bluuebunny/crossref_metadata_2025 huggingface dataset:
Expression of human tau in adult Drosophila melanogaster causes a sexually dimorphic sleep phenotype
Authors: Mouofo Edmond N , Catterson James , Verstreken Patrik , Spires‐Jones Tara L.
Published: January 2025

Background

Alzheimer’s disease (AD) is the primary cause of dementia, characterized by early amyloid beta accumulation, subsequent tau pathology, and eventually synaptic and neuronal loss. Sleep disturbances, a clinical phenotype in AD, are linked to amyloid beta and impaired protein clearance. However, the influence of tau pathology on sleep is less explored. Utilizing Drosophila melanogaster, we investigate the effects of adult‐onset tau expression on sleep. This study addresses a knowledge gap regarding the impact of tauopathy on sleep‐related changes contributing to our understanding of AD progression.

Method

We investigated the impact of adult‐onset pan‐neuronal expression of wildtype tau and pseudo‐phosphorylated tau E14 in male and female Drosophila, induced by the gene‐switch drug RU 486 (mifepristone). The flies were exposed to the inducer added to their food from 2‐3 days post eclosion. Utilizing the Drosophila Activity Monitor (DAMs), we monitored activity and sleep patterns following expression for 2 weeks (n>47 flies per study group) and 4 weeks (n>17 flies per study group). Subsequently, we analysed and plotted data on activity and sleep. Additionally, at the 4‐week mark, we conducted immunohistochemistry on the flies to assess neurodegeneration, and performed lifespan assays.

Result

Results consistently revealed that flies expressing tau exhibited a shorter median lifespan compared to the control group. Unexpectedly, our gene‐switch control flies displayed a marked heightened activity leading to confounding behavioural effects in our analysis. Despite the activity confounds in one control line, neither the genetic controls nor the RU inducer affected sleep phenotypes, allowing investigation of sleep disruptions due to tau expression. We observe female but not male flies expressing tau have increased day sleep bouts length compared to controls. The pseudrophosphorylated E14 tau expression exacerbated/accelerated the phenotype compared to wild‐type tau. Immunohistochemistry showed elevated vacuoles in tau‐expressing flies indicating neurodegeneration which likely caused the sleep phenotype.

Conclusion

Our results indicate that pathological tau expression in Drosophila melanogaster causes neurodegeneration and increase sleep in females. These results indicate that pathological tau may directly contribute to sleep disruption in humans and provides a new model system to further our understanding of the role of tau in neurodegeneration.
The human master circadian clock is vulnerable to tau pathology in the early stages of Alzheimer’s: a postmortem neuropathology using spatial in‐situ proteomics
Authors: Son Gowoon , Mladinov Mihovil , Pereira Felipe Luiz , Li Song Hua , Tu Chia‐Ling , Judge Grace , Suemoto Claudia Kimie , Leite Renata Elaine Paraizo , Paes Vitor Ribeiro , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Spina Salvatore , Seeley William W. , Chang Wenhan , Neylan Thomas C. , Grinberg Lea T.
Published: January 2025

Background

Alzheimer’s Disease(AD) patients experience circadian rhythm disorder. The circadian rhythm is synchronized by a master clock, the suprachiasmatic nucleus(SCN), which is spatially well‐conserved but a tiny nucleus in the hypothalamus. Little is known about the molecular and pathological changes that occur in the SCN during AD progression.

Method

We examined postmortem brains of 12 controls without AD neuropathological changes (Braak0) and 39 subjects with progressive ADNC stages. We quantified neuronal numbers‐arginine vasopression(AVP) and vasoactive intestinal protein(VIP) neurons‐ plus ADNC burden in SCN. We performed analysis in adjacent hypothalamic nuclei as regional controls: supraoptic nucleus(SON) and paraventricular nucleus(PVN) both sites of AVP+ neurons. Moreover, we performed In‐situ proteomics using GeoMx Digital Spatial Profiling(DSP) in the three nuclei (total of 897 ROIs), including probes for 39 proteins commonly dysregulated in AD.

Result

SCN neurons in Braak6 had sixteen times higher p‐tau levels than Braak0. Neurofibrillary tangles were found exclusively in SCN(Fig. 1). However, there was not significant p‐tau upregulation in SON and PVN in all the same stage. Additionally, the SCN showed increases in glial proteins already in Braak1(Fig. 2), whereas these proteins remained unaltered in the other nuclei, including that they displayed a milder pattern of protein dysregulation in Braak1, consistent with its lower tau expression observed in histology and DSP.

Conclusion

Our study sheds light on the previously unexplored molecular and pathological changes occurring in SCN during AD progression. The SCN is vulnerable to AD‐tau pathology and show immune dysregulation even at Braak1 but protected against beta‐amyloid accumulation. This vulnerability pattern in SCN supports the idea that SCN dysfunction contributes to circadian rhythm disturbances in AD, observed even in the stage before the onset of cognitive disorder. Furthermore, the preservation of SON, a neighboring nucleus with AVP neurons but not directly connected in a neuronal circuit with the SCN, corroborates that SCN is early vulnerable to AD. PVN neurons exhibited similar but milder pattern of protein dysregulation in the early stages to the SCN, implying the effect may be caused by the efferent projection from the SCN. These results open up opportunities for tailored interventions to alleviate circadian rhythm disruptions in AD.
Omics analysis of Alzheimer’s disease stratified by the microglial polygenic effect
Authors: Kikuchi Masataka , Miyashita Akinori , Hirota Yu , Hara Norikazu , Hasegawa Mai , Sakakibara Yasufumi , Sekiya Michiko , Saito Yuko , Murayama Shigeo , Iijima Koichi M. , Ikeuchi Takeshi
Published: January 2025

Background

Recent single‐cell omics analyses have revealed that microglia change into reactive microglia when Aβ accumulates in the brain and exhibit Aβ phagocytosis. However, reactive microglia are less likely to be induced in TREM2 mutation carriers. This microglia‐centred pathological mechanism may be considered one of the pathologies of AD. However, a single gene mutation, such as a TREM2 mutation, can rarely explain the pathology of AD. Therefore, polygenic effects involving multiple gene mutations have been proposed. In this study, we propose a polygenic risk score (PRS) to quantify the microglial polygenic effect. We stratified patient groups by this PRS and examined differences in pathogenesis based on omics analysis using postmortem brains.

