bluuebunny/crossref_metadata_2025 huggingface dataset:
The VLPO analog in the human hypothalamus shows tau‐driven extreme loss of sleep‐regulating neurons in PSP and Alzheimer’s disease: unveiling the basis of NREM sleep dysfunction in tauopathies
Authors: Rastegar‐Pouyani Shima , Lew Caroline , Satpati Abhijit , Leite Renata Elaine Paraizo , Suemoto Claudia Kimie , Spina Salvatore , Seeley William W. , Walsh Christine M , Neylan Thomas C. , Grinberg Lea T.
Published: January 2025

Background

Sleep dysfunction is commonly seen in Alzheimer’s disease (AD) and Progressive Supranuclear Palsy (PSP), potentially worsening these conditions. Investigating early neuropathological changes in human sleep‐promoting neurons, which often precede cognitive decline, is crucial for understanding the basis for sleep dysfunction as possible treatments yet remain underexplored. We used postmortem brains of AD and PSP patients to quantify neuronal numbers and tau burden in the intermediate nucleus of the hypothalamus (IntN), VLPO analog, known for its role in sleep maintenance.

Method

Postmortem human brain tissues from three groups were used: healthy controls, progressive AD stages, and PSP. Formalin‐fixed, celloidin‐embedded hypothalamic tissue was cut at 30‐micron. Slides were immunostained for galanin (GAL), an IntN neuronal marker, phosphorylated‐tau (p‐tau) antibodies, and counterstained with Gallocyanin. The total number of GAL‐expressing neurons and/or p‐tau deposition were estimated using the stereology.

Results

In a cohort of 7 cases (Table 1), we found a significant decrease in neuronal population and volume in the IntN in both AD and PSP patients, with a more pronounced decline in PSP. However, the neuronal density was not changed in any of the AD or PSP conditions, reflecting a simultaneous neuronal and volume loss. GAL‐positive neurons were more resilient in AD, showing better preservation than in PSP. In both AD and PSP, p‐tau‐positive neurons increased compared to the controls. Notably, in AD, tau aggregates were present in both GAL‐positive and negative neurons, while in PSP, GAL neuronal population decreased more than the others, and tau aggregates were only observed in GaL‐negative neurons (Fig. 1).

Conclusion

In both AD and PSP, our research reveals substantial neuropathological changes in the IntN, with PSP exhibiting more pronounced alterations. These changes align with observed sleep dysfunction in both conditions. PSP features severe insomnia, although wake‐promoting neurons remain relatively intact, thus a significant reduction in neurons controlling NREM‐sleep could account for its clinical sleep disturbances. Conversely, AD displays a decline in wake‐promoting neurons and a gradual, moderate loss of NREM neurons, both leading to excessive daytime sleepiness and sleep fragmentation, yet overall preserved total sleep time. These findings deepen our understanding of NREM sleep dysfunction in tauopathies, offering insights for targeted interventions.
Myeloid Differentiation Factor 2 Inhibition Attenuates Brain Pathologies in the Obese Pre‐diabetic Condition
Authors: Oo Thura Tun , Nawara Wichwara , Arunsak Busarin , Chunchai Titikorn , Apaijai Nattayaporn , Pratchayasakul Wasana , Liang Guang , Chattipakorn Nipon , Chattipakorn Siriporn C
Published: January 2025

Background

Excessive high‐fat diet (HFD) consumption develops the obese pre‐diabetic condition, which initiates neuroinflammation and numerous brain pathologies, resulting in cognitive decline (1). A cinnamamide derivative compound (2i‐10) is recently identified as a novel myeloid differentiation factor 2 (MD‐2) inhibitor, and has been shown to attenuate inflammation via toll‐like receptor 4 (TLR4) signaling pathway (2). However, the effects of 2i‐10 on the neuroinflammation, brain pathologies and cognitive function in the obese pre‐diabetic rats have never been studied.

Method

Male Wistar rats were fed one of two diets for 16 weeks: either a normal diet (ND; n = 8) or a high‐fat diet (HFD; n = 32). At week 13, ND‐fed rats were intraperitoneally administered a vehicle for 4 weeks, while HFD‐fed rats were randomly divided into 4 groups (n = 8/group). Each subgroup was intraperitoneally administrated either vehicle, 10mg/kg/day of 2i‐10, 20mg/kg/day of 2i‐10, or 40mg/kg/day of 2i‐10 for 4 weeks. At the end of week 16, the novel object location (NOL) test was examined in each rat. Brains were rapidly removed to determine hippocampal inflammation, adult hippocampal neurogenesis, brain oxidative stress, dendritic spine density, amyloidogenic pathology.

Result

HFD‐fed rats developed the obese pre‐diabetic condition. Hippocampal inflammation was observed in HFD‐fed rats, as evidenced by increased hippocampal TLR4 and TNF‐α expressions. Moreover, HFD‐fed rats not only had significantly higher hippocampal amyloid‐β/APP ratio and brain MDA levels, but also had significantly lower levels of adult hippocampal neurogenesis, hippocampal dendritic spine density, resulting in cognitive decline. Although all doses of 2i‐10 attenuated systemic insulin resistance, brain pathologies and cognitive impairment, 2i‐10 (40mg/kg/day) showed the highest efficacy in attenuating brain inflammation, brain oxidative stress, amyloid‐β deposition, as well as improving adult hippocampal neurogenesis, hippocampal dendritic spines, resulting in the restoration of cognitive function in obese pre‐diabetic rats (P < 0.05, Figure 1).

