of NGN2‐GFP fusion gene driven by tetracycline‐responsive promoter. The validation of NGN2‐iNs confirmed the development of mature molecular, cellular, and synaptic properties. LOAD iNs have a significant reduction in the motile mitochondria in axons, increased accumulation of pTau, and altered bioenergetics compared to the control neurons. At CP2 concentrations relevant to in vivo treatment in APP/PS1 and 3xTgAD mice, significant reduction of pTau was associated with improved cellular bioenergetics, restored mitochondrial motility, and increased resistance to H2O2 induced oxidative stress.

Conclusion

LOAD neurons carrying ApoE4/4 alleles recapitulate LOAD phenotype allowing validation of a novel mitochondria‐targeted therapeutics. These data support previous observations in AD mice demonstrating that mild inhibition of MCI induce mild energetic stress with subsequent activation of multifaceted adaptive stress response and neuroprotective mechanisms improving cellular energetics and mitochondrial morphofunction in LOAD human neurons. Further efforts will be focused on the determination of mechanisms of neuroprotection.
BrainNetScore: Enhancing Alzheimer’s disease risk prediction using genetic‐guided brain volumetric phenotype network
Authors: Nam Yonghyun , Woerner Jakob , Jung Sang‐Hyuk , Suh Erica H , Shou Haochang , Shen Li , Kim Dokyoon
Published: January 2025

Background

Alzheimer’s disease (AD), characterized by significant brain volume reduction, is influenced by genetic predispositions related to brain volumetric phenotypes. While genome‐wide association studies (GWASs) have linked brain imaging‐derived phenotypes (IDPs) with AD, existing polygenic risk scores (PRSs) based models inadequately capture this relationship. We develop BrainNetScore, a network‐based model enhancing AD risk prediction by integrating genetic associations between multiple brain IDPs and AD incidence.

Method

Utilizing UK Biobank GWAS summary statistics, we constructed a brain connectivity network from 96 regional brain volume IDPs. This network was expanded into a heterogenous BrainNet graph, incorporating 96 IDPs and 12,043 common variants (SNPs) linked to each IDP. Individual genotype data from independent cohorts, including the Alzheimer’s Disease Neuroimaging Initiative (ADNI), were analyzed. Label propagation algorithms generated individualized predicted scores for IDPs, subsequently aggregated into BrainNetScore via logistic regression.

Result

BrainNet was built from GWAS summary statistics of 96 brain volume IDPs and individual genotype data for 914 samples (550 AD cases, 364 cognitive normal controls) from ADNI. We compared the predictive performance of BrainNetScore against conventional PRS models (Figure 1). The combined PRS + BrainNetScore model showed a superior average AUC of 0.684 ± 0.034, over PRS only (0.595 ± 0.075) and BrainNetScore only (0.666 ± 0.029) models. Including sex as a covariate and APOE genotypes further enhanced predictive accuracy (0.778 ± 0.043).

Conclusion

BrainNetScore significantly improves AD risk prediction when combined with PRSs. This highlights the potential of network‐based approaches and comprehensive genetic analysis in developing personalized medicine strategies for AD. Future work should extend this model to diverse populations.
Impact of Abnormal Phosphorylation on the Oligomerization of Tau Repeat R2
Authors: Man Viet H
Published: January 2025

Background

Reversible post‐translational modifications, phosphorylation and dephosphorylation, on tau protein play a critical role in the microtubule (MT) modulation. However, abnormal tau phosphorylation, which occurs in tauopathies such as Alzheimer’s disease (AD), causes the dissociation of tau from MTs. The dissociated tau then aggregates into sequent forms from soluble oligomers to paired helical filaments (PHF), and insoluble neurofibrillary tangles (NFTs), a hallmark of AD. In this study, we examine the impact of abnormal phosphorylation on monomeric and dimeric structures of tau repeat R2 peptides, which is the essential segment for tau fibrillization and somehow can represent the full‐length tau.