Methods

Whole‐genome sequencing and bulk brain tissue RNA‐seq of the frontal cortex were performed using postmortem brain samples from 100 subjects with Braak senile plaque (SP) and neurofibrillary tangle (NFT) staging information. In addition, single‐nuclei RNA‐seq (snRNA‐seq) was performed on 15 of these subjects (healthy subjects: 8 subjects, AD patients: 7 subjects).

Result

We divided AD patients into low and high groups by microglial PRS and performed bulk brain tissue RNA‐seq analysis. We identified 112 differentially expressed genes and found that those genes were related to autophagy and inflammation. To further validate these findings at the single‐cell level, we identified cell clusters containing microglia based on snRNA‐seq. Gene expression analysis of microglia in 3 AD patients with low PRS and 4 AD patients with high PRS suggested altered transcriptional profiles of immune cells and phagocytosis. In addition we observed different microglial subtypes in different PRS.

Conclusion

The stratification analysis of AD by PRS suggests that microglial reactivity differs among AD patient groups. Future detailed microglial observations in postmortem brains from AD patients with low PRS and those with high PRS will further elaborate our results.
Synergistic associations of CD33 variants and hypertension with poor cognitive function, brain atrophy, and cerebral blood flow among dementia‐free older adults: a population‐based study
Authors: Zhu Min , Tian Xunyao , Han Xiaodong , Liu Cuicui , Tian Na , Zhang Heng , Song Lin , Tang Shi , Cong Lin , Wang Yongxiang , Hou Tingting , Qiu Chengxuan , Du Yifeng
Published: January 2025

Background

Evidence has emerged that the inflammation and immune mechanisms are involved in the relationship between hypertension (HTN) and cognitive impairment. We sought (1) to examine the combined effects of HTN and CD33, an immune‐related and robust cognitive impairment susceptibility locus, with cognitive function in older adults and further (2) to explore the underlying mechanisms.

Method

This population‐based study included 4444 dementia‐free participants (age ≥65 years) in MIND‐China; of these, data on gray matter volume were available in 1047 persons and cerebral blood flow (CBF) in 85 persons. We used general linear regression models to examine the associations of CD33 rs3865444 and HTN with cognition, brain atrophy, and CBF, and the mediation models to explore associations among them.

Result

Among participants carrying CD33 rs3865444 CC genotype, HTN history, high pulse pressure, and late‐life HTN were significantly associated with low cognitive performance, HTN history as well as midlife HTN was correlated with small volume of gray matter. Notably, rs3865444 CC genotype significantly moderated the mediation effect of gray matter volume on the association between HTN and global cognition (mediation effect: 9.33%). Furthermore, HTN was correlated with low CBF in individuals carrying rs3865444 CC. Similar results were obtained among individuals free of mild cognitive impairment.

Conclusion

The current study reveals the synergistic associations of immune‐related CD33 rs3865444 and HTN with low cognitive function and brain atrophy in dementia‐free older adults. These joint effects of HTN and CD33 on cognition may be related to the disruption of CBF and blood brain barrier function.
The Effect of Amyloid‐Beta on Empathy‐like Behavior in Rats
Authors: Rostami Zahra , Parvin Hadi Choubdar , Khodagholi Fariba , Ansari Mitra
Published: January 2025

Background

Empathy is a complex behavior enabling individuals to recognize and sense the emotional situation of others. Empathy requires cognitive, emotional, and learning abilities to understand and react to the suffering of others. The current study evaluates the effect of Amyloid‐Beta (Aβ), an aggregated peptide involved in Alzheimer’s disease on empathy‐like behavior.

Method

Aβ was injected bilaterally in the hippocampal tissue of 14 Wistar rats. Aβ‐injected rats were compared to the control group during an empathic behavioral task for 12 days. Empathy was evaluated using the helping behavior of the subject toward his soaking cage‐mate rat. Opening time latencies with or without soaker response were considered as empathy indicators, and their change in two groups was modeled with a linear mixed‐effect model.

Result

Results of the model demonstrated that opening time latency with soaker response, as the major empathy indicator, had decreased in the Aβ group (p‐value = 0.002). Furthermore, the opening time latency without soaker response, the indicator of the helper rat’s solid action independent from social interaction, showed alteration in the Aβ group, the same as the opening time latency with soaker response, which was significantly decreased compared to the control animals (p‐value<0.001).