Conclusion

These findings suggest that MD‐2 inhibition could be the potential strategy for attenuating brain dysfunctions in the obese pre‐diabetic condition.
Tetrahydroxy stilbene glycoside ameliorates neuroinflammation for Alzheimer’s disease via cGAS‐STING
Authors: Gao Dan
Published: January 2025

Background

Alzheimer’s disease (AD), also known as senile dementia, is the most common degenerative disease of the central nervous system. Neuroinflammation is currently believed to be a crucial factor in the progression of AD, while its exact mechanism remains unclear.

Method

APP/PS1 AD mice were treated with a natural active ingredient tetrahydroxy stilbene glucoside (TSG) at 40 mg/kg/day and 80 mg/kg/day respectively for 5 consecutive months, and then the Morris water maze test (MWM) and the novel object recognition test were performed to assess the effect of TSG on the cognitive and memory ability of AD mice. Moreover, central microglia activation, peripheral inflammation as well as the correlated cGAS‐STING signal pathway were analysed by Immunostaining and ELISA, which was further verified in BV2 cell experiments.

Result

Treating with TSG, learning‐memory ability of AD mice was distinctly improved. Meanwhile, it was observed that the expressions of serum inflammatory cytokines and the activation of microglia in cerebral cortex and hippocampus were suppressed after TSG treatment, which was probably attributable to the decrease of cyclic GMP‐AMP synthase (cGAS) and stimulator of interferon genes (STING) triggered immune response and NLRP3 inflammasome activation. Furthermore, cell culture experiments employing LPS combined with IFN‐γ induced microglia activation showed that TSG reversed the polarization status of M1‐type microglia to restore the quiescence, and cGAS‐STING elevation was observed in the activated microglia and normalized by TSG incubation. In addition, TSG suppressed the production of inflammatory cytokines such as IL‐1β, IL‐6, TNF‐ α, IFN‐ αand IFN‐β, as well as the expression of IFN regulatory proteins such as IFIT1 and IRF7 in the LPS/IFN‐γ‐stimulated inflammatory response in BV2 cell. Finally, it was also verified that TSG are, in part, through a cGAS‐STING dependent pathway and triggered NLRP3 inflammasome activation to inhibit neuroinflammation through interfering with cGAS‐STING inhibitors.

Conclusion

Our findings highlight the health benefits of TSG and its potential application in preventing cognitive disorders by inhibiting neuroinflammation through cGAS‐STING signaling pathway in AD.
Phospholipase gamma2: A candidate genetic risk factor for Alzheimer’s disease that can alter synaptic function in DG‐perforant pathway of hippocampus
Authors: Roy Avishek , Erhardt Anael , Deforges Severine , Mulle Christophe
Published: January 2025

Background

PhospholipaseC γ2 (PLCG2) is known to have direct link with genetic risk factors for Alzheimer’s like dementia (AD). PLCG2 has been previously demonstrated to have association with Aß uptake through microglia. And mostly expressed in dentate gyrus (DG) network of hippocampus.

Method

WT mouse were transfected with sh‐RNA of LV‐PLCG2 (U6 promotor, GFP as reporter; shRNA) or scrambled (used as control; shNT). Whole‐cell patch‐clamp recordings were performed on acute slices with glass pipette (<3‐4MΩ) at ‐70mv, which was accompanied with morphometry of perforant pathway (PP)‐DG circuitry. Two‐tailed Mann‐Whitney test was used for statistics unless otherwise mentioned, p<0.05 was considered to be significant.

Result

We found significant increase in APhalf width (p = 0.0274), rheobase (p = 0.0046) in shRNA on the other hand, input resistance (p = 0.0159), number of spike vs current injection (p = 0.0268) was significantly decreased. However, there were no significant change was observed in APonset (p = 0.6105), APamplitude (p = 0.7345), RMP (p = 0.7591) and firing threshold (p = 0.5247) in shRNA group when compared to shNT. mEPSC amplitude was found to be reduced (p = 0.0288) in shRNA condition, even the cumulative probability of mEPSC amplitude was also found to be significantly altered after silencing of PLCG2 gene in DG cells (p = 0.0014; Kolmogorof‐Smirnov test). mEPSC frequency of the miniature activity of transfected DG cells were did not show significant change (p = 0.7707). Sholl analysis of the DG cells expressing shRNA showed a decrease in the number of intersections vs distance from soma (P<0.05), accompanied by significant decrease in dendritic length (p = 0.0501), dendritic volume (p<0.0001) and dendritic surface area (p = 0.0273). When spine density was measured we have found a significant decrease in cumulative distribution of spine density (p<0.0001; Kolmogorof‐Smirnov test), which is tightly associated with decrease in spine length (p = 0.0209) and spine head diameter (P<0.0001). Furthermore, these dendritic and spine morphometric alteration is also accompanied with the decrease in the volume of mossy fiber gigantic bouton (mfB) with alteration in the number of filopodia per mfBs (p<0.05).