Methods

Wild‐type tau repeat R2 (wtR2) was taken from an experimental structure of R2‐microtubule complex (PDB code 6CVN). The phosphorylated Ser289 R2 peptide (pS289R2), phosphorylated Ser293 R2 peptide (pS293R2), and phosphorylated Ser289 and Ser293 R2 peptide (pS289+pS293R2) were obtained by phosphorylating the wtR2 at Ser289 and/or Ser293 residues. Extensive replica exchange molecular dynamics simulations using all‐atom force field and explicit solvent were carried out. The structures of R2 monomers and dimers sampled by the simulations were characterized and compared.

Results

For monomeric conformations, the phosphorylation enhances intramolecular interaction, compactness and β content. For dimeric cases, the phosphorylation increases intermolecular interaction, β‐sheet formation and turn‐coil structural transition. Interestingly, the phosphorylated residue strongly interacts with cations, resulting in a pSer‐cation‐pSer bridge.

Conclusion

Overall, our results suggest that abnormal phosphorylation at Ser289 and/or Ser293 accelerates the oligomerization of R2 peptides, and consequently it may promote tau aggregation. Furthermore, we also found a pSer‐cation‐pSer bridge formed, thus uncovering the essential role of cation ions in the oligomerization of the phosphorylated R2 repeat. Our findings suggest that phosphorylation at Ser289 and/or Ser293 should be taken into consideration when screening the inhibitors of tau oligomerization.
Loss of GABAB receptor 1 signaling facilitates activation of disease‐associated microglia in the mouse model of Alzheimer’s disease
Authors: LI JIALI
Published: January 2025

Background

Disease‐associated microglia (DAM), which cluster around Aβ plaques, represent a significant pathological hallmark of Alzheimer’s disease (AD) and play a complex role in influencing neuroinflammation, mediating synapse loss, and participating in the phagocytic clearance of Aβ. Nonetheless, the precise mechanisms by which microglial activation extends beyond the traditional M1 and M2 classifications, encompassing a diverse spectrum of states, especially for DAM, closely intertwined with physiological and pathological conditions under Alzheimer’s circumstances remain elusive.

Method

Here, we first combined biochemical techniques and bioinformatic analysis to test and quantify the expression of GABABR1 in both human and mouse AD models. Next, primary microglial cultures, siRNAs, immunohistochemistry, EEG recording and behavior tests were also used for in vitro and in vivo tests of loss of GABABR1 signaling in DAM activation, AD‐like pathology, and sleep impairment in this study.

Result

Firstly, we identified that the mRNA expression and protein levels of GABAB receptor 1 (GABABR1) deceased in microglia in the AD brain, especially in DAM compared to resting microglia. Next, we found that Aβ treatment directly lowered GABABR1 expression in microglia. We further found that knocking down GABABR1 in microglia decreased Trem2 expression, which increases the risk of Alzheimer’s pathogenesis. On the contrary, activating GABABR1 in microglia increased C1qb levels. Notably, the administration of 3xTg mice with the GABABR1 agonist cerebrolysin significantly not only restored microglial shape in the mPFC and hippocampus, with fewer branches but also reduced Aβ and hyperphosphorylation of tau levels in the mPFC and hippocampus and improved behavioral deficits and sleep impairment in AD mice.

Conclusion

Our findings delineate a novel role of loss of the GABABR1 signaling in AD‐associated DAM activation, and elevating GABABR1 activity within DAM holds promise for enhancing microglial structure and function, ultimately alleviating AD‐like pathology and behavioral deficits in the mouse model of Alzheimer’s disease.
Circulating metabolites and risk of incident dementia: A prospective cohort study
Authors: Huang Shu‐Yi
Published: January 2025

Background

Identifying circulating metabolites associated with dementia, cognition, and brain volume may improve the understanding of dementia pathogenesis and provide novel insights for preventive and therapeutic interventions.

Method

This cohort study included a total of 87,885 participants (median follow‐up 9.1 years, 54% female) without dementia at baseline from the UK Biobank. 249 plasma metabolites were measured using nuclear magnetic resonance spectroscopy at baseline. Cox proportional regression was used to examine the associations of each metabolite with incident dementia (cases = 1134), Alzheimer’s disease (AD; cases = 488), and vascular dementia (VD; cases = 257) during follow‐up. Dementia‐associated metabolites were further analyzed for association with cognitive deficits (N = 87,885) and brain volume (N = 7756) using logistic regression and linear regression.