Conclusion

This result provides good evidence for the disruption of empathy due to a cognitive defect in helper rats’ emotional cue perception during Aβneurotoxicity. Together, these findings help to understand the impact of neurodegenerative disorders on empathic behavior and decode the altered components of empathy in the course of the disease.
Examining the shared genetic liability between late‐life onset psychosis and major psychiatric, cognitive and personality phenotypes
Authors: Creese Byron , Ismail Zahinoor , Ballard Clive G , Corbett Anne , Aarsland Dag , Gibbs Olly , Moodie Ellie
Published: January 2025

Background

When assessed in the Mild Behavioral Impairment (MBI) framework, late‐life onset psychotic like symptoms (MBI‐psychosis) are associated with incident cognitive decline and dementia. One approach to examining the genetic basis of this association, is to use Polygenic Risk Scores (PRS) to determine whether genetic propensity for late‐life onset psychosis is shared with other traits. We aimed to elucidate the shared genetic liability between Educational Attainment, Intelligence, Reasoning, Memory, Neuroticism, Alzheimer’s Disease, Major Depression, Schizophrenia and Bipolar Disorder and Mild Behavioral Impairment (MBI)‐Psychosis in later life.

Method

A total of 7,307 older adults without dementia were included in the analytical sample. MBI‐Psychosis status (present or absent) was determined by the Mild Behavioral Impairment Checklist (MBI‐C) rated by participants and study partners (that is ‘self’ and ‘informant’ ratings). Each PRS was tested in a logistic regression model with MBI‐Psychosis status as the dependent variable, and with age, sex and ancestry as covariates.

Result

Higher PRS for Major Depression, Schizophrenia and Neuroticism were all associated with an higher odds of MBI‐Psychosis. PRS for schizophrenia was only associated with self‐reported MBI‐psychosis, not informant reported MBI‐psychosis (see Figure 1). Higher PRS for Educational Attainment and Intelligence were both associated with lower odds of MBI‐Psychosis. In analysis stratified by self‐reported education level, the relationship between higher PRS for educational attainment and lower odds of MBI‐psychosis was only present in those we left school at 16.

Conclusion

In early life, psychosis is known to overall with cognitive, psychiatric and personality traits. These data extend this observation to later‐life psychosis. The significance of the differences between self and informant reported symptoms are yet to be determined but may be a mix of measurement error and the different respondents having a propensity to report symptoms which reflect different etiologies. We also show that established protective factors against cognitive decline, like educational attainment, in later life may also extend to late life neuropsychiatric syndrome.
Neuroprotective potential of quetiapine against streptozotocin‐induced sporadic Alzheimer’s disease
Authors: Kumari Shilpa , Attri Paras , Deshmukh Rahul Renukadas
Published: January 2025

Background

In previous studies, we found that quetiapine activates the AKT signaling which further inhibits the action of GSK3β. Quetiapine has been reported to possess neuroprotective potential in schizophrenia and other neurodegenerative models.

Method

On day 1st and 3rd, rats received bilateral intracerebroventricular (i.c.v.) administration of STZ (3 mg/kg). From day 8 to day 21 of treatment of quetiapine, a GSK3‐β inhibitor and neuroprotective medication, was given at dose levels of 2.5, 5, and 10 mg/kg/i.p. Morris water maze and Object recognition test was performed for the evaluation of cognitive impairment, whereas biochemical, histopathological, neuroinflammatory were evaluated by hippocampal and cortical brain region on 22nd day.

Result

ICV‐STZ results in cognitive impairment, spatial and non‐special learning deficit in OFT, MWM and ORT tests respectively, including elevation in the levels of nitrite and MDA and decreased antioxidant enzymes GSH, SOD and Catalase levels, also produced degenerative changes in dentate gyrus, CA1, CA2 and CA3 region of hippocampus as well as cortex in rat brains. Whereas, Quetiapine treatment significantly attenuated STZ‐induced cognitive deficit, oxidative stress and improved density of surviving neurons in hippocampal/cortical region of rat brains.

Conclusion

The conclusive outcomes of the present study, clearly indicate neuroprotective potential of quetiapine in neurodegenerative pathogenesis associated with cognitive dysfunction.
The relationship between psychosocial factors and cognitive test performance in a South African cohort
Authors: Dreyer Anna Jane , Nightingale Sam , Roux Celine Le , Thomas Kevin G. F. , Sabin Caroline , Winston Alan , Khoo Saye , Joska John
Published: January 2025

Background

Accurate assessment of cognitive impairment in low‐income settings may require consideration of complex psychosocial variables (PV). Failure to consider the association of PV with biological factors, such as HIV, could lead to false classification of cognitive impairment. We investigated the impact of PV on cognitive performance in people with HIV (PWH) and without in a low‐income area of Cape Town, South Africa.

Method

273 (178 PWH) participants were recruited and 185 (145 PWH) followed‐up at 1‐year. We investigated the relationship between comprehensive cognitive testing (7 domains) and 12 PV: 5 current (income, employment, assets, accommodation, mood) and 7 recalled at childhood (assets, quality of education, exposure to trauma and violence, parental education and employment), as well as standard variables typically measured in cognition studies (age, sex, years of education). Univariable and multivariable linear regression models investigated relationships between PV (clustered using principal component analysis) and global cognitive performance (measured by global T‐score). Propensity score modelling adjusted for variables significantly associated with HIV status, to determine the direct effect of HIV status on global T‐score.

Result

PWH had significantly lower scores than people without HIV in 9/12 PV (ps<.015). At baseline, 8/12 PV significantly predicted global T‐score (ps<.007), which clustered into 3 components reflecting current PV, childhood PV and experience of childhood trauma. In addition to standard variables, residing in a shack remained in multivariable analysis at baseline (β = 2.40, p = .007), and lower childhood PV at follow‐up (β = 0.82, p = .035). Unadjusted, HIV status was associated with a reduction in global T‐score of 3.72 units at baseline and 2.46 at follow‐up. At baseline, after adjustment for standard variables, the HIV association was reduced by 25.8% to 2.76, and additional adjustment for PV reduced by 41.4% to 2.18. At follow‐up, adjustment for standard measures reduced by 41.9% to 1.43 and addition of PV by 56.1% to 1.08.

