bluuebunny/crossref_metadata_2025 huggingface dataset:
MiR‐223‐3p plays a role in sex‐biased intercellular communication between macrophages and microglia
Authors: Prajapati Paresh , Geleta Urim , Wang Wang‐Xia
Published: January 2025

Background

The characterization of intercellular communication between peripheral immune cells and the central nervous system (CNS) are essential for understanding the brain’s response to aging and disease states, such as Alzheimer’s disease. MicroRNAs (miRNAs) constitute a class of small non‐coding RNAs that play a crucial role in regulating various biological and pathological processes, including those related to immunity and inflammation. MiR‐223‐3p, residing on the X chromosome, is a pivotal miRNA involved in the inflammatory response, with its expression being enriched in macrophages/microglia. However, the impact of miR‐223‐3p on the intercellular communication and the subsequent neuroinflammation remains unclear.

Method

MiR‐223‐3p knockout (KO) and genetic background matched wildtype (WT), female and male mice were used in the studies. Microglia were isolated from the brain tissues of 3‐week‐old pups and enriched using the EasySep™ Mouse CD11b Positive Selection Kit. Bone marrow‐derived macrophages (BMDMs) were isolated from 6 months old mice. Microglia isolated from WT mice were co‐cultured with BMDMs isolated from 1) female miR‐223‐3p KO, 2) male miR‐223‐3p KO, 3) female WT, and 4) male WT mice. The BMDMs were pre‐treated with LPS/IFNγ or vehicle control media before incubating with microglia for 24 hrs. RNAs were then extracted from microglia for RT‐qPCR quantification of inflammatory markers.

Result

Our initial screening of gene expression through RNA‐seq studies reveals that the absence of miR‐223‐3p in bone BMDMs leads to a notable sex‐specific alteration in the expression of immune and inflammatory genes. RT‐qPCR analysis of microglia revealed a distinct alteration in the expression of inflammatory genes when co‐cultured with KO BMDMs relative to WT BMDMs. In particular, microglia co‐cultured with BMDMs from KO mice induced a substantial expression of IL1b, TNFα, CXCL10, H2Aa, H2EB1, and APOE compared to WT mice. Nevertheless, strong induction of CD86 was observed in microglia co‐cultured with male KO BMDMs compared to that of female KO BMDMs, while APOE, H2Ab1, and CD74 were higher in microglia co‐cultured with female KO BMDMs.

Conclusion

These preliminary results suggest that the expression of miR‐223‐3p in peripheral macrophages may play an important role in sex‐biased inter‐cellular communication that ultimately will impact the inflammatory response in the CNS.
Alterations in gut microbiome composition, function, and rhythmicity are modulated by time‐restricted feeding in Alzheimer’s disease mice accompanying rescue of brain pathology and memory
Authors: Whittaker Daniel S. , Maissy Erica S , Richter R. Alexander , Zuffa Simone , Ramos Stephany Z Flores , Zarrinpar Amir , Desplats Paula
Published: January 2025

Background

Studies using Alzheimer’s disease (AD) models suggest that gut bacteria contribute to amyloid pathology and systemic inflammation. Further, gut‐derived metabolites serve critical roles in regulating cholesterol, blood‐brain barrier permeability, neuroinflammation, and circadian rhythms. Recent studies from the Alzheimer’s Disease Neuroimaging Initiative have shown that serum‐based gut‐derived metabolites are associated with AD biomarkers and cognitive impairment. We recently reported a time‐restricted feeding (TRF) intervention that restored brain transcription, increased Aβ clearance, reduced amyloid deposition, and improved memory deficits in AD mice (PMID:37607543). Here we investigated gut microbiome alterations in the APP23 mouse stool and terminal ileum and evaluated the role of the microbiome and metabolome in the beneficial effects of TRF.

Methods

Adult male and female APP23 transgenic (TG) and littermate non‐transgenic (NTG) mice (n = 3‐4/sex/genotype/condition) underwent ad libitum feeding (ALF) or a TRF protocol consisting of 6‐hours of active‐phase feeding followed by 18‐hours fasting for 3‐months. Metabolomics, metagenomics and metatranscriptomics were performed on ileum and stool (collected every 4‐hours for 24‐hours) from mice used in our TRF intervention study.

Results

Metagenomic analyses revealed that the stool microbiome composition and genomic functions were altered in APP23 TG compared to NTG mice and were further uniquely modulated in TG mice on TRF. Notably, stool metabolites relating to metabolism and neuroimmune function were differentially abundant in TG mice and partially restored by TRF. The stool microbiome and metabolome presented distinct diurnal cycling dynamics. TG mice showed a significant loss of rhythmic genomes which were markedly increased by TRF, indicative of broad entrainment of microbial rhythmicity. Ileal diurnal dynamics further differentiated TG mice on TRF. Ileal metatranscriptomic analysis revealed that TRF also reversed bacterial compositional and functional alterations in TG mice, including the attenuation of elevated inflammation‐related bacterial transcripts.

Conclusions

TG mice showed alterations in microbiome composition, function, and rhythmicity. The unique microbiome induced by TRF regulated functions and metabolites implicated in AD and may represent one of the pathways by which TRF rescued pathology and cognition in AD mice.
Antagonism between Hyperphosphorylated Tau and Heme Oxygenase‐1 in Alzheimer’s Disease
Authors: Hagar Hsiao‐Tien Chien , Kuo Min‐Hao
Published: January 2025

Background

Abnormal phosphorylation of tau is key to Alzheimer’s disease progression. The details of cellular dysfunction or death caused by hyperphosphorylated tau remain unclear. It is crucial to understand the mechanism for drug design. We use our PIMAX system to synthesize hyperphosphorylated tau that causes cell and neuron death at low‐micromolar concentrations. This work reveals the likely relationship between heme oxygenase 1 and pathological tau.

