bluuebunny/crossref_metadata_2025 huggingface dataset:
Molecular Docking for pharmacokinetics and drug‐likeness of Naringenin and its protective effects against streptozotocin induced cognitive deficits in mice
Authors: Yadav Monu
Published: January 2025

Background

The current study aimed to investigate the chemical interaction of naringenin with the possible receptors and enzymes involved in the pathogenesis of cognitive deficits and tested their ADME and toxicity. Furthermore, in‐vivo studies have also done to evaluate the effect of naringenin and its nanoparticles on STZ‐induced cognitive decline in mice.

Method

Naringenin were evaluated against the active sites of β‐secretase 1 (PDB: 3UQU), human insulin‐degrading enzyme (PDB: 4RE9), insulin receptor tyrosine kinase (PDB: 1IR3), glycogen synthase kinase‐3 β (PDB: 3L1S), phosphoprotein phosphatase 2A (PDB: 3P71), human superoxide dismutase I (PDB: 5YT0), catalase‐3 (PDB:3EJ6), and human acetylcholinesterase (PDB: 4EY7) in comparison of rivastigmine using molecular docking studies. Further, the naringenin and rivastigmine were subjected to test their pharmacokinetic and lead‐likeness properties by employing the Swiss ADME web server. Moreover, a toxicity study has been performed for both naringenin and rivastigmine with the help of a Protox‐II web server.

Result

Naringenin has a better binding affinity than rivastigmine with all the potential receptors. In in‐vivo behavioral, biochemical mitochondrial and histopathological studies, naringenin nanoformulation showed more significant cognitive enhancement results as compared to pure naringenin when studied against STZ induced cognitive deficits.

Conclusion

The results demonstrated that it would be worthwhile to explore more naringenin nanoformulation to expose the therapeutic effects for the treatment of cognitive deficits and neuroprotecive effects.
Modelling synaptic tau and Aβ pathology in human organotypic brain slice cultures
Authors: McGeachan Robert I.
Published: January 2025

Background

Maintaining synaptic health is essential for normal neurological function, yet neurodegenerative diseases like Alzheimer’s disease and Progressive Supranuclear Palsy (PSP) exhibit synaptic loss. In these conditions, synaptic loss precedes neuronal degeneration, and the degree of synaptic loss correlates closely with the severity of clinical symptoms. Both Aβ, which accumulates in amyloid plaques in AD, and tau protein which accumulates intracellularly in tauopathies, including AD and PSP, accumulate within synaptic terminals. In model systems, the accumulation of Aβ and tau in synapses has been linked to synaptic dysfunction, synaptic loss, and the spread of pathology trans‐synaptically. However, there is currently a lack of data studying the synaptotoxic effects of these pathologic proteins in live human synapses.

Method

To address this, we usenovel human organotypic brain slice cultures derived from neurosurgical peritumoral access tissue. Employing a powerful repeated measures design to account for donor tissue variability, slices from each case were cultured with either medium, soluble protein extract (sp‐extract) from PSP (n = 6) or AD (n = 5) brain, or sp‐extracts immunodepleted for tau or Aβ respectively.

Result

Using high‐resolution array tomography, and linear mixed effect modelling of the data, our findings reveal that exogenous PSP‐derived tau (p = 0.002) and AD‐derived Aβ (p = 0.004) are taken up into living human post‐synapses, and within 72 hours AD‐derived Aβ causes a loss of synaptophysin puncta (p = 0.002). Our data further suggests that oligomeric tau has a greater propensity for synaptic uptake than phospho‐tau Ser202, Thr205 (AT8). Interestingly, PSP‐derived tau induces an astrogliosis (p = 0.001) and an associated increase in synaptic engulfment (p < 0.001) in our slice culture model.

Conclusion

Human organotypic brain slice cultures can be used a valuable tool to study the effects of disease derived tau and Aβ on human synapses.
Multi‐omic cell type‐level inference of mechanisms underlying non‐coding genetic variants for Alzheimer’s disease
Authors: Kuksa Pavel P. , Carter Luke , Cifello Jeffrey , Leung Yuk Yee , Wang Li‐San
Published: January 2025

Background

Recent Alzheimer’s disease (AD) genome‐wide association studies () have identified >75 risk loci, with >98% of genome‐wide significant variants residing in non‐coding genomic regions, making it more difficult to infer their functional contexts. In this study, we aim to jointly 1) fine‐map causal loci/variants, and 2) identify affected cell types and functional elements by interrogating large‐scale collections of thousands of heterogenous, cell type‐specific functional genomic (FG) datasets.

Method

We analyzed the full genome‐wide summary statistics (n = 21,101,114 variants) from the recent AD GWAS (Bellenguez et al, 2022) (Ncases = 111,326, Ncontrols = 677,663). The variants were analyzed using the recently introduced Bayesian framework (Bayesian tissue score, BTS https://bitbucket.org/wanglab‐upenn/workspace/projects/BTS) on >70,000 harmonized genome‐wide cell‐type level FG tracks (FILER; Kuksa et al, 2022), including those for FANTOM5 enhancers, Roadmap ChromHMM enhancers, ENCODE DNase hypersensitivity sites and active histone marks, and EpiMap enhancers (4,225 tracks). Using BTS, we calculated Bayesian prior odds for each of the annotation tracks overlapped with genome‐wide GWAS signals and then computed annotation‐specific causal variant and loci posteriors. With this systematic, hypothesis‐free multi‐omic approach, we jointly analyzed and ranked AD‐relevant loci, variants, and their functional contexts (affected cell types and corresponding genomic features).