Conclusion

PWH in this setting have lower psychosocial indices, both now and in childhood, which are associated with lower cognitive test performance as an adult. This is incompletely mitigated by adjustments for standard variables which could result in misclassification of PWH as cognitively impaired if PV are not taken into account.
A scoping review of the wide array of Alzheimer’s disease theories and hypotheses supports a multifactorial etiology
Authors: Duchesne Simon , Rousseau Louis‐Simon , Potvin Olivier , Belzile Florence , Welch Laurie‐Ann , Cournoyer Béatrice , Arseneau Marianne , Lapierre Véronick , Poulin Sara‐Maude , Hudon Carol
Published: January 2025

Background

There is a common agreement that Alzheimer’s disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Our objective was to perform a scoping review of original manuscripts describing hypotheses and theories of AD published in past decades.

Methods

We reviewed 127 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases (from inception to 14 Sept 2023). Each entry was characterized as having a single or multifactorial focus and assigned to one of 15 theoretical groupings. Impact was tracked using open citation tools.

Results

We found that three quarter of studies proposed a hypothesis characterized as being single‐focus (97/127), with the most important theoretical groupings being the Amyloid group, followed by Metabolism and Mitochondrial dysfunction, then Infection and Cerebrovascular. Three stages can be discerned in terms of hypotheses generation. The first phase (∼1980‐1995) included the establishment of the main thrusts that have endured to this day (Amyloid, Glial, Infection, Inflammation, Metabolism, Oxidative stress, and Proteinopathies hypotheses; multifactoriality; and neurotoxicity). In the second phase (1995‐2005), the importance of the Cerebrovasculature, Mitochondrial dysfunction, and Neurotransmitters were recognized. Lately (2005‐2023), evidence towards Genetics (outside of the autosomal dominant form of AD), and especially Gut/Brain interactions came to the fore. Impact, as measured by total citations count, followed a similar pattern. Out of a total of 19,996 citations for the 127 papers, the most cited single‐focused grouping was Amyloid (52%), followed by Mitochondrial dysfunction (6%, reaching 10.0% when adding Metabolism articles), then Cerebrovascular (5%) and Oxidative Stress (4%).

Conclusion

When viewed together, these multi‐faceted reports reinforce the notion that AD affects multiple sub‐cellular, cellular, anatomical, and physiological systems at the same time but at varying degree between individuals. Future work should integrate these competing views into a comprehensive, systemic framework able to capture individual and combinatorial factor evolutions and interactions, to manage its inherent complexity.
Unveiling molecular mechanism of ET‐1 induced vascular insult through RNAseq analysis
Authors: Gupta Mayank , Talukdar Ankita , Hussain Rehab , Diwakar Latha
Published: January 2025

Background

Vascular Dementia (VaD) is the second most prevalent cause of dementia, arising from the blockage of blood vessels in the brain. One event responsible for the blockage or narrowing of small blood vessels is transient ischemic attack (TIA), and these changes resolve within 24 hours in humans. The molecular mechanism underlying these changes in recovery in small vessels still needs to be investigated. To address this gap, we have developed a mouse model by administering endothelin‐1 (ET‐1) into the lateral ventricles. This disrupts small vessel integrity, which leads to learning and memory deficits after 3 days of a single ET‐1 injection. Intriguingly, there is a subsequent recovery in these deficits after 30 days, mimicking the clinical scenario of TIAs. Bulk RNA sequencing from microvessels was performed to elucidate further the factors involved in recovery mechanisms.

Method

ET‐1 injection was given to 4 groups of C57BL6/J mice, and mice were sacrificed at different time points of 3, 15, and 30 days along with saline counterparts. Microvessels were extracted from the pooled cortex and hippocampus, followed by RNA isolation. RNA samples were subjected to the cDNA library preparation, and RNA sequencing was conducted using the Illumina NovaSeq 6000® instrument. Transcriptomic analysis was carried out in the Linux environment. Differential gene expression was performed using R.

Result

We observed biological processes such as vasculature development, angiogenesis, and wound healing start upregulating after 3 days of a single ET‐1 injection, whereas several processes involved in ion transport chains were downregulated. Further, biological processes for muscle development, mitochondrial electron transport chain, and neuronal development were upregulated after 15 days of a single ET‐1 injection. No biological processes were affected after 30 days of a single ET‐1 injection, suggesting a possible complete recovery from ET‐1‐mediated vascular insult by the 30th day.

Conclusion

Our results highlight the temporal dynamics of biological processes in response to a single ET‐1 injection. It offers valuable insight for understanding the mechanism behind the recovery and factors involved in this process after vascular insult, paving the way for therapeutic targets.
3‐O Sulfated Heparan Sulfate as an Emerging Drug Target and Biomarker for Alzheimer’s Disease
Authors: Wang Chunyu , Liu Jian , Wang Lianchun , Mah Dylan , Zhang Fuming
Published: January 2025

Background

Heparan sulfate (HS) interacts with many important proteins. These interactions are primarily driven by electrostatics, with specificity determined by sulfation patterns. Although 3‐O‐sulfation is a rare modification in HS, several genome‐wide association studies (GWAS) revealed that the Hs3st1 gene, encoding HS‐3‐O‐sulfotransferase‐1, is significantly linked to late onset AD risk.

Method

NMR, SPR, glycan array were used to study HS‐protein interactions. A novel LC‐MS/MS method was developed to quantify the low abundance 3‐O‐sulfated HS from human brain, with 13C labeled calibrants. Alexa‐488 labeled Tau and ApoE was used to assess tau cell surface binding and uptake in HS3ST‐1 knockout cellular lines.