Methods

To understand the molecular underpinnings by which p‐tau kills cells, we used label‐free mass spectrometry to examine the proteomic changes of the SH‐SY5Y neuroblastoma cells after six‐hour treatment with 1 µM of recombinant hyperphosphorylated tau (p‐tau). HO‐1 reduction was among the most prominent alterations instigated by p‐tau. Accordingly, we then tested the hypothesis that HO‐1 deficiency was key to cell death following p‐tau treatment by examining whether supplying extra HO‐1 to cells treated with p‐tau would exhibit resistance. Lastly, we examined the physical interaction between HO‐1 and p‐tau by photo‐crosslinking.

Result

One micromolar of p‐tau causes drastic morphological changes and death of cells after 16 – 20 hours of treatment. Six hours after the addition of p‐tau, SH‐SY5Y cells still maintained normal morphology, but mass spectrometry revealed conspicuous proteomic changes, among which heme oxygenase‐1 (HO‐1) showed the most significant reduction, whereas several other proteins were upregulated under the same condition. The role of HO‐1 in p‐tau mediated cell death was confirmed by the observations that SH‐SY5Y cells exhibited increased resistance to p‐tau if HO‐1 was overexpressed or when cells were co‐treated with recombinant p‐tau and HO‐1 proteins. HO‐1 protects cells likely through a direct interaction with p‐tau because photo‐crosslinking resulted in a high‐molecular‐weight protein complex detectable by both tau and HO‐1 antibodies.

Conclusion

Hyperphosphorylated tau likely physically sequesters HO‐1 as part of the mechanisms of tau pathology. Upregulating HO‐1 confers cellular resistance to hyperphosphorylated tau. Our observations can help the design of reagents targeting the interface between p‐tau and HO‐1. Such reagents may have therapeutic potentials for Alzheimer’s disease and other tauopathies.
Persistently elevated AD risk in hiPSC‐derived cortical neurons after developmental and adult Pb exposure
Authors: Xie Junkai , Zhao Han , Wu Shichen , Bowman Aaron B , Freeman Jeniffer , Yuan Chongli
Published: January 2025

Background

Exposure to environmental chemicals such as lead (Pb) during vulnerable developmental periods and even in adult stage can result in adverse health outcomes later in life. Human cohort studies have demonstrated associations between Pb exposure and Alzheimer’s Disease (AD) onset in later life which were further corroborated by findings from animal studies. The molecular pathway linking Pb exposure and increased AD risk, however, remains elusive.

Method

In this work, we used human iPSC‐derived cortical neurons as a model system to study the effects of Pb exposure on AD‐like pathogenesis in human cortical neurons. We exposed neural progenitor cells and differentiated neurons derived from human iPSC to Pb concentrations of 0, 15, and 50 ppb for 48 hours, simulating developmental and adult Pb exposure, respectively. Various techniques, including immunofluorescence, Western blotting, RNA‐sequencing, enzyme‐linked immunosorbent assay (ELISA), microelectrode array (MEA), and Förster resonance energy transfer (FRET) reporter cell lines, were employed to assess changes in AD‐like pathogenesis in differentiated cortical neurons. The susceptibility of Pb‐exposed neurons to cellular stressors such as PHF‐Tau and MPP+ was evaluated through secondary stress assays.

Result

Exposing neural progenitor cells to low dose Pb, mimicking a developmental exposure can result in altered neurite morphology. Differentiated neurons exhibit altered calcium homeostasis, synaptic plasticity, epigenetic landscape along with elevated AD‐like pathogenesis markers, including phosphorylated Tau, Tau aggregates and Aβ42/40. Furthermore, Pb‐exposed cortical neurons exhibited significantly increased calcium dynamics and overall neuronal activity. Adult neurons exposed to Pb demonstrated heightened vulnerability to PHF‐Tau and MPP+‐induced cytotoxicity, with these changes persisting even after Pb withdrawal.

Conclusion

Collectively, our findings propose a plausible molecular mechanism to account for the increased risk of AD in populations with a history of Pb exposure.
Aβ‐ and Tau‐Mediated Neuronal Excitability Derived from fMRI Predicts Grey Matter Atrophy in Alzheimer’s Disease
Authors: Sanchez‐Rodriguez Lazaro M , Bezgin Gleb , Carbonell Felix , Therriault Joseph , Arias Jaime Fernandez , Servaes Stijn , Rahmouni Nesrine , Tissot Cécile , Stevenson Jenna , Rosa‐Neto Pedro , Medina Yasser Iturria
Published: January 2025

Background

Despite amyloid‐β (Aβ) plaques and tau neurofibrillary tangles being recognized as major Alzheimer’s Disease (AD) hallmarks, their synergistic contribution to neuronal activity remains unclear. We developed a neuroimaging‐based personalized brain activity model to assess the in‐vivo functional impact of AD pathophysiology. In previous reports, model‐inferred neuronal excitability predicted disease progression (i.e., cognitive performance and certain biological markers) [1,2]. Here, we investigate its relationship with brain tissue atrophy.

Method

We used Aβ and tau PET scans, structural T1‐weighted 3D MRI and resting‐state functional MRI from 132 subjects in the TRIAD cohort (https://triad.tnl‐mcgill.com/, Fig. 1a). The participants were diagnosed as cognitively unimpaired (CU, N = 81, 71.15 ±7.73 yrs, 63 F), mild cognitive impairment (MCI, N = 35, 72.1±7.84 yrs, 17 F) or Alzheimer’s disease (AD, N = 16, 69.45 ± 9.10 yrs, 8 F).