Result

The BTS pipeline identified 131 non‐HLA genomic regions with 49,049 variants, across 1,294 overlapping annotation tracks on 640 cell types, with up to two distinct causal signals in each locus. BTS prioritized 152 annotations tracks with >2 prior odds (3.60 causal prior odds average) across 108 cell types belonging to the blood (57), brain (21), heart (12), digestive (12), (6) tissue categories. In total, 94 genomic loci and 119 variants prioritized in these cell types (posterior > .5).

Conclusion

Large‐scale evaluation of AD GWAS data provides insights into functional contexts and potentially causal biological mechanisms of AD.
Molecular insights into the heterogeneity of depression in Alzheimer’s disease: A single‐cell transcriptomic analysis
Authors: Lutz Michael W , Man Zhaohui , Chiba‐Falek Ornit
Published: January 2025

Background

Patients with Alzheimer’s Disease (AD) frequently manifest comorbid neuropsychiatric symptoms (NPS) with depression and anxiety being most prevalent. Previously we identified shared genetic risk loci between AD and major depressive disorder (MDD). In another study, we constructed a polygenic risk score (PRS) based on MDD‐GWAS data and demonstrated its performance in predicting depression onset in LOAD patients. Furthermore, using bulk brain transcriptomic data, we discovered sex‐dependent differentially expressed genes in AD comorbid with depression compared to AD only. Here we aimed to investigate in‐depth differences in gene expression on a cell‐type specific level between autopsied AD brain tissues from patients with depression compared to patients without evidence for depression.

Method

Single nucleus (sn)RNA‐seq data from the ROSMAP study (available through AMP‐AD) was analyzed, specifically, dorsolateral pre‐frontal cortex datasets from 14 brains with AD comorbid depression and from 19 brains with AD and absence of depression. Depression was determined by clinical diagnosis and CES‐D scores. Differential gene expression (DEG) was performed using Nebula with case/control status based on clinical diagnosis of depression and age, sex, PMI and subject identified included as covariates.

Result

FDR‐significant DEG were found for multiple cell types with the greatest majority of DEGs for inhibitory neurons (n = 548) followed by astrocytes (n = 109). Most of the genes in these cell types were upregulated. In addition, MS4A6A gene was found to be significantly upregulated in microglia, supporting our prior results showing the pleiotropic role of MS4A6A in both MDD and AD. Pathway analysis for the inhibitory neuron DEGs showed significant enrichment for terms related to mitochondrial function including: mitochondrial electron transport and mitochondrial ATP synthesis coupled with electron transport, suggesting mitochondrial dysfunction.

Conclusion

The results demonstrated numerous depression‐associated cell‐type specific DEGs in AD brains. Our single‐cell analysis provides mechanistic insight into the risk to develop comorbid depression in AD and advances our understanding of shared molecular etiologies and dysregulated pathways between AD and MDD. This knowledge has a translational impact toward the identification of actionable targets as novel therapies to treat depression earlier in disease stages as a means to delay or alleviate depression onset in AD.
Examining Methylation at the Intersection of Genetic Risk To Alzheimer’s Disease And Alcohol Use Disorder
Authors: Pathak Gita , Pietrzak Robert H , Levey Daniel , Montalvo‐Ortiz Janitza , Kranzler Henry , Gelernter Joel , Polimanti Renato A
Published: January 2025

Background

Alcohol Use Disorder (AUD) affects over 15 million individuals in the United States, contributing to oxidative stress, neuroinflammation, and elevating the risk of neurodegeneration. Despite this, the connection between AUD and aging conditions, particularly Alzheimer’s disease (AD), remains unclear. AD, with a heritability of 60‐80%, is genetically linked, necessitating an exploration of the molecular implications of AUD and genetic susceptibility to AD.

Method

Participants were assessed for AUD using DSM‐5 criteria, and genotype data were imputed with the TOPMED reference panel. The polygenic score (PGS) of AD was calculated in European ancestry participants (mean±SD, 40.12 ±13.3 yrs; N = 4,915), adjusting for age, sex, and genetic ancestry. Methylation was assayed using the Illumina EPIC array using blood to conduct an epigenome‐wide association study (EWAS) on the interaction between PGS‐AD and AUD at 657,226 CpG sites in a subset of participants (N = 452). Intrinsic and extrinsic epigenetic age acceleration (IEAA, EEAA) were calculated using Hannum and Horvath’s epigenetic clocks.

Result

We observed a significant association between PGS of AD and AUD diagnosis (cases = 34%; OR = 1.44; p = 0.005). The subsequent EWAS revealed top CpG sites in genes associated with AD pathogenesis, including RLF, CD2AP, GLUL, GJA3, TRIM26, JAG2, RERE, SRRM3, COL11A2. For these top CpGs, we investigated the beta (methylation intensity) in individuals with high‐PGS of AD (top 25% quantile) and stratified them by AUD diagnosis. Briefly, the top two CpG sites in AUD cases‐cg01101221(RLF; p = 5.51E‐07) was hypomethylated (p = 0.0205); and cg05804888(CD2AP; p = 4.61E‐06) was hypermethylated (p = 0.0142). We also observed interaction of AUD and PGS of AD is associated with accelerated aging‐ IEAA and EEAA from both Horvath and Hannum’s clocks (p<8.56E‐06<0.0092).