Result

We have demonstrated that tau, the major component of neurofibrillary tangles, specifically recognizes the 3‐O‐sulfation (3‐OS). In addition, ApoE, whose isoform ApoE4 is the most significant genetic risk factor for late onset AD, also interacts with 3‐OS. In addition, the affinity between ApoE isoform and heparin correlates with AD risk, with ApoE4 having the highest affinity to heparin, while the protective ApoE2 and Christchurch having significantly lower affinity. With a novel LC‐MS/MS method for quantifying 3‐O‐sulfation, our recent studies have further demonstrated a marked increase in 3‐O‐sulfated HS in AD brains.

Conclusion

Taken together, our findings underscore the importance of 3‐OS in AD pathogenesis, suggesting its potential as a novel drug target and biomarker in Alzheimer’s disease.
Impaired mechanisms of context encoding in APP/PS1 mice are rescued by increasing cerebral blood flow
Authors: Berkowitz Laura E , Todorova Ralitsa , Cabus Dana I , Letendre Jack T , Tehrani Natalie , Shimizu Jean‐Luc , Dong Xuelai , Oliva Azahara , Fernandez‐Ruiz Antonio , Nishimura Nozomi , Schaffer Chris B
Published: January 2025

Background

Spatial disorientation is an early symptom of Alzheimer’s disease (AD). The hippocampus creates a cognitive map, wherein cells form firing fields in specific locations within an environment, termed place cells. Critically, place cells remain stable across visits to an environment, but change their firing rate or field location in a different environment. In rodent models of AD‐like pathology, place cells exhibit broadened tuning and altered responses to environmental changes. Additionally, events known as sharp wave ripples (SWRs), coordinate the firing of hippocampal neurons, including place cells, and are disrupted in mouse models of AD. Our lab found that increasing cerebral blood flow (CBF) with anti‐Ly6G antibody treatment improved performance on spatial memory tasks. Here, we investigate the effect of increased CBF on neural mechanisms associated with cognitive map stability across contexts.

Method

We investigated the association between CBF and cognitive map stability in 7‐9‐month‐old APP/PS1 mice and wild‐type controls by recording neural activity in hippocampus area CA1 using 64‐channel silicon probes. Mice were recorded as they explored open field arenas with differing environmental contexts, A and B. Place cells were identified as neurons with significant spatial information in their firing rate maps. Local field potential recordings from pyramidal and stratum radiatum layers of CA1 were used to detect awake‐SWRs (aSWRs).

Result

Place cells from APP/PS1 mice did not exhibit higher place field correlations within contexts (AA' or BB'), as compared to between (AB) contexts, suggesting these different contexts are not differentially encoded (Figure 1). In contrast, wild‐type control mice showed higher within context correlation (Figure 1). APP/PS1 mice also had a reduced rate and duration of aSWR compared to controls (Figure 2). Following treatment with anti‐Ly6G antibodies, both context discrimination by place cells and duration of aSWR increased in APP/PS1 mice (Figure 2).

Conclusion

These results highlight the association between place cell stability and subsequent aSWR dynamics as a potential mechanism contributing to an impaired cognitive map in AD. Importantly, the rescue of behavioral features and aSWR physiological properties following anti‐Ly6G antibody treatment suggests that increasing CBF may be a candidate therapy to mitigate spatial memory impairments in AD.
The P301L tau mutation alters extracellular vesicle biogenesis in astrocyte and contributes to astrocyte‐mediated tau pathology in a human iPSC‐derived model of tauopathies
Authors: You Yang , Mann Sean D , Lu Wenyan , Poon Wayne W. , Ikezu Seiko , Kanekiyo Takahisa , Dickson Dennis W. , Sławek Jarosaw , Wszolek Zbigniew , Ikezu Tsuneya
Published: January 2025

Background

Tauopathies are a group of neurodegenerative disorders which are characterized by the accumulation of abnormal tau protein in the brain. However, the mechanistic understanding of pathogenic tau formation and spread within the brain remains elusive. Astrocytes are major immune reactive cells in the brain and have been implicated in exacerbating tau pathology by releasing extracellular vesicles (AEVs) containing pro‐inflammatory cytokines and chemokines upon activation. Our prior investigation revealed a significant association between AEVs and tau pathology development, as well as cognitive function, by analyzing brain‐derived EV proteins from AD patients. In this study, we explore the potential roles of AEVs in tau pathogenesis using a human induced pluripotent stem cell (iPSC) model.

Method

We obtained two male P301L tau mutant iPSC lines from a Polish family with frontotemporal dementia. By including two male control lines, these iPSCs were differentiated into astrocytes (iAs) and characterized by immunocytochemistry and subjected for bulk RNAseq. Bioinformatics analysis was conducted to compare the transcriptome profile between wild‐type (WT) and P301L iAs. EVs from WT and P301L iAs were isolated by ultracentrifugation combined with size exclusion chromatography. Characterization of WT and P301L iAEVs involved nanoparticle tracking analysis, nano‐flow cytometry and super‐resolution microscopy.

Result

We successfully differentiated WT and P301L mutant iPSC lines into astrocytes with >99% purity. P301L iAs displayed distinctive astrocyte reactivity compared to WT cells, with elevated levels of pan‐reactive astrocyte genes (e.g., GFAP, CD44) and decreased expression of neuroprotective A2 astrocyte‐specific genes (e.g., TM4SF1, PTGS2). Additionally, gene enrichment set analysis of RNAseq data revealed dysregulation in the endo‐lysosomal pathway and extracellular matrix in P301L iAs compared to WT iAs. The count of intraluminal vesicles marked by CD9+ were reduced in P301L iAs compared to WT cells. Moreover, we observed a significant increase in the internalization of Tau by P301L iAs compared to WT iAs following incubation with preformed Tau fibrils, resulting in an augmented release of tau‐containing EVs from P301L iAs.