In our whole‐brain neuronal activity model, the individual regional Aβ and tau burdens mediate neuronal excitability (Fig. 1b). By maximizing the similarity between simulated and real resting‐state signals, we estimated the contributions by Aβ, tau and their interaction (Aβ∙tau). A post‐hoc correlation analysis sought to determine if the reconstructed excitability values aligned with grey matter atrophy assessed via voxel‐based morphometry.

Result

Fig. 1c (left) presents the relationship between average intra‐brain grey matter volume and the obtained excitability values. Reduced grey matter volume significantly associated with the participants’ neuronal hyperactivation. Such a behaviour was additionally observed in region‐specific analyses, particularly at brain regions with grey matter alterations by AD, including the parahippocampal gyrus, fusiform gyrus, amygdala, hippocampus, entorhinal cortex and posterior cingulate gyrus (Fig. 1c, center). The effect of Aβ and tau’s interaction on neuronal excitability was the only variable of interest predicting grey matter volume (Fig. 1c, right).

Conclusion

The computationally derived excitability values inversely correlated with grey matter volumes at the brain regions that most prominently showcase neurodegeneration in AD. Our results are consistent with previous observations [1,2] of increased excitability in parallel with pathological spread and the loss of neurons in the AD brain, also highlighting the fundamental role played by Aβ and tau functional interactions.

References

[1] Sanchez‐Rodriguez et al, 2023 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10370127

[2] Sanchez‐Rodriguez et al, 2023 https://doi.org/10.1101/2023.09.15.557737
Proteomic characterization of the TgF344 AD rat model of Alzheimer’s disease as a function of disease and therapeutic treatment
Authors: Chaubey Kalyani , Voorhees Jaymie , Vázquez‐Rosa Edwin , Yu Youngmin , Wang Xinming , Barker Sarah , Franke Kathryn , Cintrón‐Pérez Coral , Williams Noelle S. , Paul Bindu D , Pieper Andrew A.
Published: January 2025

Background

Alzheimer’s disease (AD) is a severe neurodegenerative condition that affects millions of people worldwide. The TgF344 AD rat model, which exhibits early depression‐like behavior followed by later cognitive impairment, is widely used to evaluate putative biomarkers and potential treatments for AD. The P7C3 neuroprotective compounds have shown protective efficacy for both brain pathology and neuropsychiatric impairment in this model. To better understand the underlying pathophysiology and the mechanisms underlying therapeutic protection, we are investigating the associated changes in signaling pathways.

Method

We conducted unbiased label‐free proteomic analysis of AD rat brains. Animals were treated daily for 6 months with either P7C3 compounds or vehicle, from 9 months of age to 15 months of age. At 15 months of age, cognitive function and depression‐like behavior were evaluated, and brain tissue was isolated for the proteomic study. Differentially expressed proteins in AD and AD animals treated with P7C3 compounds were categorized into functional categories and pathways to provide insight into disease pathology and treatment.

Result

At this stage, rats had developed depression‐like behavior, but did not yet display cognitive impairment. We found 855 differentially expressed proteins in AD vehicle rats compared to WT littermate vehicle rats. Interestingly, 125 of these proteins returned to normal WT levels in AD animals treated with P7C3. Our study showed that major metabolic pathways and pathways related to neurodegeneration were highlighted at this time point. Most of these metabolic and neurodegenerative pathway‐related proteins returned to normal levels in TgF344 AD rats treated with P7C3 compounds.

Conclusion

Pathway analysis of the differentially expressed proteins in AD that were normalized by P7C3 treatment were enriched in oxidative phosphorylation, glycolysis, tricarboxylic acid cycle, autophagy, tight junction, steroid and bile acid biosynthesis pathways. This provide insights into the pathophysiology of this AD model and complementary insights into future therapeutic opportunities.
Cross‐species systems biology target prioritization leads to the development of antisense oligonucleotides as a potential therapeutic approach for progressive supranuclear palsy
Authors: Min Yuhao , Wang Xue , Bergman Jeremiah , Sotelo Katie D , Reddy Joseph S. , Quicksall Zachary , Nguyen Thuy , Mitchell Adriana O , Dickson Dennis W. , Kawatani Keiji , Inoue Yasuteru , Kanekiyo Takahisa , Allen Mariet , Is Ozkan , Ertekin‐Taner Nilüfer
Published: January 2025

Background

Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.g. Alzheimer’s disease), we systematically integrated multi‐omics data from human brains of PSP and control donors with cross‐species validation to nominate high‐confidence therapeutic targets. We plan to translate our findings into safe and effective treatments for PSP using antisense oligonucleotides (ASO).

Method

We analyzed brain gene expression profiles in PSP and control individuals at bulk tissue (N = 408) and single‐cell levels (snRNAseq, N = 36). Cell‐type‐specific expression perturbations were systematically prioritized using a cross‐species validation paradigm, including rTG4510 tau mice and tau‐overexpressing Drosophila models. We conducted in vitro screening of ASO candidates against our prioritized target genes. ASO efficacy and toxicity were measured. RNAseq experiments will be performed to interrogate off‐target effects. The safety and efficacy of the lead ASOs will be assessed in PSP‐patient‐derived iPSC models.

Result

We previously reported discovery of novel genes with significant differential expression in PSP brains, characterized their brain cell‐specificity and validated them using snRNAseq data. We prioritized 21 genes using gene expression data from a mouse tauopathy model. Validation of these 21 high‐priority genes using a Drosophila tau model nominated astrocytic STOM, KANK2, and DDR2 as potential therapeutic targets for PSP. Knocking down their expression in Drosophila significantly rescues tau‐mediated neurodegenerative pathology. In vitro screening identified ASO leads that reduced the target expressions at mRNA and protein levels with low cellular toxicity.