Conclusion

The identified genes have been implicated in AD pathogenesis, such as CD2AP’s association with Aβ production and GLUL’s role in brain lipid metabolism. The study also highlighted the association between AUD and PGS‐AD interaction and accelerated epigenetic aging. While the CpG associations did not reach Bonferroni significance, our ongoing research aims to extend these findings to other ancestries and cohorts to improve statistical power. Thus providing a comprehensive understanding of the complex interactions between AUD diagnosis and genetic susceptibility to AD.
Applying Digital Spatial Profiling of the Transcriptome to Elucidate Disease Mechanisms of Psychosis in Alzheimer’s disease
Authors: Thomas‐Hegarty Jacob , Lunnon Katie , Pishva Ehsan , Smith Adam , Weymouth Luke , Eyres Michael , Frost Lucy , Marshall Gayle , Platt Eleanor , Creese Byron
Published: January 2025

Background

Psychosis occurs in 30‐40% of individuals with AD. New insights into disease mechanisms may lead to novel pharmacological targets and treatments. Previous studies have focused on bulk tissue analysis with limited results. Digital spatial profiling (DSP) is a new technique for spatial analysis of RNA or proteins in fixed tissue. It allows quantitative profiling with spatial complexity to be collected from samples in a non‐destructive manner. In this pilot study we used DSP to compare whole transcriptome data in amyloid beta and non‐amyloid beta regions in participants with and without psychosis (AD+P; AD‐P).

Method

Six post‐mortem brain samples from prefrontal cortex were provided by the Kings College London Brains for Dementia Research (BDR) brain bank. Frozen and formalin fixed, paraffin embedded (FFPE) sections were supplied in order to test the platform on each type. Psychosis positive and negative groups were selected based on Neuropsychiatric Inventory (NPI) assessments. Samples were hematoxylin and eosin (H&E) stained as well as stained with fluorescent antibodies for AT8, NeuN, SYTO13 and Aβ. Regions of interest (ROIs) are selected based on morphology markers and tissue morphology (see Figure 1 for Amyloid ROI selection).

Result

H&E staining revealed the frozen samples to be too badly degraded so the analysis was conducted on FFPE sections. AT8 staining showed widespread tau pathology to the extent that it was not possible to confidently select non‐tau ROIs. Analysis of Aβ plaque containing and Aβ plaque free regions, comparing AD+P and AD‐P groups, found 314 differentially expressed genes in plaque free regions, and 172 differentially expressed genes in plaque containing regions (Figure 2). Of these 172 genes, 28 were not differentially expressed in plaque free regions, forming a plaque‐specific signature of genes differentially expressed in AD+P.

Conclusion

This pilot study demonstrates the potential of the NanoString GeoMx™ DSP platform as an innovative spatial transcriptomics methodology for investigating AD+P with the potential to uncover differentially expressed genes that may be missed by bulk RNA sequencing studies. FFPE sections appear to be optimal. Analysing earlier stage disease and more sections per subject may help with better differentiation of tau and non‐tau ROIs.
Differential Roles of Human Tau Isoforms in the Modulation of Inflammation and Development of Neuropathology
Authors: Spencer Brian , Ngolab Jennifer , Schueler Aaron , Sung Daniel , Rissman Robert A
Published: January 2025

Background

Alzheimer’s disease (AD) is the most common tauopathy and characterized by the progressive accumulation of Aß and tau. Tau is expressed in two major isoforms containing either 3 or 4 c‐terminal repeats labeled as 3R and 4R tau. While these two isoforms occur in roughly equimolar ratios in AD, most research focus and mouse models of tau center only the 4Rtau protein and not 3Rtau. We recently generated a 3Rtau transgenic mouse to model Pick’s disease which is characterized by the preferential accumulation of 3Rtau. To generate a more human representative model of AD tauopathy and understand specific tau isoform‐mediated neurodegeneration, we generated a transgenic mouse line expressing both 4Rtau and 3Rtau and determined how this impacted the timing and severity of neuropathological and behavioral changes.

Method

3Rtau‐tg and 4Rtau‐tg mice were crossed to generate 3R/4Rtau‐tg bigenic mice. At 3, 6, and 9 months of age, mice were assessed for learning and memory (Morris water maze), cognitive ability and depression (nesting) and hyperactivity (open field). After behavior assessment, mice were sacrificed, and brains were analyzed by IHC for tau accumulation, neuronal loss, and gliosis. Frozen brains were also analyzed for tau protein accumulation by immunoblot and RNA expression by qPCR.

Result

3R/4Rtau bigenic mice expressed increased tau and phosphorylated tau in the hippocampus and cortex compared to 3R or 4R transgenic cohorts as early as 3 months of age. In addition to increased tau pathology, increased astrogliosis and microglia was seen in the bigenic mouse compared to single transgenic tau mice. Finally, the bigenic mouse had significantly greater behavioral deficits compared to either 3Rtau or 4Rtau‐tg mice in spatial learning and memory as well as reduced nest building indicative of depression and/or cognitive deficits.

Conclusion

This new mouse model of tauopathy better recapitulates the pattern, severity and accumulation of tau and associated neuropathology and behavioral changes observed in human tauopathies such as AD and FTD. This new model should supplant existing single transgenic tau models for validation of therapeutic targets and investigations of novel therapies for ADRD.
Molecular Characterization of Knock‐In Mouse Models Harboring Genetic Risk Factors for Late‐Onset Alzheimer’s Disease
Authors: Carter Gregory W
Published: January 2025

Background

Determining the precise genetic mechanisms that contribute to LOAD, both in coding and noncoding variants, will enable a deeper understanding of pathogenesis and advance preclinical models for the testing of targeted therapeutics.

Methods

We have introduced candidate genetic variants in the EPHA1, BIN1, CD2AP, SCIMP, KLOTHO, PTK2B, ADAMTS4, IL1RAP, IL34, and PTPRB loci into a sensitized mouse model already harboring humanized amyloid‐beta, APOE4, and Trem2.R47H alleles knocked in to a C57BL/6J background. Variants were selected based on predicted function, cross‐species conservation, increased risk of LOAD, and allele frequency. Coding variants were chosen in PTPRB, IL34, and KLOTHO while promoter and/or enhancer variants were modeled for the remaining loci. Genome editing with CRISPR‐Cas9 was performed and mouse cohorts were aged to four and 12 months. Homogenized brain hemispheres were assayed from both male and female mice with RNA‐seq. Transcriptomic changes were compared to postmortem human brain data to determine disease relevance.