Conclusion

Our findings suggest a potential alteration in EV biogenesis in P301L iAs, potentially contributing to astrocyte‐mediated tau pathology. Future investigations will focus on understanding how AEVs contribute to tau propagation and accumulation.
Neuropsychological test performance in mild cognitive impairment with Lewy bodies: a meta‐analysis
Authors: Wyman‐Chick Kathryn A , Bayram Ece , Gravett Stephanie , D'Antonio Fabrizia , Kane Joseph PM , Rodriguez‐Porcel Federico , Olson‐Bullis Barbara A , Bonanni Laura , Ferreira Daniel
Published: January 2025

Background

Prodromal dementia with Lewy bodies (DLB) research criteria were recently published and further work is needed to characterize the neuropsychological profile and refine clinical criteria. We performed a meta‐analysis to compare the cognitive performance of mild cognitive impairment with Lewy bodies (MCI‐LB) groups to controls, MCI due to Alzheimer’s disease (MCI‐AD), and DLB.

Method

Following PRISMA guidelines, we searched the literature for 1) English‐language studies on MCI‐LB; 2) published January 1990‐March 2023, 3) with ≥1 standardized cognitive measure; and 4) comparison data from controls, MCI‐AD, and/or DLB. Pooled means with 95% confidence intervals were calculated for demographics. Effect sizes were calculated for group comparisons on cognitive domains. Random effects meta‐analysis models were used for group comparisons.

Result

There were 3440 participants from 27 studies across 10 countries. Mean age did not differ between groups. The percentage of female subjects was lower in the MCI‐LB group than the MCI‐AD group. Mean years of education for the MCI‐LB group was lower than the controls, but similar to MCI‐AD and DLB groups (Table 1). Compared to controls, the MCI‐LB group had lower scores for the global screening, executive function, visuospatial, language, learning, and memory domains. Compared to MCI‐AD, MCI‐LB performed better on learning and delayed recall, but similarly across other domains. Compared to DLB, MCI‐LB had better scores for global screening, executive function, language, and delayed recall (Table 2). Recognition for MCI‐LB vs. MCI‐AD; visuospatial, learning, and recognition for MCI‐LB vs. DLB could not be assessed, as fewer than 3 studies reported this data.

Conclusion

Cognitive measures can help differentiate MCI‐LB from controls and DLB. Neuropsychological measures of learning and memory may be required to discriminate MCI‐LB from MCI‐AD in clinical practice but global screening measure scores appear insufficient in this regard. High heterogeneity across MCI‐LB studies highlights the need for harmonized neuropsychological research protocols.
Extracellular‐Vesicle mediated pyroptosis leads to gut‐brain axis after stroke in a mouse model of Alzheimer’s Disease
Authors: Kerr Nadine A , Higueras Alfredo Fernandez , Sanchez‐Molano Juliana , Walters Winston , Vaccari Juan Pablo de Rivero , Keane Robert W , Bramlett Helen M , Dietrich W Dalton
Published: January 2025

Background

Stroke and AD patients with gut complications often present worsened neurological outcomes. The goal of this study was to examine the role of extracellular vesicle (EV)‐mediated pyroptosis in the bi‐directional gut‐brain axis after photothrombotic stroke (PTS) in aged 3xTg mice and wildtype (WT) controls.

Method

Twelve‐month 3xTg and WT male and female mice underwent PTS using a YAG laser. Lesion volume analysis was performed at 1‐month post‐PTS. At 24 hours after PTS, intestinal and cortical tissue was collected for Western Blot analysis for the following inflammasome proteins: caspase‐1, apoptosis‐associated speck‐like protein containing a caspase recruitment domain (ASC), interleukin‐1b, and Gasdermin‐D (GSDMD). Additionally, brain and intestines were sectioned for immunohistochemical analysis of GSDMD and Amyloid‐Beta (Ab). In order to show changes in gut function, gut permeability was measured 72 hours post PTS using a FITC‐dextran assay. Moreover, we performed an adoptive transfer in which stool‐derived EVs collected from 3xTg‐ PTS and WT‐PTS mice were injected into naïve 3xTg and WT mice. Cortical lysates were examined for expression of inflammasome proteins, GSDMD, and Ab using Western Blot analysis.

Results

3xTg mice presented increased infarct volume compared to WT‐PTS mice one month after PTS. Based on Western blot analysis, we found that inflammasome proteins, GSDMD, and Ab were significantly increased in both intestinal and cortical tissue in 3xTg‐ PTS mice compared to WT‐ PTS mice at 24 hours post‐stroke. Results from the FITC‐Dextran assay showed that gut permeability was significantly increased in the aged 3xTg‐PTS mice compared to WT‐ PTS mice 72 hours post‐PTS. Additionally, our immunohistochemical analysis in both WT and 3xTg PTS mice presented evidence of activated/ameboid microglial morphology as well as the presence of GSDMD and Ab in the brain and intestines 72 hours after stroke. Lastly, we demonstrated increased levels of inflammasome proteins, GSDMD, and Ab after adoptive transfer.