Conclusion

We developed a systems biology pipeline and nominated STOM, KANK2, and DDR2 as candidate gene targets for PSP. We identified ASOs that modulate these targets’ expression without cellular toxicity, suggesting they may be suitable as potential therapeutic candidates. Importantly, the shared pathophysiology and molecular aberrations between PSP and other tauopathies, such as Alzheimer’s disease, suggests that such therapeutic candidates may be repurposed for multiple neurodegenerative diseases, further accelerating, and streamlining the therapeutic pipeline.
The sex related association between TDP‐43 and cognitive function: a population‐based autopsy study
Authors: Silva Caroline Matos , Justo Alberto Fernando Oliveira , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Grinberg Lea T. , Pasquallucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Suemoto Claudia Kimie
Published: January 2025

Background

Transactive DNA‐binding protein 43 (TDP‐43) proteinopathy is associated with neurodegeneration, including LATE and linked to cognitive deterioration. While some research suggests a higher prevalence of TDP‐43 in women, no differences have been identified among racial groups. Nonetheless, the influence of gender on cognition within the context of TDP‐43 remains uncertain. Our objective was to investigate gender and racial distinctions in the relationship between TDP‐43 presence and cognitive function.

Method

Cross‐sectional study in a population‐based sample of 1,164 Brazilians from the Biobank for Aging Studies of the University of Sao Paulo Medical School. We used linear regression to evaluate the association of progressive LATE stages with cognitive abilities evaluated by Clinical Dementia Rating Sum of Boxes (CDR‐SOB). Models were adjusted for sociodemographic (age at death, sex, education, and race), clinical variables (hypertension, diabetes, heart disease, stroke, alcohol consumption, smoking, and body mass index) and neuropathological lesions (Braak staging, CERAD, Lewy body diseases pathology, lacunar infarcts, hyaline arteriolosclerosis and cerebral angiopathy amyloid). Additionally, we investigated the interaction of TDP‐43 pathology with race (white and black) and sex on CDR‐SOB.

Result

Sociodemographic and clinical variables were different between the participants with and without LATE (Table 1). Adjusted analysis, accounting for sociodemographic and clinical factors, revealed a significant association between the presence of LATE and impaired cognitive abilities (β = 5.13, 95% CI = 3.63;6.33, p<0.001). We did not find an interaction between race and LATE (p = 0.73). However, we found a significant interaction between TDP‐43 and sex (p = 0.001) (Figure 1). Upon conducting a stratified analysis, LATE had a more pronounced impact on cognitive abilities in women than in men (Men: β = 2.56, 95% CI = 1.26;3.86, p<0.001; Women: β = 4.94, 95% CI = 3.52;6.36, p for interaction <0.001).

Conclusion

The presence of LATE is associated with poor cognition, particularly in women.
Cerebral vascular mitochondrial function is dependent on APOE genotype and estrogen status
Authors: Kehmeier Mackenzie N , Famiano Alexandra , Leonhardt Thomas A , Ferguson Sky J , Alkayed Nabil J , Walker Ashley E
Published: January 2025

Background

Postmenopausal females who carry an APOE4 allele are at higher risk of late‐onset Alzheimer’s Disease (LOAD) compared to age‐matched APOE4 males. Estrogen deficiency predisposes females to an increased risk of vascular, cognitive and metabolic impairments. Estrogen and APOE genotype are known to impact metabolic and mitochondrial function in the brain, but their effects on cerebral vessels are unknown. Thus, the purpose of this study was to determine the interaction between APOE genotype and estrogen deficiency in relation to cerebrovascular mitochondrial function.

Method

Young female homozygous APOE3 and APOE4 mice (n = 6‐8 per group; 6 months old) fed a high‐fat diet were ovariectomized (“ovx”), ovariectomized and supplemented with 17β‐estradiol (0.36 mg, 60‐day release, “estradiol”), or left intact (“sham”). At 2 months after ovariectomy, a glucose tolerance test (GTT) was performed, then cerebral arteries and arterioles were dissected, incubated in saponin, then assessed for mitochondrial respiration in response to substrates probing carbohydrate metabolism (Oroboros). Data are presented as mean±SEM.

Result

There was an interaction between APOE genotype and ovx/estradiol status in relation to cerebrovascular complex I (CI)‐ (p = 0.04) and complex II (CII)‐coupled respiration (p = 0.04). Additionally, there was a significant effect of genotype, such that vessels from APOE3 mice had greater CI‐coupled respiration than vessels from APOE4 mice (p = 0.02). When examining differences between APOE3 groups, APOE3‐estradiol mice had a 53% greater CI‐coupled respiration than APOE3‐sham mice (15.4±3.4 vs. 7.2±1.2 pmol/(s*mg), p = 0.03) and a 60% greater CI‐coupled respiration than APOE3‐ovx mice (6.2±1.6 pmol/(s*mg), p = 0.007). The APOE3‐estradiol group also had greater CI+CII‐coupled respiration compared to both APOE3‐sham (50.8±7.1 vs. 27.3±1.7 pmol/(s*mg), p = 0.006) and ovx groups (28.0±5.7 pmol/(s*mg), p = 0.009). Interestingly, CI and CI+CII coupled respiration did not differ between sham, ovx, and estradiol in APOE4 mice (p>0.05). Maximal uncoupled respiration was greater in the APOE3 mice than APOE4 mice (p = 0.01). Whole‐body glucose tolerance did not differ between groups (all p>0.05).