Results

Transcriptomic effects from these genetic variants recapitulated a variety of human gene expression patterns observed in LOAD study cohorts, particularly when signatures were partitioned into Alzheimer’s relevant biodomains. By 12 months of age, PTPRB*D57N mice exhibited neuroimmune signatures that correlate with postmortem LOAD cases relative to controls. A noncoding variant in the EPHA1 region primarily altered apoptotic processes, potentially driven by expression changes in CASP2 at the locus. The BIN1 promoter variant exhibited both neuroimmune and oligodendrocyte‐related changes that correlated with LOAD modules. These changes were more pronounced with age, supporting their role in age‐related dementia.

Conclusions

We have characterized in vivo signatures of nine genetic candidates for LOAD, identifying alterations in specific LOAD‐related pathways in each variant on a sensitized genetic background. These results provide animal models for preclinical testing of therapeutics designed to correct specific molecular alterations that contribute to LOAD pathology and progression.
Pre‐clinical development of AVB‐101, an AAV gene therapy treatment for frontotemporal dementia with progranulin mutations
Authors: Lee Youn Bok , Miranda Carlos J , Allison Joseph , Kaliszewska Aleksandra , Bekele Yalem , Hosseini Paniz , Joubert Romain , Walker Zoe , Furtado Joana , Gumus McQuinn , Fernandes Alinda , Brock Olivier , Bouchard Page , Bloom Alex , Lee Do Young , Shaw Christopher E
Published: January 2025

Background

Frontotemporal dementia (FTD) presents with a change in personality, behaviour and language and is the second most common cause of young‐onset dementia after Alzheimer’s disease. Loss of function mutations in GRN, encoding progranulin (PGRN), causes FTD in the heterozygous state, accounting for 5‐10% of all FTD cases. PGRN is essential for normal lysosomal function and neuronal survival. The PGRN reduction observed in FTD‐GRN patients leads to lysosomal dysfunction, associated with the mis‐accumulation of neuronal TDP‐43 and exaggerated microglial reactivity that accelerates neurodegeneration. FTD‐GRN represents a serious condition with significant unmet needs. AVB‐101 is being developed as a one‐time treatment for FTD‐GRN administered bilaterally into the thalamus (ITM) by convection‐enhanced delivery using a stereotaxic neurosurgical procedure.

Methods

AVB‐101, a recombinant AAV9 vector, was designed to minimise vector dose and to restrict PGRN expression to neurons by engineering a cassette that includes (i) a codon‐optimised GRN sequence, (ii) PGRN expression enhancers and (iii) a neuron‐specific promoter. In vitro experimental testing of the construct was initially conducted in neuronal cultures. Efficacy studies were conducted in Grn knockout mice. Biodistribution studies were conducted first in sheep to optimize the route of administration and extended to non‐human primates (NHPs) to assess the safety and tolerability of AVB‐101.

Results

AVB‐101 induces robust levels of PGRN expression in neurons when tested in vitro. In vivo, AVB‐101: (a) can suppress neuronal lipofuscinosis even at the lowest dose tested in Grn null mice; (b) in sheep resulted in dose‐dependent and widespread cortical and basal ganglia PGRN expression even at doses lower than commonly used with direct cerebrospinal fluid delivery modalities; (c) results in no expression of PGRN outside the CNS regardless of the animal model used; (d) in NHPs was well tolerated, with no mortality or clinically evident adverse effects; (e) in sheep and NHP drives PGRN expression to human‐equivalent physiological levels in the temporal and frontal lobes, which are the cortical regions most severely affected in FTD‐GRN.

Conclusions

The preclinical data suggest that intrathalamic infusion of AVB‐101 constitutes a novel and promising approach to supplement PGRN in the CNS, supporting the clinical development of AVB‐101 for FTD‐GRN.
Computational search for the interactors of alternatively spliced TREM2 isoforms
Authors: Liang Junyi , Menon Aditya Aditya , Tomco Taylor , Bekris Lynn M. ,   Group of GMI staff Dr. Lynn Bekris
Published: January 2025

Background

Alzheimer’s disease (AD) hallmarks are amyloid plaques and tau tangles. APOE and TREM2 are the strongest genetic risk factors for AD. Triggering receptor expressed on myeloid cells 2 (TREM2) is increasingly recognized to play a central role in amyloid beta clearance and microglia activation in AD. TREM2 has several described ligands, including amyloid beta, apoE and tau. It is known that canonical full‐length TREM2 interacts with DAP12 which in turn activates downstream pathways. One study describes TREM2 interaction with TMEM59 as a regulator TMEM59 protein degradation through cell membrane protein–protein interaction. Three TREM2 alternative splicing isoforms have been described. Little is known about protein–protein interactions with all of three of these TREM2 isoforms. The hypothesis of our study is that full‐length TREM2 and its alternative splicing isoforms interact with other undescribed proteins. The aim of this study was to perform a systematic computational search for new interactors of different TREM2 isoforms by employing several state‐of‐the‐art structural bioinformatics tools, from initial large‐scale screening to identify a one‐on‐one corroborative simulation and fine visualization.

Method

ProteinPrompt software random forest method was used to scan mega libraries in the Homo sapien proteome to identify potential interactors of TREM2 isoforms. The top 5 predictions from ProteinPrompt were simulated in PEPPI, in order to verify the authenticity of the interactions. The TREM2 isoforms and their newfound interactors, identified by ProteinPrompt and validated by PEPPI, were then built into heterodimeric complex in AlphaFold Multimer.