Conclusion

Results from the study, reflect critical insight of PLCG2 regulating neuronal and/or synaptic activity, which may underlie the cognitive dysfunction (viz. recognition memory) and synaptic alteration to the PP‐DG circuitry seen in AD.
Enrichment of somatic cancer driver mutations in Alzheimer’s disease microglia and its association with neuroinflammation
Authors: Huang August Yue , Zhou Zinan , Talukdar Maya , Miller Michael B , Chhouk Brian , Enyenihi Liz , Rosen Ila , Stronge Edward , Zhao Boxun , Kim Dachan , Choi Jaejoon , Khoshkhoo Sattar , Kim Junho , Ganz Javier , Travaglini Kyle J , Gabitto Mariano I , Hodge Rebecca D , Kaplan Eitan S , Lein Ed S , De Jager Philip L. , Bennett David A. , Lee Eunjung Alice , Walsh Christopher A
Published: January 2025

Background

Alzheimer’s disease (AD), an age‐associated neurodegenerative disorder, is characterized by progressive neuronal loss and the accumulation of misfolded proteins such as amyloid‐β and tau. While neuroinflammation, mediated by microglia and brain‐resident macrophages, plays a pivotal role in AD pathogenesis, the intricate interactions among age, genes, and other risk factors remain elusive. Somatic mutations, known to accumulate with age, instigate clonal expansion across diverse cell types, impacting both cancer and non‐cancerous conditions.

Method

Utilizing molecular‐barcoded deep panel sequencing, which enables sensitive detection of somatic mutations with allele fractions as low as 0.1%, we profiled clonal somatic mutations among 149 cancer driver genes in 311 prefrontal cortex samples from AD patients and matched controls. Fluorescence‐activated nuclei sorting and single‐nucleus RNA sequencing were further used to study the cell‐type composition and transcriptomic impact of somatic mutations.

Result

Our study unveiled an elevated occurrence of somatic single‐nucleotide variants and insertions/deletions within cancer driver genes in AD brains. Recurrent somatic mutations, often multiple, were observed in genes associated with clonal hematopoiesis (CH). Remarkably, these somatic mutations were specifically enriched in CSF1R+ microglia and exhibited signals of positive selection, suggesting mutation‐driven microglial clonal expansion (MiCE) in AD brains. Single‐nucleus RNA sequencing of temporal neocortex samples from an additional 62 AD patients and matched controls revealed a nominal increase in mosaic chromosomal alterations (mCAs) associated with CH in AD microglia, with microglia carrying mCA exhibiting upregulated pro‐inflammatory genes, resembling the transcriptomic features of the disease‐associated state in AD.

Conclusion

Our findings indicate that proliferation‐related somatic mutations in microglia are prevalent in normal aging but further enriched in AD, driving MiCE and promoting inflammatory, disease‐related microglial signatures. This study provides crucial insights into microglial clonal dynamics in AD, potentially paving the way for novel approaches to AD diagnosis and therapy.
A therapeutic roadmap to restore the SORL1‐retromer recycling complex
Authors: Merchant Kalpana M.
Published: January 2025

Genetic, cell biology and autopsied brain tissue studies indicate that deficits in the SORL1‐retromer complex play a critical role in the pathogenesis of Alzheimer’s disease (AD). SORL1 is an endosomal receptor that interacts with the retromer heterotrimer core complex consisting of VPS26‐VPS35‐VPS29. Together, SORL1‐retromer regulate endosomal recycling of several AD‐related cargos such as amyloid precursor protein. In cell and animal models, deficits in SORL1 or retromer core levels recapitulate the prototypical biomarker signature and cytopathology of AD. Thus, restoration of SORL1‐retromer recycling function offers an attractive therapeutic opportunity to slow or stop the progression of AD. This talk will detail a multi‐modality drug development strategy founded on precision neurology principles. Specifically, there will be a discussion on small molecules and gene therapy drug development programs targeting SORL1 and/or the retromer core as well as a comprehensive biomarker strategy that has been integrated into the programs to de‐risk and facilitate clinical drug development.
Chronic traumatic encephalopathy neuropathologic change is associated with higher stage limbic‐predominant age‐related TDP‐43 encephalopathy
Authors: Song Hailong , Ameen‐Ali Kamar E , Kennedy‐Dietrich Claire , Dolle Jean‐Pierre , Lee Eddie B , Smith Douglas H , Stewart William
Published: January 2025

Background

Traumatic brain injury (TBI) is recognized as one major, potentially modifiable risk factor for neurodegenerative disease (NDD). Autopsy studies describe a range of neuropathologies in a proportion of individuals surviving late after TBI, most frequently the tau associated pathology, chronic traumatic encephalopathy neuropathologic change (CTE‐NC). In addition to tau, other NDD pathologies are described. Of these, deposition of abnormally phosphorylated transactive response DNA‐binding protein 43 (pTDP‐43) has been reported in association with CTE‐NC. However, to date the prevalence and distribution of pTDP‐43 in CTE‐NC and its distinction from pathology of wider NDD has not been formally assessed.

Method

Patients with history of exposure to repetitive mild traumatic brain injury (rmTBI) and documented NDD (n = 30), together with age‐matched controls with no known TBI exposure, either with (n = 24) or without (n = 18) NDD, were identified within the CONNECT‐TBI archive. Whole slide digital images of standardized brain tissue sections stained for pTDP‐43 (1D3) were reviewed, and the pattern and distribution of pathology mapped.