Conclusion

Overall, these results indicate that APOE genotype modulates the impact of estrogen on the cerebrovasculature. We found that 17β‐estradiol enhances cerebrovascular mitochondrial function in APOE3 mice but not APOE4 mice. The results suggest that estradiol supplementation may have more therapeutic benefit for APOE4 non‐carriers.
The Association Between Mild Behavioral Impairment‐Apathy Symptoms and Cognitive Symptoms
Authors: Vellone Daniella Alicia , Guan Dylan X. , Ismail Zahinoor
Published: January 2025

Background

Apathy may appear as a less acute late‐life syndrome; however, it is associated with accelerated progression to dementia and contributes to adverse outcomes for patients and caregivers. These findings are not surprising since apathy can cause individuals to forego activities that improve cardiovascular and cognitive health (e.g., exercise), while inadvertently engaging in behaviors associated with greater dementia risk (e.g., social isolation). The objective of this research was to investigate the association between apathy symptoms (in the context of mild behavioral impairment [MBI)]) and cognitive symptoms. We hypothesized that greater MBI‐apathy severity would be significantly associated with greater severity of cognitive symptoms.

Method

All participants enrolled in the Canadian Platform for Research Online to Investigate Health, Quality of Life, Cognition, Behaviour, Function, and Caregiving in Aging (CAN‐PROTECT) aged ≥50 years who had complete MBI‐Checklist (MBI‐C) and Everyday Cognition (ECog‐II) scores were included (n = 1339). Apathy domain scores for interest, initiative, and emotional reactivity were also generated using the six MBI‐C apathy items, and total apathy severity was the sum of all three domain scores. Likewise, ECog‐II domain scores for memory, language, visual‐spatial, and executive function were calculated as the sum of domain items, and total ECog‐II severity was the sum of all domains. Negative binomial regressions (zero‐inflated, if appropriate) assessed associations between total apathy severity and ECog‐II total scores. Domain‐specific analyses were also conducted. Covariates included age, sex, years of education, and non‐apathy MBI (affective dysregulation, impulse dyscontrol, social inappropriateness, psychosis) score.

Result

Across all participants (mean age = 64.5±7.4; 79.5% female), higher MBI‐apathy scores were associated with more severe cognitive symptoms (standardized β [95%CI], 7.2% [4.3‐10.2%]; p<0.001). Higher interest (16.5% [9.4‐24.1%]; p<0.01) and initiative (18.4% [11.9‐25.4%]; p<0.001) apathy domain scores were associated with more severe cognitive symptoms. Total apathy score was also associated with ECog‐II memory (4.9% [2.4‐7.4%]; p<0.001), language (5.6% [2.5‐8.6%]; p<0.001), visual‐spatial (8.3% [3.3‐13.2%]; p<0.01), and executive (10.7% [6.7‐14.7%]; p<0.001) domain scores.

Conclusion

These findings provide valuable insight into the complex interplay between apathy and cognitive function, with potential implications for the development of targeted interventions for those affected by apathy‐related cognitive deficits.
Pathogenic Mechanism of PRNP 2‐Octapeptide Deletion Mutation in Creutzfeldt‐Jakob Disease
Authors: Wu Yiming , Nan Haitian , Zhang Yan
Published: January 2025

Background

Prion diseases are a group of neurodegenerative diseases associated with prion protein. The disease can be caused by mutations in the PRNP gene, the gene that encodes prion protein. An octapeptide repeat on the N‐terminus of prion protein plays an important role in normal intercellular function of prion protein. At present, numerous prion disease patients with PRNP 2‐octapeptide deletion mutation case have been reported, but it is still unclear whether and how the mutation causes the disease. In this study, we aim to preliminarily identify the pathogenicity of PRNP 2‐octapeptide deletion mutation.

Method

The gDNA sample was obtained from a patient with familial creutzfeldt‐Jakob disease. The gDNA was identified to contain heterozygous PRNP 2‐octapeptide mutation deletion. We separated and amplified the gene and constructed N1 plasmid models with overexpression of the gene. Finally, we transfected HEK‐293T cell with the plasmid and used Western Blot to quantify the difference of apoptosis level of the mutated gene group and the control group.

Result

Due to limited sample size, the result shows no significant statistical difference between the experimental group and the control group, but still reflected potential trend of increased apoptosis (p<0.1).

Conclusion

Further study of this mutant gene is necessary to determine its pathogenicity.
Everyday functioning beyond cognition: Using Structural Equation Modelling to explore relationships between cognitive domains and everyday functioning in Alzheimer’s disease
Authors: van der Landen Sophie M. , Postema Merel C. , Tewolde Mukrabe E. , Barkhof Frederik , van Harten Argonde C. , Teunissen Charlotte , van de Giessen Elsmarieke , Ponds Rudolf W. H. , van der Flier Wiesje M. , Rhodius‐Meester Hanneke F.M. , Sikkes Sietske A. M.
Published: January 2025

Background

Alzheimer’s disease (AD) causes increasing cognitive and functional impairments, and both are therefore important outcome measures for intervention studies. Cognition and everyday functioning are often used interchangeably, yet the extent of their relationship is still unclear. We therefore aim to assess the relationship between different cognitive domains and everyday functioning across the AD spectrum.