Result

We identified 26 metabolites associated with incident dementia, of which six were associated with incident AD and five were associated with incident VD. These 26 dementia‐related metabolites were subfractions of intermediate‐density lipoprotein, large low‐density lipoprotein (L‐LDL), small high‐density lipoprotein (S‐HDL), very‐low‐density lipoprotein, fatty acids, ketone bodies, citrate, glucose, and valine. Among them, the cholesterol percentage in L‐LDL (L‐LDL‐C%) was associated with lower risk of AD (HR[95%CI] = 0.92[0.87‐0.97], p = 0.002), higher brain cortical (β = 0.047, p = 3.91 × 10‐6) and hippocampal (β = 0.043, p = 1.93 × 10‐4) volume. Cholesteryl ester to total lipid ratio in L‐LDL (L‐LDL‐CE%) was associated with lower risk of AD (HR[95%CI] = 0.93[0.90‐0.96], p = 1.48 × 10‐4), cognitive deficits (odds ratio = 0.98, p = 0.009), and higher hippocampal volume (β = 0.027, p = 0.009). Cholesteryl esters in S‐HDL (S‐HDL‐CE) were associated with lower risk of VD (HR[95%CI] = 0.81[0.71‐0.93], p = 0.002), but not AD.

Conclusion

Taken together, circulating levels of L‐LDL‐CE% and L‐LDL‐C% were robustly linked to risk of AD and AD phenotypes, but not with VD. S‐HDL‐CE was associate with lower risk of VD, but not with AD or AD phenotypes. These metabolites may play a role in the advancement of future intervention trials. Additional research is necessary to gain a complete comprehension of the molecular mechanisms behind these associations.
Immunodepletion of amyloid‐associated matrisomal proteins reduces Aβ in hiPSC‐derived neurons
Authors: Siciliano Benjamin , Li Qianjin , Ayoubi Riham , Laflamme Carl , Zoeller Elizabeth , Du Yuhong , Fu Haian , Wen Zhexing , Levey Allan I. , Betarbet Ranjita
Published: January 2025

Background

Large‐scale unbiased proteomic profiling studies have identified a cluster of 31 proteins co‐expressed with APP, which is termed the matrisome module 42 (M42). M42 is enriched in AD risk genes, including APOE, with mostly secreted proteins that bind heparin, collectively strongly correlate with the burden of brain pathology and cognitive trajectory, and localize to amyloid plaques in AD brain. For these reasons, M42 has been nominated as a novel therapeutic target for enabling drug discovery by our TREAT‐AD Center. Here we immunodeplete several M42 proteins including MDK, SFRP1, HTRA1, QPRT, PTN, and SMOC1 using iPSC‐derived neurons modeling autosomal dominant AD to investigate effects on amyloid production.

Method

The AD‐related APP Swedish mutation (APP KM670/671NL) was introduced into the well‐characterized wildtype control iPSC line (WTC‐11), and programming by the transcription factor neurogenin‐2 (NGN2) was used to generate cultures of high purity excitatory neurons. Inhibition of a collection of M42 proteins with strong correlation with AD endophenotypes was performed by treating neurons with recombinant monoclonal antibodies. Western blot was used to confirm immunodepletion of the secreted protein targets, as well as to measure p‐Tau and total Tau. Enzyme‐linked immunosorbent assay (ELISA) kits specific for human Aβ40 and Aβ42 were used to quantify Aβ species.

Result

Aβ40, Aβ42, p‐Tau (AT8), p‐Tau (S396), and total Tau, as well as ECM‐associated proteins (MDK, SFRP1, HTRA1, QPRT, PTN, SMOC1) were elevated in neuronal media and cell lysate derived from hiPSCs carrying the APP Swedish mutation relative to WT controls. Immunodepletion of MDK, HTRA1, and PTN reduced Aβ species in neuronal media, while immunodepletion of QPRT increased Aβ species and SFRP1 showed no significant changes.