Result

Overall, prevalence of pTDP‐43 pathology was similar among rmTBI patients (40%) and their age‐matched controls with NDD (33%; p = 0.7778). However, while pTDP‐43 was typically localized in controls with NDD and in rmTBI patients without CTE‐NC (limbic‐predominant age‐related TDP‐43 encephalopathy [LATE] stage 1‐2), in patients with CTE‐NC this pathology was more often widespread and high stage (LATE stage 3; p = 0.0045).

Conclusion

These results demonstrate rmTBI is associated with higher stage LATE pathology than in equivalent age matched controls and individuals with wider, non‐TBI related NDD. Further studies are required to characterize the association between TBI and TDP‐43 proteinopathy, including the contribution, if any, of this pathology to clinical sequelae of TBI related neurodegenerative disease.
Harmonization of data from neuropsychological tests used in different prospective studies‐ Descending a Tower of Babel
Authors: Shishegar Rosita , Cox Timothy , Markovic Shaun J , Tallapragada Bhargav , Bourgeat Pierrick , Dore Vincent , Laws Simon M , Porter Tenielle , Burnham Samantha C. , Feizpour Azadeh , Weiner Michael S. W. , Hassenstab Jason J. , Morris John C. , Rowe Christopher C. , Villemagne Victor L , Masters Colin L. , Fripp Jurgen , Lim Yen Ying , Doecke James D. , Sohrabi Hamid R. , Maruff Paul
Published: January 2025

Background

Cognitive dysfunction is central to clinicopathological models of Alzheimer’s disease (AD). While AD prospective studies assess similar cognitive domains, the neuropsychological tests used vary between studies, limiting potential for aggregation. We examined a machine learning (ML) data harmonisation method1 for neuropsychological test data to develop a harmonised PACC score for the Alzheimer’s Dementia Onset and Progression in International Cohorts (ADOPIC) consortium.

Method

ADOPIC included longitudinal clinicopathological data from AIBL (N = 1765), ADNI (N = 1779) and OASIS (N = 440) cohorts (Table 1). Harmonization involved three stages. First, cognitive domains of interest and the neuropsychological tests assessing each were defined. Second, a standardized scoring and naming convention was established for demographic and neuropsychological outcomes. Third, the ML harmonisation approach1 was applied. Test scores present in one cohort, but not another, were treated as missing and imputed using ML before calculating a PACC1. Imputation utilized data from neuropsychological tests, age, sex, years of education, and APOE‐ɛ4 status. We validated the harmonized PACC (H‐PACC) by randomly simulating missing cognitive scores and analysing percentage error of imputed scores versus actual data1. Validity of harmonized scores was determined by their sensitivity to decline associated with amyloid positivity and clinical disease stage. Linear mixed models (LMMs) modelled trajectory of change on H‐PACC and AIBL PACC scores (including identical tests), with time, CDR‐global score, and amyloid status (Aβ‐/Aβ+) interactions as fixed effects. Sex and age at baseline were covariates. Variation in baseline and decline in PACC scores was modelled using random intercepts and slopes. Effect sizes for LMMs were computed with pseudo‐R‐squared.

Result

Percentage errors for imputed neuropsychological test scores showed high accuracy with low standard deviations (Figure 1). Sensitivity to clinicopathological disease stage was qualitatively similar for the H‐PACC and AIBL PACC (Figure 2), both discriminating (p<0.001) annual decline rates of Aβ+ CDR 0.5 and CDR≥1 groups from Aβ‐ CDR 0 group. Effect sizes were substantial, with H‐PACC and AIBL PACC data explaining 95% and 93% of variance, respectively.

Conclusion

The H‐PACC, developed via ML harmonization, was precise and has utility for aggregating neuropsychological test data to be used in prospective AD studies.

References:

1https://doi.org/10.1002/alz.044302

2https://doi.org/10.1093/bioinformatics/btr597
Clinical presentations of atypical forms of Alzheimer's Disease and its correlates with functional imaging: the importance of early detection, a series of cases
Authors: Mariani Francesca
Published: January 2025

Background

The prevalence of Dementia in Latin America countries is growing and early presentations of Alzheimer´s Diseases with atypical forms are even more frequently. As the clinical presentation of these variants shows an overlap with other dementia disorders, the differential diagnosis is often challenging. We presented three cases of atypical forms of AD who count with cognitive assessment and pet imaging confirmation in order to being able to discuss the most important points of clinical assessment in every case.

Method

Case 1: 60‐year‐old woman with a 2‐year history of progressive anterograde memory deficit, that evolved with a typical corticobasal syndrome with extrapyramidal signs and left superior limb dystonia. Case 2: 65‐year‐old woman with a 1‐year history of progressive visual loss, difficulty in stimuli detection that evolved with memory loss and Anosognosia. Case 3: 68‐year‐old man with a 2‐year history of speech difficulties with reduced fluency and verbal initiative, compromise in naming, repetition and understanding of syntactic relationships. Associate alexia and agraphia. In evolution adds executive and memory impairment, visuoconstructional deficits and ideomotriz apraxia. The three cases count with 18F‐FDG and 11C‐PIB PET/ CT studies supported the diagnosis of Alzheimer’s disease.