Results

CD9, a cell surface glycoprotein involved in cell‐cell adhesion and migration, was identified as a new interactor for two TREM2 isoforms. CALM, a calcium binding protein involved in calcium metabolism, was identified as a new interactor for a third TREM2 isoform.

Conclusion

The predicted interaction of CD9 or CALM with TREM2 isoforms suggests a possible role of TREM2 in cell adhesion and calcium regulation. Both cell adhesion and calcium regulation are two biological systems previously implicated in Alzheimer’s disease.
Positive Carrier for MAPT
Authors: Jacobs Linde L ,   Cure MAPT FTD
Published: January 2025

Dementia was a condition I was aware of from a very young age as I witnessed my grandmother decline, and my mother step into the role as a caregiver, health care director and power of attorney. I was taught the foundation for this process by direct observation of my mother’s actions. One aspect of caregiving that isn’t teachable is the emotional pain, anguish, sadness and guilt that often accompanies that role. My mother started exhibiting symptoms of FTD in 2010, right as I was graduating college. Despite having a family history, it took 8 harrowing years to receive a correct diagnosis and genetic testing. It was then confirmed that my family possesses the MAPT mutation causing bvFTD. My mother passed away in 2021 at the age of 62. Shortly after her passing, I learned that I was a positive carrier for the MAPT gene as well.

This started a new mission by using my past experience, to change the present, in hopes for a future. Currently, my future is not a guarantee, but I will not wait for the next 10 years hoping for a cure by staying quiet. Instead, I am using this time of waiting to use my voice and failed experiences with my mother, to motivate change, understanding and awareness for FTD. Further, I am using the knowledge of my genetic status to engage with the scientists and researchers to help in ways I am capable of driving progress forward. Being honest about the psychosocial implications genetic testing has on a person is that this test doesn’t have to render them useless, but use it to propel them forward. I look toward the future with hope knowing that the community fighting this disease is doing everything they can to find a solution. If there isn’t light at the end of my tunnel, I hope the light of the journey I led will burn so bright with persistence, strength and perseverance that my daughters will have the resilience to survive another generation of caregiving. All while they await their unpromised future because of genetic MAPT FTD.
Connection between APOE4 and tau is mediated via amyloid‐beta and Alzheimer’s co‐pathologies in human autopsy brains
Authors: Gawor Klara , Verrept Sam , Laureyssen Celeste , Tomé Sandra O. , Vandenberghe Rik , Vandenbulcke Mathieu , Van Damme Philip , von Arnim Christina , Otto Markus , Ghebremedhin Estifanos , Ronisz Alicja , Ospitalieri Simona , Blaschko Matthew , Van Dongen Jasper , Sleegers Kristel , Thal Dietmar Rudolf
Published: January 2025

Background

Alzheimer’s disease (AD) brains commonly exhibit various co‐morbid pathologies, with cerebral amyloid angiopathy (CAA) being the most prevalent, affecting 70‐90% of patients. CAA can be restricted to medium and large vessels or extend to capillaries. Additionally, AD patients often show pathologies involving phosphorylated‐TDP‐43 (pTDP‐43) and alpha‐synuclein (αSyn), typically demonstrating an amygdala‐predominant subtype. The apolipoprotein E ε4 allele (APOE ε4) is a major genetic risk factor for Amyloid Beta (Aβ) pathology, but uncertainties remain regarding its impact on phosphorylated‐tau (pTau) and pTDP‐43.

Methods

To address this knowledge gap, we conducted a neuropathological examination of 237 brains, including 89 AD patients. We assessed pTau stages, Aβ phases, capillary involvement in CAA, and the presence of pTDP‐43 in the hippocampus. We also examined αSyn in the medulla oblongata, identifying the amygdala‐predominant variant using additional staining. APOE genotyping was performed on all individuals from frozen or paraffin‐embedded brain tissue.

Results

Our structural‐equation model revealed interrelationships among AD‐related neuropathologies, APOE, and age. We confirmed previous findings on substantial influence of the APOE ε4 allele on Aβ levels. We also identified an equally robust effect on capillary CAA, even after adjusting for the impact of Aβ on this pathology. Amygdala‐predominant αSyn was also affected by the presence of an APOE ε4 allele. Significant associations were observed between pTau and all measured pathologies. Importantly, after accounting for interactions, APOE ε4 showed no effect on pTau and pTDP‐43.

Conclusions

Our study suggests that APOE ε4 primary influence on pathological Tau is likely mediated through associations with Aβ, capillary CAA, and amygdala‐predominant αSyn. Similar conclusions might hold for APOE ε4 and p‐TDP‐43, although further confirmation with a larger sample size is needed. Despite indications from animal models, our results suggest that the impact of APOE ε4 on pTau in the human brain may be minimal, linked to its high interconnection with other brain pathologies.
Targeting protein O‐Glcnacylation to rescue cognitive defects and Alzheimer‐like signatures in a mouse model of down syndrome
Authors: Domenico Fabio Di , Lanzillotta Chiara , Prestia Francesca , Tramutola Antonella , Barone Eugenio , Perluigi Marzia
Published: January 2025

Background

Disturbances of protein O‐GlcNAcylation have pointed out as a possible link between altered brain metabolism and cognitive decline. We previously demonstrated the disruption of O‐GlcNAcylation homeostasis, as an effect of altered OGT and OGA regulatory mechanism, and we confirmed the relevance of O‐GlcNAcylation in the appearance of Alzheimer disease hallmarks in the brain of a murine model of Down syndrome (DS). Furthermore, we provide evidence for the neuroprotective effects of brain‐targeted OGA inhibition (Thiamet G). The primary objective of this study is to provide evidence for the neuroprotective effects of brain‐targeted OGA inhibition (Thiamet G) by analyzing mice cognition and molecular pathways associated with Alzheimer‐like neurodegenenration.