Conclusion

hiPSCs with the APP Swedish mutation express and secrete increased levels of several M42 amyloid‐associated proteins as in human AD. Reductions in Aβ species following immunodepletion of MDK, HTRA1, and PTN demonstrate the utility of hiPSC models for probing M42 function and therapeutic potential for AD.
Characteristics of Cognitively Unimpaired Older Adults with Motoric Cognitive Risk
Authors: Large Stephanie E. , Hall James , O'Bryant Sid E.
Published: January 2025

Background

The concept of motoric cognitive risk (MCR) combines subjective cognitive concern (SCC) with slowed gait speed. The concept allows for the incorporation of cognitive and functional slowing into a measure of risk assessment. This study explores differences in cognitive functioning in cognitively unimpaired older adults with MCR and those without subjective cognitive concern and without slow gait speed.

Method

Data from 310 cognitively unimpaired participants from an epidemiological study of aging was collected. The MCR was defined as 1 standard deviation above the mean (controlled for age category and gender) for a four‐meter gait speed walk test and the report of SCC. Then each participant with MCR was matched with an equivalent non‐cognitively impaired participant with no SCC and matching for age, gender, and education. Two participants with MCR were excluded due to not having a match. T‐tests were performed comparing performance on the Geriatric Depression Scale (GDS) and raw scores Wechsler Memory Scale III sub tests Logical Memory I, II and Digit Span, Spanish English Verbal Learning Test (SEVLT) and Trail Making Test Part B.

Result

308 participants were included in the study with a mean age of 65.04 (8.4), mean education of 11.10 (4.72). The results showed significant differences between the MCR and no MCR groups in on the GDS t (306) = 7.99, p <.001, SEVLT immediate t (306) = ‐5.05, p < .001, SEVLT delayed t (306) = ‐4.84, p <.001, Logical Memory I t (306) = ‐3.79, p <.001, Logical Memory II t (306) = ‐4.18, p < .001, Trail Making Test Part B t (285) = 3.05, p = .003. The digit span sub test was not significant.

Conclusion

The study results demonstrate a significant difference in cognitive test performance and depression between those with MCR and without. This supports MCR as a distinct group and potentially as a tool to identify those at risk for later cognitive decline. Future research should examine the relationship between depression and MCR to determine causality, ATN markers in MCR and utility of MCR as a diagnostic category.
Brain microRNAs differentially expressed in age‐related cerebral pathologies
Authors: Luo Tianze , Vattathil Selina M. , Schneider Julie A. , Bennett David A. , Wingo Thomas S. , Wingo Aliza P.
Published: January 2025

Background

MicroRNAs (miRNAs) are important post‐transcriptional regulators of gene expression, but we have limited insight into their role in age‐related cerebral pathologies. Here, we investigated the association between miRNAs and nine age‐related cerebral pathologies in participants of the ROS/MAP cohorts.

Method

MiRNA sequencing was performed on samples from the dorsolateral prefrontal cortex of 617 brain donors from participants of the ROS/MAP cohorts. Following quality control, miRNAs were filtered to 528 verified miRNAs, which were included in the global miRNA differential expression (DE) analysis. A genome‐wide miRNA DE analysis was performed for global Alzheimer’s disease (AD) pathology, Lewy body pathology, TDP‐43, hippocampal sclerosis, arteriolosclerosis, cerebral amyloid angiopathy, cerebral atherosclerosis, gross cerebral infarct, and microinfarct. Two models were tested for each outcome: first, a minimally adjusted model adjusting for potential confounding factors, and a fully adjusted model that further adjusted for co‐existing cerebral pathologies to identify independently associated miRNAs. Gene set enrichment analysis (GSEA) was performed on the targets of DE miRNAs to identify the putative biological pathways underlying these pathologies.