Methods

In this cross‐sectional study, we included 613 participants (Mean age ± Standard Deviation = 64 ± 8 years, n = 298(52%) female) from the memory‐clinic based Amsterdam Dementia Cohort, who were amyloid‐β positive based on cerebrospinal fluid. Cognitive functions were assessed using a standardized neuropsychological test battery assessing three domains: memory (Rey Auditory Verbal Learning Test (RAVLT) and Visual Association Test (VAT)), executive functioning (Trail Making Test‐B, Digit Span forward and backward, and letter fluency DAT) and language (animal fluency and naming condition of the VAT). Everyday functioning was assessed by the proxy‐based Amsterdam Instrumental Activities of Daily Living Questionnaire (A‐IADL‐Q). Structural equation modelling (SEM) analysis was performed to examine the relationship between each of the cognitive domains (i.e., composite Z‐scores) as independent variables and everyday functioning as dependent variable, adjusted for age, sex and education. The relations between latent variables (cognitive domains) were calculated while accounting for measurement error in observed variables (cognitive tests).

Results

Of the 613 participants, the majority had a dementia diagnosis (n = 443, 72%), followed by mild cognitive impairment (n = 100, 16%) and subjective cognitive decline (n = 70, 11%). The SEM showed good model fit (CFI = 0.822), and confirmed that the latent cognitive domains (identified as memory, executive functioning and language) were substantially explained by their respective observed indicators with standardized estimates ranging from 0.44 to 0.91. Taking into account interdependencies and unexplained variance, the standardized estimate of memory was significantly related to the A‐IADL‐Q, demonstrating that approximately 28% of variance was explained by memory functioning.

Conclusion

Memory performance was found to be uniquely related to difficulties in everyday functioning, although to a limited extent. Our findings suggest that factors beyond cognition substantially contribute to everyday functioning, highlighting that both have independent value as outcome measures.
Language switching and executive control in bilinguals with Mild Cognitive Impairment
Authors: Calabria Marco , Suades Anna , Juncadella Montserrat , Ortiz‐Gil Jordi , Ugas Lidia , Sala Isabel , Lleo Alberto
Published: January 2025

Background

Bilingual Language Control (BLC) is a dynamic processing system that enables speakers to mitigate cross‐language interference while conversing and transitioning between languages. Research indicates that neurodegenerative diseases may compromise the effectiveness of language‐switching abilities in bilingual individuals, particularly those impacting the frontostriatal pathways. However, it remains unclear whether neurodegeneration affecting other neural pathways, such as Mild Cognitive Impairment (MCI), might influence the efficiency of BLC.

Method

The study involved 40 patients diagnosed with MCI and 30 older adults. All participants were proficient bilinguals in Catalan and Spanish and early proficiency in both languages. Each participant engaged in a set of five tasks, including one task focused on language control (language switching) and four non‐linguistic control tasks: task switching, n‐back, Spatial Stroop, and flanker task.

Result

MCI patients exhibited higher switch costs (switch minus repeat trials) compared to healthy controls, while demonstrating similar mixing costs (repeat minus single trials). Within the non‐linguistic control domain, MCI patients showed significant performance deficits only in the n‐back task when compared to controls. The regression analysis model, which incorporated the performance of non‐linguistic tasks as predictors for language switching performance, did not yield statistical significance.

Conclusion

Notably, language control abilities may be compromised in bilingual patients even in the absence of neurodegeneration in brain regions traditionally linked to language selection and inhibition, such as the basal ganglia. Crucially, cognitive decline appears to have a more pronounced impact on language‐switching abilities than on the monitoring of the two languages. However, the existence of language control deficits does not correlate with executive control deficits, suggesting that these two control domains are not entirely overlapping.
Bilingualism and education may have distinct reserve/resilience trajectories: Evidence from white matter changes
Authors: Thanissery Nithin , Kenchaiah Raghavendra , Mekala Shailaja , Jala Sireesha , Khokhar Sunil Kumar , Rajan Amulya , Kashyap Vani , Surampudi Bapiraju , Kaul Subhash , Alladi Suvarna
Published: January 2025

Background

Bilingualism and education have been known to enhance reserve/resilience through white matter (WM) microstructural changes. Reserve/resilience is the ability of the brain to cope with neurocognitive adversities. Two key hypotheses have been proposed under this framework. Firstly, brain reserve, which refers to the structural integrity of the brain to preserve cognitive functioning. Secondly, cognitive reserve, which suggests that cognitive functioning can be maintained despite reduced structural brain integrity. Notably, the concepts of brain reserve and cognitive reserve exist along a continuum of brain health. Given the criticism surrounding bilingual literature due to the potential influence of education, the present study aims to delineate the effects of bilingualism and education (proxy measures of reserve/resilience) on WM integrity.

Method

40 cognitively normal older adults (20 bilinguals and 20 monolinguals) were recruited. Cognitive evaluation was carried out using a set of assessments/tests (see Table 1). Diffusion tensor imaging was done using a 3‐Tesla scanner. Tract‐based spatial statistics was performed. Fractional anisotropy (FA), axial diffusivity, radial diffusivity, and mean diffusivity were assessed.

Result

Bilinguals did not differ from monolinguals in age, sex, and socioeconomic status (Table 1). Bilinguals were more educated than monolinguals. Bilingual older adults had lesser WM integrity (i.e., lesser FA values) compared to monolinguals in the regions that adapt to bilingual experience as well as those that are affected by aging (figure 1). Despite having lesser FA, bilinguals had similar cognitive functioning compared to monolinguals (Table 1). Contrastingly, higher education was associated to higher FA values in several commissural and association WM fibres (figure 1). Education also showed a positive relationship with cognitive scores (figure 2).