Method

The neuroprotective effects of Thiamet G was evaluated in DS mice by analyzing mice performances in the novel object recognition and Y maze tests. Furthermore we analyzed by immunochemical methods APP and tau modification, and by proteomic approach using ESI‐MS/MS technique, we identified brain proteins whose O‐GlcNAcylation levels resulted significantly modulated by the treatment.

Result

Data supported the beneficial effect Thiamet G in DS mice hippocampus. The rescue of OGA activity was able to restore protein O‐GlcNAcylation, rescue cognitive impairments and reduce AD‐related hallmarks. In particular, the recovery of O‐GlcNAcylation was associated with the modulation of protein specific O‐GlcNAc levels occurring to several components of neuronal architecture, stress response mechanisms and energy production.

Conclusion

Our work emphasizes the central role of altered protein O‐GlcNAcylation in DS neuropathology and lays the foundations to consider the rescue of protein O‐GlcNAcylation as a valuable therapeutic strategy to reduce the alterations of brain metabolism and the development of AD‐hallmarks.
Will I get dementia? – Symptoms and worries of individuals affected by subjective cognitive decline
Authors: Kiene Franziska , Hildebrandt Helmut , Roheger Mandy
Published: January 2025

Background

Subjective cognitive decline (SCD) is a condition, where individuals report persistent decline of cognitive abilities, even though this decline is not detectable by neuropsychological screenings. Individuals with SCD are at a higher risk of suffering from mild cognitive impairment (MCI) and Alzheimer’s disease (AD) in the future. It is important to better understand SCD to develop prevention measures, before a transition from a possible preclinical stage to MCI and AD.

Method

To get an insight into SCD symptomatology, focus group discussions with individuals affected by SCD were conducted. A comprehensive neuropsychological assessment was done beforehand. Focus groups were audio‐recorded, transcribed and analyzed with MAXQDA. Content analysis was performed using inductive and deductive approaches.

Result

4 group discussions with 16 participants in total (11 female, 5 male) were conducted. Although, a decline was reported for each cognitive domain (attention, memory, orientation, visuocognition, speech, executive functioning, learning), participants especially reported a decline of abilities typically impaired in AD: word‐finding, episodic memory and orientation, with declining word‐finding being amongst the first noticed symptoms, most frequently expressed and heavily affecting, as it leads to social withdrawal due to difficulties in conversations. Participants also frequently mentioned a declining prospective memory, short term memory and working memory. Individuals with SCD are especially concerned about a progression of decline and suffering from AD in the future. 9 participants already sought medical help due to SCD.

Conclusion

SCD as a possible preclinical stage of AD needs to be further researched. Although, individuals with SCD are experiencing impairments in their everyday life, they are not receiving support within the German health care system, as often no objectifiable cognitive impairments are detected by simple screening tools. Therefore, results of this study will be used to develop a questionnaire for measuring SCD. The aim is to develop an ambulatory SCD questionnaire to categorize the subjective feeling of cognitive decline and to identify subjects which should be assessed thoroughly.
Atherosclerosis in carotid arteries associated with cerebrovascular lesions
Authors: Pontes Beatriz Carvalho , Leite Renata Elaine Paraizo , Farias‐Itao Daniela Souza , Barbosa Maria Eduarda , Braga Maria Eduarda , Yahagi‐Estevam Maristella , Paes Vitor Ribeiro , Justo Alberto Fernando Oliveira , Pasqualucci Carlos Augusto , Grinberg Lea T. , Nitrini Ricardo , Jacob‐Filho Wilson , Suemoto Claudia Kimie
Published: January 2025

Background

The atherosclerotic plaque in carotid arteries has been associated with dementia. Clinic radiological studies in older adults suggest that the composition of atherosclerotic plaque in the carotid artery can predict vascular dementia (VD) or mixed dementia. The proposed study aims to assess components of atherosclerotic plaques in the carotid arteries, particularly concerning cerebrovascular lesions using racially diverse autopsy samples.

Method

We used data from the Biobank for Aging Studies at the University of São Paulo Medical School. We included participants aged 50 years or older at the time of death with a post‐mortem interval of less than 24 hours and a next of kin who had at least weekly contact with the deceased (n = 505). The plaque composition was evaluated using the Atherosclerotic Plaque Analyzer (APA) software. Cerebrovascular lesions included lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy evaluated microscopically in 13 samples areas. Logistic regression models adjusted for sociodemographic and clinical variables were used to investigate the associations between plaque composition and cerebrovascular deceased.

Results

After the exclusions for missing data, 193 participants were included (mean age 79.4±10.0 years, 51.3% were women, and 61% were White) (Table 1). A higher percentage of lipid deposition in the plaque was associated with higher odds of cerebral amyloid angiopathy (OR = 1.01, 95% CI = 1.03; 1.27, p = 0.007). We found no association between the other plaque components and cerebrovascular diseases (Table 3).