Result

With minimally adjusted models, we found DE miRNAs in global AD pathology, Lewy body pathology, arteriolosclerosis, and cerebral amyloid angiopathy. Extending the analysis to adjust for co‐existing cerebral pathologies, we identified 75 independently associated miRNAs for global AD pathology, 45 for Lewy body pathology, 3 for arteriolosclerosis, and 1 for cerebral amyloid angiopathy at FDR < 0.05. Interestingly, we found miRNAs that are shared between AD hallmark pathologies and other age‐related cerebral pathologies. GSEA of target genes of the independently associated DE miRNAs identified biological pathways related to glutathione metabolism, synaptic functions, cellular transport, and innate immune responses altered in arteriolosclerosis at FDR < 0.05.

Conclusion

We identified DE miRNAs in multiple age‐related cerebral pathologies. Our study unveiled shared DE miRNAs between AD hallmark pathologies and other age‐related cerebral pathologies. GSEA results informed putative biological pathways altered in arteriolosclerosis. Collectively, our findings shed light on the role of miRNAs in age‐related cerebral pathologies and establish a basis for future mechanistic studies.
Macroscale structural covariance network reveals the biological mechanisms of neuropsychiatric symptoms in the Alzheimer’s continuum
Authors: Jiang Jiwei , Zhao Kun , Zheng Peiyang , Jiang Shirui , Xu Jun
Published: January 2025

Background

The intricate and heterogeneous phenotypes associated with neuropsychiatric symptoms (NPSs) encumber exploration of their role in the neuropathology and underlying biological mechanisms of Alzheimer’s disease (AD) continuum.

Method

An individual‐level Regional Radiomics Similarity Network (R2SN) for 487 patients with AD continuum (376 with NPSs vs. 111 without NPSs) were developed to find the R2SN connections associated with NPSs and refine the subtypes of NPS in the AD continuum. Distinct brain network dysfunction, multimodal neuroimaging burden, and clinical measures/progression of each NPS subtype were analyzed. Gene set enrichment analysis (GSEA) was used to explore the biological mechanisms underpinning the various NPS subtypes and their connections to the biological pathways leading to the AD continuum.

Result

Three NPS subtypes were identified based on 300 distinct key R2SN connections. Compared to AD patients without NPS, the first NPS subtype (sNPS) and third NPS subtype (moNPS) exhibited significant opposite pattern of brain connectivity damage, while the second NPS subtype (miNPS) showed minimal differences (Figure 1). Moreover, both sNPS and moNPS subtypes exhibited diminished performance at baseline and rapid decline in the MMSE and MoCA scores, while no statistically significant difference was discerned between the miNPS subtype and those without NPS. Furthermore, both sNPS and moNPS subtypes exhibited reduced regional grey matter volume and cortical thickness in the frontal, temporal, and parietal lobules, while miNPS subtype lacks significant structural brain changes but exhibited higher corrected cerebral blood flow in the inferior frontal gyrus and anterior cingulate cortex, suggesting early compensatory cerebral hyperperfusion (Figure 2). GSEA unveiled the shared and subtype‐specific gene pathways, elucidating each subtype’s unique biological mechanisms associated with the contribution of NPS‐related specific brain connectome dysfunctions to AD progression (Figure 3).

Conclusion

This is the first study to identify three distinct NPS subtypes in the AD continuum through a data‐driven approach, bridging the gap in the knowledge on the contributions of NPSs to the onset and development of AD. Our study constitutes a step toward resolving stagnant research progress on NPS management strategies based on clinical symptoms, and offers new insights into precise interventions for these patients.
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

Background

The 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.

Method

Forty 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.

Result

The 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.

Conclusion

Omega‐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

SORL1 (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

Background

SORL1 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.

Method

Here 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.

Result

We 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.

Conclusion

We 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

Background

The 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.

Methods

We 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.

Results

Prioritized 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%.

Discussion

Specific 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

Background

An 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.

Method

Eighteen 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.

Result

Ovariectomized 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).

Conclusion

These 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

Background

The 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.

Methods

We 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.).

Results

We 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.).

Conclusion

Genetic 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

Background

Synaptic 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.

Method

The 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.

Result

The 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.

Conclusion

Inhibition 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

Background

Heterogeneity 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.

Method

Postmortem 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.

Result

Biochemical 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.

Conclusion

These 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

Background

Our 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.

Methods

Twenty‐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.

Results

Iron 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).

Conclusion

Mdivi‐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.