Result

This are three cases of atypical presentations of AD with imaging biomarkers confirmation and its particular cognitive assessment characteristics. In two cases, the beginning of the functional history is what marks the differential, in the third case, the evolution is what marks the characteristics of the disease.

Conclusion

Even when we have imaging studies, and especially when we do not have them, which is the majority of cases in Latin America, the clinical examination and in‐depth history are crucial to detect early symptoms. These symptoms could constitute the key elements for an adequate differential diagnosis. Likewise, atypical cases invite us clinicians to carry out rigorous and timely follow‐up, without taking the clinical presentation of our patients for granted. The advancement of technology and imaging biomarkers has changed the way we do clinical work, but we must not forget the value of the latter.
Tau different conformers; seeds ‐ how do the first ones arise?
Authors: Lövestam Sofia ,   Scheres and Goedert
Published: January 2025

Background

Intermediate species in the assembly of amyloid filaments are believed to play a central role in neurodegenerative diseases and may constitute important targets for therapeutic intervention.

Method

We used time‐resolved cryogenic electron microscopy (cryo‐EM) to study the in vitro assembly of recombinant truncated tau into paired helical filaments of Alzheimer’s disease or into filaments of chronic traumatic encephalopathy.

Result

We report the formation of a shared first intermediate amyloid filament, with an ordered core comprising residues 302‐316. At later time points, the first intermediate amyloid disappears and we observe many different intermediate amyloid filaments, with structures that depend on the reaction conditions. At the end of both assembly reactions, most intermediate amyloids disappear and filaments with the same ordered cores as those from human brains remain.

Conclusion

Tau filaments assemble via polymorphic intermediates.
Introduction to what we still need to learn about ARIA
Authors: Sperling Reisa A
Published: January 2025

The short introduction will highlight what we have learned about amyloid related imaging abnormalities (ARIA) since 2011 and the critical questions that remain to be elucidated. In particular, we need to better understand the risk factors and mechanisms that underlie the relatively rare symptomatic cases. We will highlight the importance of bi‐directional translational research to bring insights from the laboratory to the clinic and findings from clinical trials back to the bench.
CAA and ARIA: Emerging Concepts and Opportunities for Translation
Authors: Greenberg Steven M.
Published: January 2025

Two broad classes of mechanisms have emerged for understanding the Amyloid‐Related Imaging Abnormalities (ARIA) associated with anti‐beta‐amyloid immunotherapy. One set of mechanisms proposes that ARIA is driven by large‐scale transfer of antibody‐bound amyloid from brain parenchyma to the perivascular and vascular compartments. This class of mechanisms is indirectly supported by neuropathological evidence that immunotherapy substantially clears plaque amyloid while increasing vessel‐associated amyloid, but has been difficult to directly demonstrate.

The second set of mechanisms proposes that ARIA is substantially driven by direct antibody binding to vascular amyloid deposits (cerebral amyloid angiopathy or CAA). The role of CAA in generating ARIA is supported by observations on propensity of transgenic mouse models with vascular amyloid to develop ARIA. Another line of supporting evidence comes from the striking neuroimaging similarities between ARIA and the spontaneous occurring syndrome of CAA‐related inflammation, a clinical entity that appears to be triggered by generation of anti‐amyloid autoantibodies. This class of mechanism predicts that CAA present prior to initiating immunotherapy should increase ARIA risk, a hypothesis supported by recent identification of cerebral microbleeds and cortical superficial siderosis on baseline MRI as independent risk factors for subsequent ARIA.

Identifying causative pathways to ARIA—the role of preexisting CAA in particular—should provide a blueprint towards future trials aimed at preventing or mitigating ARIA’s clinical impact.
The role of glial cells in neuroinflammation in the context of Alzheimer’s disease
Authors: Ferreira Rafaella de Lima Corrêa , Heimfarth Luana , Ferreira Sergio T , Ribeiro Felipe C
Published: January 2025

Background

Alzheimer’s disease (AD) stands as the predominant form of dementia worldwide. The pathogenesis of AD encompasses elevated brain levels of amyloid‐β oligomers (AβOs), recognized as central neurotoxins linked to AD. The accumulation of AβOs is neurotoxic, resulting in detrimental effects such as synapse loss, mitochondrial dysfunction, and impairment of proteostasis mechanisms. Neuroinflammation, particularly the activation of microglia and astrocytes to pro‐inflammatory states, has been implicated in the pathogenesis of various neurodegenerative diseases. This study aimed to investigate the role of microglia and astrocytes within the framework of AD pathophysiology.

Method

Here, we explored changes in morphology and function of glial cells in experimental models of AD, assessing (1) in vitro activation of microglia and astrocytes induced by AβOs, and (2) in vivo microglia and/or astrocytic activation in mice receiving an intracerebroventricular (icv) infusion of AβOs. Analysis of cytokine expression and glial markers was conducted using qPCR, ELISA, and fluorescence microscopy.

Result

Initial results suggest an upregulation of glial activation markers, such as GFAP and F4/80, and complement immune system markers such as C1q, seven days post icv infusion of AβOs. No significant differences were observed in TNF‐α expression. Immunofluorescence analyses further indicate heightened nuclear translocation of NFkB in microglia cultures exposed to AβOs for 3 hours.