Conclusion

In an autopsy study, the deposition of lipids in the carotid atheroma plaque was associated with cerebral amyloid angiopathy. Further autopsy studies in larger samples are needed to confirm our findings.
Characterizing Mild Behavioral Impairment and Its Relationship to Cognition in Community‐dwelling older Latinos from the Boston Latino Aging Study
Authors: Alcina Jorge , Munera Diana , Badillo‐Cabrera Alex L , Félix Nikole A Bonillas , Martinez Lusiana , Giudicessi Averi , Kaplan Elizabeth , Martinez Jairo E. , Vila‐Castelar Clara , Schwab Nadine A , Gomez Liliana A Ramirez , Catalan Marta Gonzalez , Saldana Daniel G , Gatchel Jennifer R. , Quiroz Yakeel T.
Published: January 2025

Background

Latinos represent the fastest‐growing subpopulation of U.S. older adults and are 1.5 times more likely than non‐Latino Whites to be diagnosed with Alzheimer’s disease and related dementias. Mild Behavioral Impairment (MBI) describes emergence of new neuropsychiatric symptoms in individuals over 50, and is associated with late‐life depression, cognitive decline, and dementia. Despite its clinical relevance, the relationship between MBI and dementia risk is poorly understood in diverse populations. Here, we assessed MBI symptoms in older, community‐dwelling Latinos and examined the relationship of these symptoms to objective and subjective cognition.

Method

53 participants from the Boston Latino Aging Study were included, ages 55 years and older, 71% female, mean age 64.13 ± 6.79 years, mean education 12.30 ± 5.12 years, 49 cognitively unimpaired, and 4 with mild cognitive impairment. Objective cognition was measured using the Preclinical Alzheimer’s Cognitive Composite‐5 (PACC5). Neuropsychiatric symptoms were measured with the Mild Behavioral Impairment Checklist (MBI‐C; self‐report) domains of interest motivation and drive (IMD) and mood anxiety (MA). Subjective cognitive decline was assessed with the Cognitive Function Instrument (CFI; self‐report). Associations among MBI‐C domains, CFI, and cognition were examined using Spearman’s correlation, controlling for age, sex, and education.

Result

Mean total MBI‐C IMD domain score was 2.37 ± 3.59, mean total MBI‐C MA domain score was 2.45 ± 3.79 and mean total CFI score was 3.60 ± 3.51. Higher scores on the MBI‐C IMD were associated with higher CFI (r = .606, p < .001) and lower PACC scores (r = ‐.333, p = .015). Higher scores on the MBI‐C MA were associated with higher CFI (r = .384, p = .005). There were no other significant associations.

Conclusion

Community dwelling older Latinos endorsed MBI symptoms of IMD and MA captured using the MBI‐checklist self‐report. MBI IMD symptoms were associated with greater subjective decline and worse objective cognition. Findings underscore the need for screening and management of neuropsychiatric symptomatology in Latino/a/e/x adults, and that such symptoms can be captured using the MBI‐checklist. Future longitudinal studies with larger samples are needed to further understand cognitive effects of neuropsychiatric functioning in Latino/a/e/x and other minoritized groups.
Alzheimer’s disease pathologies are pathogen‐driven
Authors: Hyde Vanesa R. , Zhou Chaoming , Fernandez Juan R. , D'Aiuto Leonardo , Shemesh Or A.
Published: January 2025

Background

Alzheimer’s disease (AD) is diagnosed via postmortem detection of extracellular amyloid beta (Aβ) plaques or oligomers and intracellular hyperphosphorylated tau. These canonical pathologies are key players in AD etiology. A complementary line of research suggests that common human pathogens serve as the initial seeding agents which facilitate the pathologies of AD.

Method

Low (n = 8), mild (n = 9), and advanced (n = 10) Alzheimer’s disease brain samples were subjected to expansion microscopy (ExM), a tissue manipulation method which enables the imaging of biological samples at 40nm resolution. For our purposes, we used a novel version of ExM, decrowding expansion pathology (dExPath), which exposes inaccessible protein epitopes to antibody staining while enabling super resolution imaging. Observations from these human brain samples were then modeled using human iPSC neuronal 3D brain organoids and primary rodent cultures.

Result

Using dExPath, we visualized pathogen‐related proteins within our Alzheimer’s disease human brain samples. We discovered a clear colocalization between AD pathologies and pathogen‐derived proteins. When utilizing human brain organoids and rodent cultures as model systems for the human brain, we used pathogen infection to replicate the AD pathologies observed in the AD human brain.

Conclusion

Our results suggest that (1) neurons exposed to pathogens produce human AD pathologies and (2) AD pathologies may be antimicrobial. With these important roles in mind, our continued research focuses on isolating the mechanisms by which AD pathologies arise in response to common pathogens.
Exploring Protective Alleles in the Pathogenesis of Alzheimer’s Disease Using Mouse Models
Authors: Green Kim N.
Published: January 2025

Background

Several variants have been identified that protect against the development of Alzheimer’s disease (AD). Understanding how these alleles convey protection inform us not only about the disease pathogenesis, but also guide therapeutic strategies. The UCI MODEL‐AD consortium has developed several protective alleles including a putative gain of function variant of ABCA7, and the APOE Christchurch variant. Here we have explored the impacts on these variants in animal models of AD to elucidate their mechanisms of protection.

Method

CRISPR‐Cas9 was used to introduce either murine equivalent of ABCA7 V1613M, or APOE R136S (Christchurch) into the murine genome. Mice were then bred to homozygosity with either the 5xFAD mouse model of amyloidosis (Abca7 and Apoe), or the PS19 mouse model of tauopathy (Apoe), and then phenotyped across multiple ages using histology, biochemistry, and single cell spatial transcriptomics and proteomics.

Result

Abca7V1613M variant dramatically reduced Ab production, protected against the formation of parenchymal plaques, and against increases in cortical and plasma neurofilament light chain. ApoeR136S produced divergent effects in glial populations depending on the stimulus. In 5xFAD mice it decreased plaque number and size, and increased the microglial response to the plaques, as evidenced by upregulated disease associated gene expression and protein expression. In PS19 mice tau pathology was mildly increased, but the glia response was markedly suppressed with ApoeR136S. Plasma neurofilament light chain was reduced by ApoeR136S in 5xFAD mice but not PS19 mice.