Conclusion

Taken together these results indicate an important role for EV signaling and pyroptosis in disruption of the bidirectional gut‐brain axis after stroke in aged 3xTg mice in an animal model of stroke.
Intermittent cold exposure reversed high‐fat diet‐induced metabolic and cognitive dysfunctions in mice
Authors: Barros Wellinghton de Medeiros , Bellozi Paula Maria , Bezerra Maria Luiza Soccio , Domingues Daniel , Garcia Pereira Louise Tavares , Goulart Jair Trapé , Amato Angélica Amorim , de Bem Andreza Fabro ,   Laboratory of Bioenergetics and Metabolism – Department of Physiological Sciences, University of Brasília – Brasília/DF, Brazil
Published: January 2025

Background

Recent research has demonstrated that the consumption of high fat diet (HFD) can lead to metabolic dysfunctions and cognitive impairments in both mice models and humans. Given the potential negative effects of HFD, it is crucial to explore non‐pharmacological alternatives that can serve as a potential treatment for both metabolic dysfunctions and behavioral effects induced by HFD. Therefore, the aim of this study is to assess the impact of chronic and intermittent exposure to cold temperature on the metabolic and cognitive changes associated with HFD consumption.

Methods

Male and female C57Bl/6 adult mice were divided into 8 groups exposed to different diets and temperature conditions (HFD or control diet (CD) and, cold (4oC) or room temperature (RT) (22oC) exposure for 10 weeks). The ∆ of body mass, brown adipose tissue (BAT) temperature and oxygen consumption as well as behavior were evaluated after the experimental period.

Results

HFD increased the body mass in females (CD+RT x HFD+Cold p = 0.02) and males (CD+RT x HFD+RT p < 0.0001), however, cold exposure was able to reverse this metabolic outcome (male HFD+RT x HFD+Cold p = 0.01). Cold exposure increased BAT temperature (female: CD+Cold x HFD+RT p = 0.0005; male CD+RT x CD+Cold p = 0.0005, CD+RT x HFD+Cold p = 0.024, HFD+RT x HFD+Cold p = 0.035). Regarding oxygen consumption, UCP‐1‐linked respiration decreased in the female mice fed a HFD (CD+RT x HFD+RT p = 0.04), however, cold exposure reverted this effect (HFD+RT x HFD+Cold p = 0.03). Interestingly, we observed that the consumption of HFD caused recognition memory deficits in both female (p = 0.0728) and male (p = 0.51) mice that were reversed by cold exposure (female: p = 0.04, and male: p = 0.002).

Conclusions

With the present data we can infer that cold exposure can increase the activity of BAT, thereby mitigating the harmful effects of HFD on cognition and metabolism. In summary, chronic and intermittent cold exposure has proven capable of attenuating the deleterious metabolic and cognitive effects induced by HFD consumption in mice.
Utilizing Latent Dirichlet Allocation and Differential Abundance to Identify Microbial Communities in both the Oral and Fecal Microbiome Associated with Alzheimer’s Disease
Authors: Huang Ziyuan , Zeamer Abigail L , Ward Doyle , Jo Cynthia , Bucci Vanni , Haran John P
Published: January 2025

Background

Several studies have found that oral and gut microbiome and their byproducts can impact Alzheimer’s Disease (AD). The objective of our study is to analyze metagenomic sequencing data from paired oral and fecal microbiomes, along with clinical variables, to identify communities of bacteria associated with AD. This research aims to improve our understanding of the microbiome community matrix, and how these communities interact and correlate with AD status compared to healthy controls (HC) through an oral‐gut microbial axis.

Method

The study includes 223 HC and 43 individuals with AD. During each visit, paired oral and fecal samples were collected, along with clinical variables. Metagenomic profiling was done on all samples. Latent Dirichlet Allocation (LDA) was applied to identify differences in microbial species groups between these two body sites in realtion to AD status. LDA is used as a topic modeling method to uncover the complex structure and function of microbial communities. Subsequently, differential abundance (DA) analysis was performed to identify species with differential abundance at each body site.

Result

We identified microbiotal communities sharing similar characteristics and pinpointed representative bacteria within these communities that are highly relevant to AD. Within the oral microbiome, we have identified 27 topics, including several bacteria that are highly relevant to AD. These included Alistipes (beta = 3.919232e‐01), Paraprevotella xylaniphila (beta = 1.227791e‐01), Desulfovibrio (beta = 6.013213e‐02), and Lachnospiraceae (beta = 2.304369e‐02). In the gut, we have identified 50 topics, reflecting the gut is more complex the oral microbiome. Notable bacteria in the gut microbiome include Actinomyces oricola (beta = 6.959554e‐01), Roseburia (beta = 8.861444e‐02), Bacteroidetes (beta = 5.010610e‐01), and Actinomyces gerencseriae (beta = 3.048668e‐02).

Conclusion

Our study has identified a variety of bacteria that exhibit novel community patterns that associate with AD. In the gut, A. gerencseriae and other oral microbiomes were observed in AD patients. Also, the microbial communities differ between AD and HC. Thereforth, we conclude that translocation of oral and gut microbiota may contribute to AD through an oral‐gut‐microbiome axis.
Induction of VCID via hyperhomocysteinemia leads to vision and retina changes in mice
Authors: Weekman Erica M. , Rogers Colin B , Sudduth Tiffany L. , Wilcock Donna M.
Published: January 2025

Background

Diagnosis of Alzheimer’s disease (AD) via MRI is costly and can be limited by regional availability. With the recent advancements and discovery of amyloid in the retina, diagnosis of AD and the effect of AD pathology on the retina is becoming well characterized. However, the prevalence of vascular contributions to cognitive impairment and dementia (VCID) and its effects on the retina are less well known. With the retina being a highly vascularized tissue and the considerable overlap of AD with VCID, it is imperative to understand the effect of VCID on vision.