Conclusion

The results align with a pivotal role of glial cells in AD pathogenesis, showcasing activated glial activity in both in vitro and in vivo models. In the context of chronic processes, these cells may persist in an activated state, releasing cytokines, complement components, and chemokines, potentially contributing to Aβ production and accumulation, thereby exacerbating pathology.
APOE genotype modifies benefits of calorie restriction against aging
Authors: Qiao Wenhui , Chen Yixing , Ren Yingxue , Ikezu Tadafumi C , Johnson Stephen , Li Fuyao , Chen Kai , Pan Meixia , Kashyap Sonu , Bueser Katrina Rae , Wetmore Allison , Kurti Aishe I. , Meneses Axel D. , Owens Jada A. , Chini Eduardo N. , Chen Jun , Han Xianlin , Bu Guojun , Zhao Na
Published: January 2025

Background

The efficacy of Calorie Restriction (CR) in enhancing cognition, promoting healthy aging, and extending lifespan is well‐established. Yet, it remains unclear whether the apolipoprotein E (APOE) genotype, a known modifier for aging and age‐related disorders, influences the beneficial effects of CR in countering aging.

Methods

To investigate this question, we utilized humanized APOE mouse models, which express APOE2, APOE3, or APOE4 alleles systematically (refer to as E2, E3, and E4 mice). These mice were subjected to either ad libitum (AL) feeding or 30% CR feeding, starting from 12 months and continuing up to 20 months of age (N = 11‐20/ genotype /group, mixed sex). We monitored energy expenditure using the Comprehensive Laboratory Animal Monitoring System (CLAMS). Additionally, we evaluated anxiety levels and memory capabilities through various behavioral tests. Finally, we collected brain, blood, and feces samples for transcriptomic, lipidomic, and microbiomic analyses.

Results

CLAMS measurements showed that CR significantly decreased the metabolic rate in E3 and E4 mice, but not E2 mice, during the non‐feeding period of the CR group, compared to the AL group. Furthermore, CR reduced anxiety and enhanced associative memory in E3 and E4 mice relative to the AL group. Brain transcriptomics revealed that CR upregulated the cholesterol synthesis pathway, potentially improving myelination‐related pathways in E3 and E4 mice. This finding was further validated by the increased staining intensity of myelin basic protein (MBP) observed in E3 and E4 mice from an independent cohort. In contrast, these effects were not pronounced in E2 mice. Additionally, while CR’s impact on the brain lipid profile was minor across all APOE genotypes, it significantly altered blood lipid profile of E2 mice, with minimal changes observed in E3 and E4 mice. Finally, in microbiomics, CR led to notable changes in the abundance of Bifidobacterium species in E3 and E4 mice and Lactobacillus species in E2 mice.

Conclusions

Our study highlights the role of APOE genotypes in modulating the diverse effects of CR on cognition, brain transcriptomics, lipid metabolism, and the microbiome, providing a crucial foundation for considering APOE genotypes in developing prevention strategies for aging and age‐related disorders.
TDP‐43 regulates the ubiquitination degradation of BMAL1, cellular glucoseutilization and energy absorption
Authors: Gu Jianlan , Zhang Liti , Yan Ruolan , Chu Dandan , Liu Fei
Published: January 2025

Background

Circadian rhythm disorder is not only a characteristic of neurodegenerative diseases but may participate in driving the pathological development in early stages of these diseases. Transactive response DNA‐binding protein of 43 kDa (TDP‐43) knockdown and its pathological aggregation are associated with severe neurodegenerative diseases such as amyotrophic lateral sclerosis.

Methods

C57BL/6 mice were sleep deprived and sarcrificed at ZT0, ZT6, ZT12, and ZT18 and detected by Western blots. M17 cells infected with Lenti/TDP‐43KO and then performed to RNA sequencing, and detected by qPCR to verify the RNA‐seq results. Mice were intracerebroventricular injected with AAV/shTDP‐43 and detected by Western blots and qPCR. HEK‐293T cells were transfected with TDP‐43, TDP‐43KO or treated with MG132 or cycoheximide and performed to immunoprecipitation and detected by Western blots.

Results

Herein we found that TDP‐43 expression exhibited rhythmic patterns and regulated the expression of multiple circadian genes such as BMAL1, CLOCK, CRY1, and PER2, particularly affecting the mRNA and protein levels of BMAL1; knockdown of TDP‐43 in mice brain also changed the autonomous circadian wheel behavior, cognitive and balance ability of the animal. Further, we discovered that TDP‐43 could at least regulate the expression and alternative splicing of USP13, thereby affecting the protein level of USP13 and the ubiquitin‐mediated degradation of BMAL1 and regulated the AMPK signaling pathway, resulted in changing the cellular glucose uptake and ATP production.