Conclusion

The study demonstrate that bilingualism is associated with better cognitive reserve (preserved cognition despite reduced structural integrity), while education is associated with better brain reserve (better structural integrity and cognition). Advances in reserve/resilience theory propose that the neuroprotective effect, which is responsible for better structure (brain reserve) will be followed by a compensatory effect (cognitive reserve) as the structural integrity decline over time. Our study suggests that bilingualism and education may have two distinct reserve/resilience trajectories in the face of age‐related changes.
Involvement of the choroid plexus in Alzheimer’s disease pathophysiology: A mouse and human proteomic study
Authors: Delvenne Aurore , Vandendriessche Charysse , Gobom Johan , Burgelman Marlies , Dujardin Pieter , De Nolf Clint , Tijms Betty M. , Schindler Suzanne E. , Verhey Frans R.J. , Ramakers Inez H.G.B. , Zetterberg Henrik , Visser Pieter Jelle , Vandenbroucke Roosmarijn E , Vos Stephanie J. B. ,   EMIF‐AD MBD study group
Published: January 2025

Background

Structural and functional changes of the choroid plexus (ChP) have been reported in Alzheimer’s disease (AD). Nonetheless, the role of the ChP in the pathogenesis of AD remains largely unknown. We aim to unravel the relationship between ChP functioning and core AD pathogenesis using a unique proteomic approach in mice and humans.

Method

We used an App knock‐in mouse model, AppNL‐G‐F, with amyloid pathology to study the association between AD brain pathology and protein changes in mouse ChP tissue and CSF, using liquid chromatography mass spectrometry. Mouse proteomes were investigated at 7 weeks old (n = 5) and at 40 weeks old (n = 5). Results were compared to human AD CSF proteomic data (n = 496; from EMIF‐AD MBD, Knight ADRC, and Maastricht BB‐ACL studies) to identify key proteins and pathways associated with ChP changes in AD.

Result

Compared to wild‐type (WT) mice, AppNL‐G‐F mice aged 7 or 40 weeks old had significant differences in some protein levels in ChP tissue (Figure 1 and 2). At both ages, ChP tissue proteomic changes were related to pathways associated with epithelial cells, mitochondrion, protein modification, extracellular matrix (ECM) and lipids. Pathways related to lysosomal function, endocytosis, protein formation, actin, and complement were uniquely dysregulated at 7 weeks, while pathways associated with nervous system, immune system, protein degradation and vascular system were uniquely dysregulated at 40 weeks. Mouse CSF proteomics showed changes in similar pathways as seen in ChP tissue proteomics (Figure 3). Proteomic analyses were also performed in non‐demented human participants with abnormal amyloid but normal tau levels. Among proteins that were up‐regulated in CSF of those participants compared to controls, a significant number were predominantly expressed in the ChP (38 to 56% of the up‐regulated proteins). The dysregulated proteins with a predominant expression in the ChP in those individuals were related to similar pathways as seen in AppNL‐G‐F mice ChP tissue and CSF proteomics (Figure 3).

Conclusion

ChP changes are associated with amyloid pathology. Key pathways involved in ChP dysfunction in AD are associated with the ECM, lysosomal function, lipids, protein processing, complement, vascular system and mitochondrion. The ChP could become a novel promising target for AD treatment.
Neuroinflammatory Stress Exerts Distinct Proteomic Effects on Soma, Synapses and Mitochondria in Excitatory Neurons
Authors: Espinosa‐Garcia Claudia , Srivastava Upasna , Kumar Prateek , Tobin Brendan R , Xiao Hailian , Cheng Lihong , Bagchi Pritha , Duong Duc M , Seyfried Nicholas T , Faundez Victor , Wood Levi B , Rangaraju Srikant
Published: January 2025

Background

Neuroinflammation plays a critical role in Alzheimer’s disease pathogenesis. Neurons are anatomically divided in subcellular compartments (axons, soma, and synapses), which may be distinctly impacted by neuroinflammation. This study aims to examine cellular compartment‐specific proteomic signatures in excitatory neurons following a systemic neuroinflammatory stress.

Method

We used our innovative CIBOP (cell type‐specific in vivo biotinylation of proteins) approach to selectively label Camk2a excitatory neuron proteomes in vivo. Neuron‐CIBOP transgenic mice and their littermate controls were treated with lipopolysaccharide (LPS, [500 µg/kg, i.p.]) during 4 consecutive days, which induces robust microglial activation and sickness behavior. After euthanasia, brains were quickly removed, and crude synaptosomal fractions (P2 fractions) were prepared by differential centrifugation. Neuron‐specific biotinylated proteins were then enriched and analyzed by label‐free quantitative mass spectrometry (MS) to identify differentially‐enriched proteins (DEPs) and biological pathways (by gene set variation analysis/GSVA). Neuron‐derived biotinylated key cellular signaling pathways (MAPK and Akt/mTOR) were directly measured by Luminex in homogenates and P2 fractions (Fig. 1A).

Result

Electron micrographs validated the subcellular composition of the P2 fractions showing synaptosomes containing synaptic vesicles and mitochondria (Fig. 1B). MS studies confirmed that neuronal homogenates were enriched in microtubule and cytoskeleton‐related proteins, while P2 fractions were enriched in mitochondria and synapse‐related proteins (Fig. 1C). Interestingly, LPS induced unique compartment‐specific proteomic effects, P2 fraction has 52 unique DEPs, while homogenate has 57 DEPs, and only 2 DEPs overlapped (Fig. 1D). Neuronal homogenate proteomes showed upregulation of detoxification and oxidoreductase activity, while a reduced neuron‐synapse, somatodendritic compartment, and cytoskeleton organization. In P2 fraction proteomes, LPS upregulated mitochondrial envelope formation and metabolic activity, including purine containing compound metabolic process, but downregulated nucleoside triphosphate regulator activity. Increased aerobic respiration and mitochondria response overlapped among compartments (Fig. 1E). We also observed LPS‐induced decrease in MAPK signaling specifically in the P2 fraction, not evident at the level of whole neurons, nor at the bulk brain tissue level (Fig. 1F).