Method

We placed 6‐month‐old mice on a diet deficient in B vitamins and enriched in methionine to induce hyperhomocysteinemia (HHcy). HHcy is a risk factor for VCID, stroke and AD, and has been well characterized in our lab. After 14 weeks on diet, mice underwent the Visual‐Stimuli 4‐arm Maze (ViS4M) to identify visual and cognitive abnormalities. After behavior, brains and eyes were harvested with the left eye fixed in 4% PFA for 24hrs and the right eye flash frozen for RNA extraction. The fixed retina was flat mounted and stained for vessels, GFAP, and IBA‐1 and the flash frozen retina was used for RNA isolation and NanoString analysis.

Result

Over the seven days the mice were tested on the ViS4M, the mice on the HHcy diet showed impaired cognition and altered colored arm entries compared to control mice. HHcy mice made more 2 arm alternations than 3 or 4 arm alternations, suggesting diminished exploration. When we determined their arm transitions, we saw that the HHcy mice tended to avoid the blue arm, suggesting sensitivity to blue light. In the retina, we saw slightly less vessel volume in the HHcy diet mice along with reduced coverage of vessels by microglia and astrocytes combined.

Conclusion

The high prevalence of VCID with AD along with the impact of AD pathology on the eye makes it critical to understand the effect of VCID on the retina. In our model of HHcy induced VCID, we determined that HHcy does impair both cognition and vision and affects vessels within the retina.
Genetic Deletion of the Presinilin‐Like Peptidase SPPL2B Significantly Reduces Neuroinflammation and Halts Production and Plaque Deposition in Pre‐Clinical Models of Alzheimer’s Disease
Authors: Badman Jack , Chen Gefei , Garcia Sandra Pérez , Nilsson Per , Tambaro Simone
Published: January 2025

Background

Signal Peptide Peptidase‐Like 2b (SPPL2b) is relevant for AD, being a brain‐specific intramembrane protein involved in the cleavage of Alzheimer’s disease (AD)‐related proteins, such as BRI2, inflammatory‐related proteins like CD74, TNFalpha, and Clec7a, and synaptic proteins Neuregulin‐1 and VAMP 1‐4. SPPL2b is specifically expressed in the hippocampus and cortex. The cleavage of TNFalpha by SPPL2b promotes the inflammatory pathway. Conversely, the SPPL2b substrate BRI2 regulates amyloid precursor protein (APP) cleavage and subsequent Aβ production. This work explores the pathophysiological role of SPPL2b in AD pathogenesis and investigates the potential of inhibiting SPPL2b activity as a novel therapeutic strategy.

Method

To characterize the role of SPPL2b in the APP cleavage process and neuroinflammation, we used neurons and glia primary cell cultures from WT and SPPL2b‐deficient mice. Furthermore, we assessed the therapeutic potential of inhibiting SPPL2b by employing a new AD mouse model generated through crossbreeding state‐of‐the‐art AppNL‐G‐F knock‐in mice with SPPL2b‐deficient mice. Cells and mouse brain samples were analyzed through western blotting, immunoprecipitation, and immunofluorescence. Aβ levels were quantified using ELISA kits.

Result

The results showed a significant increase in BRI2, followed by a substantial reduction in soluble APP, Aβ40, and Aβ42 levels in the conditioned media of SPPL2b KO neurons. Immunoprecipitation of BRI2 from the cortex of those mice revealed an increased interaction between BRI2 and APP in SPPL2b KO/AppNL‐G‐F mice. Most importantly, a notable decrease in brain Aβ plaque deposition and a significant decrease in both cortical and hippocampal gliosis were observed at 4 months‐of‐age in SPPL2b KO/AppNL‐G‐F mice.

Conclusion

The results outlined in this study support a relevant connection between SPPL2b and the development of Aβ pathology in AD. In a global scenario characterized by the need to identify novel strategies to prevent and counteract AD progression, this study highlights and strengthens the importance of SPPL2b as a novel therapeutic approach for AD.
Creating human locus coeruleus organoids to study the role of the locus coeruleus in Alzheimer’s disease
Authors: Tish Margaret M , Birey Fikri , Weinshenker David , Ou Zihui
Published: January 2025

Background

The locus coeruleus (LC), is the first brain region to develop hyperphosphorylated tau (ptau) inclusions in Alzheimer’s disease (AD) and undergoes catastrophic degeneration in later stages of the disease. Importantly, the LC is the main noradrenergic nucleus in the brain and source of NE in the forebrain, and dysregulation of the neurotransmitter norepinephrine (NE) is associated with AD symptoms, as its release in the forebrain regulates attention, arousal, stress response, and learning and memory. Moreover, the LC may transmit pathogenic tau to the forebrain via its extensive projections. However, nearly all information about the LC in AD has been derived from rodent models and postmortem or human imaging studies. It is not known how the early ptau accumulation in the human LC affects neuronal function, NE transmission, or pathology propagation. We created organoids, which are 3D human cell culture models derived from human induced pluripotent stem cells, that possess many aspects of human LC structure.

Method

Organoids containing neurons resembling the LC were generated from human induced pluripotent stem cells using growth factors that induce a hindbrain fate. These organoids were then characterized using HPLC, immunohistochemistry, RNA‐scope and RNA‐sequencing.

Result

LC organoids contained higher levels of norepinephrine and dopamine than cortical organoids. They also expressed many of the proteins and RNA that are indicative of and enriched LC‐NE neurons, including tyrosine hydroxylase, dopamine beta‐hydroxylase, the NE transporter, Phox2A, and Phox2B. Additionally, bulk RNA‐seq revealed that compared to cortical organoids, the LC organoid transcriptome more closely resembled the human LC.

Conclusion

LC organoids are distinct from cortical organoids and contain many markers of human LC neurons. Studying the structure and function of LC organoids derived from both healthy controls and AD patients may provide new insights into the role of the LC in AD.