Conclusion

Our findings would expand the understanding of the role of TDP‐43 dysfunction in circadian rhythm disruption in neurodegenerative diseases and provide new mechanistic evidences supporting the interaction between circadian rhythm disruption and neurodegeneration.
Neuroprotective Effect of Inosine Against Rotenone Induced Motor deficit & Biochemical Abnormalities in Wistar Rats
Authors: Singhal Manmohan , Agrawal Mohit , Chaudhary Hema
Published: January 2025

Background

Parkinson’s disease is a hypokinetic disorder characterized by selective loss of dopaminergic in substantia nigra pars compacta (SNPc) region of mid‐brain. Dopaminergic degeneration of neurons is considered to be due to oxidative stress, neuroinflammation, neurons mitochondrial dysfunction and glutamate excitotoxicity etc. Inosine a purine nucleoside has been reported to produce anti‐oxidant, anti‐inflammatory and neuromodulatory actions in previous studies. In the current study we have investigated the role of Inosine against rotenone induced motor deficit and biochemical abnormalities in Wistar rats

Method

Rats were treated with 1.5mg/kg rotenone subcutaneously for 35 days. Inosine (50,100 and 200 mg/kg i.p.) was administered after 30 minutes of rotenone administration from day 7th to 35th day. Rotenone caused significant reduction in motor functions and body weight and produced elevation in striatal oxidative burden. The biochemical analysis revealed that there is reduction in the level of anti‐oxidants (GSH, Catalase, SOD) in the animals following rotenone administration. Whereas inosine treated rats were stable and regained their body weight.

Result

In addition inosine significantly attenuated rotenone induced motor deficit and striatal oxidative stress. Outcomes of the current study suggest neuroprotective potential of inosine and its ability to correct movement disability and thus could prone to be useful candidate molecule in the management of motor disorders.

Conclusion

Outcomes of the current study suggest neuroprotective potential of Inosine and its ability to correct movement disability and thus could prove to be useful candidate molecule in the management of motor disorders.
Exploring the neuroprotective role of ubiquinone by attenuation of oxidative stress and mitochondrial dysfunction in an experimental model of myalgic encephalomyelitis/chronic fatigue stress
Authors: Vashishth Anushka
Published: January 2025

Background

Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is categorized as a complicated disorder of extreme fatigue lasting for at least six months without any underlying medical problem and currently has no concrete treatment regimen. This is associated with neurological complications like brain fog, insomnia, psychiatric disturbances and above all neuroinflammation. A chronic forced swim test model of CFS has been established since more than a decade at our laboratory. An important biomarker in CFS is reduced levels of ubiquinone that leads to oxidative stress in neurons, thus impairing neurodevelopment, and ultimately learning and memory.

Method

A 15‐day chronic forced swim daily for 6 minutes induce CFS symptoms in mice. The neurobehavioral studies consist of assessment of locomotor activity, anxiety, motor coordination, cognitive dysfunction in addition to biochemical parameters of catalase, acetylcholinesterase, reduced glutathione, superoxide dismutase, lipid peroxidation and nitrite levels in cortex & hippocampus of mice brain. Histopathological analysis of differences between control and treatment groups was also conducted. Mitochondrial enzyme complex (1‐1V) was done to evaluate mitochondrial dysfunction. An additional in vitro study was conducted using PC12 cell lines to study ROS generation and DNA damage following cell viability in an H202 induced oxidative stress model.

Result

Treatment with ubiquinone showed a positive impact by significantly improving the behavioral, biochemical, and cellular parameters of stress after reversing the imbalance between free radicals and anti‐oxidants which is attributed to its anti‐oxidant nature. Histopathological analysis showed significant neuronal loss in diseased group (darkly stained neurons with fragmented or no nucleus and few of the cells were shrunken or sickle shaped and with altered morphology) as compared to naïve group that showed improvement on drug treatment. Results of in vitro were consistent with above findings.

Conclusion

As per available literature, this study successfully adds to the potential of ubiquinone as a treatment strategy for neurodegeneration. In an experimental model of CFS for evaluation of neurobehavioral, biochemical, and cellular changes to mitigate neuroinflammation, ubiquinone exhibits its role to be used further in research for severe neurodegenerative disorders like AD and PD. With more research this could lead to a safer and cost‐effective drug target.
Genotyping transposable element insertions and their novel application in gene mapping strategies for Alzheimer’s disease (AD) endophenotypes
Authors: Sargurupremraj Muralidharan , Yang Qiong , Jian Xueqiu , Himali Jayandra J. , Seshadri Sudha
Published: January 2025

Background

Consortium‐wide studies of volumetric brain imaging measures with single‐nucleotide polymorphisms (SNPs) have revealed numerous disease‐risk SNPs and emphasized the significance of brain imaging phenotypes as preclinical markers (endophenotypes) for Alzheimer’s disease (AD). Nevertheless, the bulk of these risk variants are in genomic regions that govern multiple genes, posing major challenges in fine‐mapping strategies. Evolutionarily conserved transposable elements are master regulators of gene expression, and by studying these endogenous gene regulatory units in relation to AD endophenotypes, we aimed to better identify the disease‐causal gene.

Method

Within the Trans‐Omics for Precision Medicine Program (TOPMed) initiative, whole‐genome sequencing data (WGS) of the Framingham Heart Study individuals were used for genotyping polymorphic transposable element insertions (pTEIs). Fitting a whole‐genome regression model, we tested the association of the genotyped pTEIs with brain‐imaging measures (N = 2,472) (white matter hyperintensity, WMH; hippocampal volume, HV; total‐brain volume, TBV) and general cognitive function, GCF (N = 2,765). We performed i) single‐variant analyses (minor allele frequency ≥ 1%) and ii) region‐based burden tests per gene collapsing rare pTEIs overlapping with canonical transcripts and regulatory marks. We examined the colocalization evidence between the pTEIs and SNPs identified in genome‐wide association studies (GWAS) for our traits of interest, thus enhancing the fine‐mapping of disease‐risk SNPs.