Conclusion

Our neuron and synaptosome‐enriched proteomics approach revealed unique molecular and signaling effects of neuroinflammation that may preferentially impact the synapses of excitatory neurons.
A novel stop‐gain SORL1 mutation from Amerindian background in a Peruvian family with Alzheimer’s Disease of the PeADI Study
Authors: Cornejo‐Olivas Mario , Griswold Anthony J. , Saldarriaga‐Mayo Ana , Mena Pedro R. , Rodriguez Richard S. , Adams Larry D. , Whitehead Patrice L. , Isasi Rosario , Illanes‐Manrique Maryenela , Sarapura‐Castro Elison , Rajabli Farid , McInerney Katalina F , Milla‐Neyra Karina , Manrique‐Enciso Carla , Beecham Gary W , Castro‐Suarez Sheila , George‐Hyslop Peter St , Araujo‐Aliaga Ismael , Cuccaro Michael L. , Vance Jeffery M. , Pericak‐Vance Margaret A
Published: January 2025

Background

Common and rare variants in SORL1 have been associated with increased risk of Alzheimer’s disease (AD). Since 2019, we have run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer’s disease and other related dementias for genetic studies (PeADI).

Method

A Peruvian family (4 AD cases and two mild cognitive impairment (MCI) cases) was recruited through the PeADI study. All six family‐member completed a full cognitive assessment, had plasma‐based biomarkers pTau181 and Aβ42/40 measured via SIMOA chemistry on the Quanterix HD‐X, and underwent whole genome sequencing. Variants within AD risk genes as determined by the ADSP Gene Verification Committee were prioritized and variant interpretation was performed according to ACMG recommendations.

Result

We identified a SORL1 c.5019G>A (p.Trp1673Ter) variant of Amerindian background in the four AD diagnosed siblings within this family. The two MCI cases did not carry the novel variant. The identified SORL1 variant corresponded to a heterozygous stop‐gain variant in exon 36 replacing tryptophan by a stop codon at position 1673 of the SORL1 protein. In‐silico analysis predicts this variant promotes nonsense‐mediated mRNA decay. This variant has not been previously reported in databases including gnomAD, LOVD and ClinVar. The 4 AD cases had on average 2.3X higher plasma pTau181 concentrations compared to the 2 MCI (2.03 ± 0.28pg/µl vs 0.88 ± 0.7pg/µl). There was no noticeable difference in the Aβ42/40 ratio. This variant is classified as likely pathogenic according to ACMG.

Conclusion

We report the first Peruvian AD family carrying a likely pathogenic stop‐gain SORL1 variant within an Amerindian background region. Further cosegregation and functional assays are required to establish the risk size of this variant for AD.
Nitro‐oxidation of BKCa mediates neuro‐ and micro‐vascular dysfunction in female 5x‐FAD mice
Authors: da Silva Josiane Fernandes , Polk Felipe Davis , Thai Stephenie H. , Frank Ella C. , Martin Paige E. , Pires Paulo
Published: January 2025

Background

Cerebral microvascular dysfunction and nitro‐oxidative stress are present in patients with Alzheimer’s disease (AD) and may contribute to disease progression and severity. A pro‐nitro‐oxidative environment can lead to post‐translational modifications of ion channels central to microvascular regulation in the brain, including the large conductance Ca2+‐activated K+ channels (BKCa). Nitro‐oxidative modulation of BKCa can resulting in decreased activity and vascular hyper‐contractility, thus compromising neurovascular regulation. We hypothesized that nitro‐oxidation of vascular BKCa function blunts micro‐ and neuro‐vascular responses in 5x‐FAD mice.

Methods

Six‐months‐old female 5x‐FAD and wild‐type (WT) littermates were used. Brain lysates were used to quantify BKCa nitro‐oxidation. Cerebral arteries lysates were used to assess BK subunit expression by qPCR. A different set of cerebral arteries were used for patch clamp electrophysiology assessment of BKCa currents, ex vivo pressure myography and quantification of calcium (Ca2+) sparks in smooth muscle cells (SMC) by spinning‐disk confocal microscopy. Basal cerebral perfusion and neurovascular coupling were assessed by laser speckle contrast imaging. Differences between means were tested using t‐tests and considered statistically significant when P<0.05.

Results

We observed that BKCa S‐nitrosylation, a proxy for nitro‐oxidative modification, was increased in the brain of AD patients and in 5x‐FAD females. In functional experiments, we observed that BKCa currents were lower in cerebral artery SMC of 5x‐FAD than in WT. As a consequence, microvascular reactivity to BKCa blockade (iberiotoxin, 30 nM) was blunted in 5x‐FAD, suggesting lower basal BKCa activity. This reduction in microvascular BKCa activity was independent of SMC Ca2+ sparks or BKCa mRNA expression. We then performed rescue experiments by incubating membrane patches and pressurized arteries with the reducing agent dithiothreitol (DTT, 10 µM), and observed that DTT restored BKCa currents and sensitivity to iberiotoxin in cerebral artery SMC from 5x‐FAD. In vivo experiments showed that basal perfusion to the frontal cortex and neurovascular coupling were lower in 5x‐FAD when compared to WT littermates.

Conclusion

These data suggest that excessive nitro‐oxidation of BKCa mediates neuro‐ and micro‐vascular impairments in female 5x‐FAD mice, and that this process is reversible and can be rescued by reducing agents.

Funding: National Institutes on Aging and Alzheimer’s Association