Conclusion

We highlight that the primary mechanism of ABCA7 appears to be via the production of Ab and plaques. On the other hand, APOE Christchurch dramatically effects glial responses to pathology, notably increasing microglial reactivity to plaques, but markedly suppressing their response to tauopathy.
CD14 in Salt‐Sensitive Hypertension‐Related Cognitive Impairments
Authors: Tang Chengyun , Burns Emily , Border Jane J. , Bunn David , Cantwell Cameron , Gregory Andrew , Johnson Claire , Dong Yanbin , Roman Richard J. , Mattson David L , Fan Fan
Published: January 2025

Background

Hypertension is a leading risk factor for the development of Alzheimer’s disease and Alzheimer’s disease‐related dementia (AD/ADRD), which is closely linked with cerebral vascular inflammation and dysfunction. We previously found that high‐salt‐treated Dahl Salt‐Sensitive (SS) rats displayed blood‐brain barrier (BBB) leakage, astrocyte activation, neurodegeneration, and cognitive impairments. CD14 functions in the Toll‐like receptor 4 (TLR4) complex to initiate proinflammatory signaling events in response to LPS. CD14 levels were elevated in the brains of human and animal AD/ADRD models. This study aims to explore the vascular contribution of CD14 to AD/ADRD.

Method

The expression of Cd14 was assessed through RT‐PCR in primary cerebral vascular smooth muscle cells (VSMCs) isolated from TgF344‐AD rats, and the results were compared to cells from control rats. The myogenic response of the middle cerebral artery (MCA) was compared between SS (SSCD14+/+), SSCD14‐/‐, and SD rats with and without the induction of hypertension with 4% NaCl diets. BBB function was detected by the leakage of injected Evans blue and fibrinogen. Brain cytokine levels were detected with Bio‐Plex Rat Cytokine 23‐Plex Assay.

Result

Cd14 emerged as one of the significantly upregulated top genes in high‐salt‐fed SSCD14+/+ rats, with a subsequent three‐fold increase observed specifically in cerebral VSMCs of AD compared with control rats. Hypertensive SSCD14+/+ rats exhibited an impaired myogenic response of the MCA compared to normotensive SSCD14+/+ rats and SD rats fed with both high‐ and low‐salt diets. Notably, the deletion of CD14 demonstrated a remarkable trend in enhancing the myogenic response of the MCA in female SSCD14‐/‐ rats. Furthermore, high salt‐fed 24‐week SSCD14+/+ rats displayed BBB dysfunction. An augmented pan‐cytokine panel was observed in low salt‐fed 12‐week SSCD14+/+ rats, and this effect was magnified in high salt‐fed 24‐week SSCD14+/+ rats.

Conclusion

These results collectively point to the potential role of CD14 in influencing vascular and immune responses, suggesting a link between CD14, hypertension, and cerebrovascular pathologies, particularly in the context of AD. Additional investigations are warranted to delve into the underlying mechanisms and ascertain whether CD14 exhibits a sex‐specific role in AD/ADRD.
Deep learning resolves cell‐type specific transcriptomes and unveils synaptic changes associated with neurodegeneration
Authors: Berson Eloise , Perna Amalia , Phongpreecha Thanaphong , Aghaeepour Nima , Montine Thomas J.
Published: January 2025

Background

Single nucleus RNA sequencing (snRNA‐seq) has revolutionized our ability to dissect transcriptional profiles in specific cell types. While nuclear sequencing enhances analysis robustness, it captures only 20‐50% of the cellular transcriptional information, limiting our comprehensive understanding of the cellular transcriptional ensemble. Therefore, we propose a computational approach to extract the cellular signal from bulk transcriptomic data from brain tissue, allowing us to investigate cell type‐specific transcriptomic programs underlying neurodegeneration.

Method

We adapted Cellformer ‐ a deep learning deconvolution model for ATAC‐seq data ‐ to RNA‐seq data. We leverage an excitotoxicity mouse model to detect cell‐type specific transcriptomic responses to injury.

Result

Cellformer accurately deconvoluted mouse brain bulk RNA into 9 major cell types (mean Pearson correlation of 0.97) (Figure 1A). Validation with single nucleus datasets reveals a significantly higher correlation (0.85) within the same cell type compared to different cell types (0.20) (P‐value < 1e‐6) (Figure 1B).

We applied Cellformer to bulk RNAseq data obtained from both tissue and nuclei isolated from the hippocampus of the same mouse. We compared these cell‐type‐specific transcriptomic signatures between healthy mice and those exposed to a low dose of Kainic Acid (KA), a potent toxin for excitatory neurons (Figure 1C). More shared information was found between snRNA and deconvoluted RNA from nuclei compared to deconvoluted tissue (Figure 1D). Interestingly, differential expression analysis revealed a greater effect of low‐dose KA exposure on deconvoluted bulk tissue compared to nuclei, pinpointing synaptic and lysosomal signaling to excitatory neuronal cells (Figure 1E‐F).

Conclusion

In this study, we introduce a computational approach utilizing the Cellformer algorithm to deconvolute bulk RNA sequencing data into cell‐type‐specific profiles, enabling in‐depth analysis of bulk RNAseq datasets. We demonstrate Cellformer’s proficiency in recovering cell‐type‐specific RNA expression patterns. By comparing deconvoluted profiles between healthy and injured hippocampi, we unveil insights previously masked by the limitations of snRNA‐seq, revealing intricate synaptic signaling dynamics. Cellformer offers the unprecedented ability to investigate extranuclear signaling in neurodegeneration.