Result

By studying the polymorphic nature of TE insertions in relation to brain‐imaging and cognitive traits, we identify evidence for multiple putative disease‐causal genes, albeit suggestive. Notably, this includes genes (BACH2, SPATA5) implicated in autoimmune and neurodevelopmental disorders, now showing pTEI‐based predisposition to cognitive decline and hippocampal atrophy. WMH and TBV risk SNPs exhibit colocalization evidence with pTEIs involved in the feature elongation of ECHDC3 and CRHR1, respectively, potentially leading to loss of gene function. Interestingly, the inclusion of ECHDC3 gene loss‐of‐function variants in burden test analysis (UK Biobank) shows association with brain maturation and ageing markers.

Conclusion

Our pragmatic approach using existing WGS data to genotype endogenous regulatory units for studying genetic underpinnings of preclinical AD markers identifies putatively novel disease‐causal genes with clear biological function. As a proof of concept, our approach highlights the scope of extending to other cohorts and AD related neurodegenerative disorders.
Selective Vulnerability of hippocampi for inducible nitric oxide synthase and 3‐nitrotyrosine in Alzheimer’s disease: A Postmortem Study
Authors: Justo Alberto Fernando Oliveira , Toscano Eliana Cristina de Brito , Paes Vitor Ribeiro , Leite Renata Elaine Paraizo , Pasqualucci Carlos Augusto , Jacob‐Filho Wilson , Nitrini Ricardo , Grinberg Lea T. , Suemoto Claudia Kimie
Published: January 2025

Background

Nitric oxide (NO) is involved in synaptic transmission and cerebral plasticity, playing a role in the memory process. However, in states of brain inflammation, hypoxia, or ischemia, there is induction of inducible nitric oxide synthase (iNOS) expression by astrocytes and pyramidal cells in the brain. Under conditions of chronic activation, there is a decoupling of iNOS dimers, leading to a massive generation of superoxide anion and peroxynitrite, O2.‐ and ONNO‐ respectively, with a significant neurotoxic role by oxidative stress. We aimed to quantify the expression of iNOS and 3‐nitrotyrosine (3‐NT, an oxidative marker of ONNO‐) in the hippocampus of individuals with AD neuropathological changes (ADNC)compared to individuals without AD pathology and investigate the association of iNOS and 3‐NT expression with cognition abilities and AD pathology.

Method

We evaluated the expression of the enzymes iNOS and 3‐NT using immunohistochemistry in the cornu ammonis (CA) and dentate gyrus from hippocampi from subjects with ADNC and the sex‐matched controls. Cognitive abilities were evaluated using the Clinical Dementia Rating (CDR) and AD pathology using Braak staging for neurofibrillary tangles and the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) for neuritic plaque. We used linear regression to examine the association of iNOS and 3‐NT with cognition and AD pathology.

Result

Sociodemographic and clinical variables were similar between the control and ADNC groups (Table 1). In individuals with ADNC, iNOS was overexpressed in the CA1 (p = 0.029) and CA3 (p = 0.030). Similarly, 3‐NT was overexpressed in CA3 (p = 0.039), shown in Figure 1. No expression was seen in the dentate gyrus for iNOS and 3‐NT. Increased levels of iNOS in CA3 were associated with AD pathology reported in CERAD score (β = 12.44, IC95% = 0.88;24;00, p = 0.036) and Braak staging (β = 25.48, IC95% = 6.12;44.84, p = 0.012), and with cognitive abilities (β = 73.05, IC95% = 29.25;149.90, p = 0.025). Increased 3‐NT levels in CA3 were associated only with cognitive abilities (β = 1.48, IC95% = 0.08;2.87, p = 0.038) (Table 2).

Conclusion

CA3 neurons shows a particular susceptibility to accumulate iNOS and 3‐NT during AD progression. The association between iNOS and functional cognition underscore the role of oxidative stress in AD pathogenesis. Of note, CA2 sector, a resistant region to AD showed no signs of oxidative stress in AD.
The signaling function of CHI3L1/YKL‐40 in neuroinflammation and Alzheimer’s disease
Authors: Huang Yu‐Wen Alvin
Published: January 2025

Background

Chitinase‐3‐like protein 1 (CHI3L1, or YKL‐40) is an important regulator of immunity and, in the brain, is primarily secreted by activated astrocytes and heralds a neurotoxic inflammatory state. While it has been well known as a high‐profile biomarker for Alzheimer’s disease (AD) and inflammatory brain conditions (e.g., aging, trauma and autoimmune disorders), the biological role of CHI3L1 in neuroinflammation and AD pathogenesis remains to be elucidated.

Method

We used a combination of in‐vitro and in‐vivo tools to recapitulate and manipulate CHI3L1 secretion in neuroinflammation, including i) cultures of primary mouse astrocytes and iPSC‐derived human neurons and neural stem cells (NSCs), and ii) established mouse models of astrocyte‐specific Chi3l1/Chil1 conditional knockout, Alzheimer’s disease (5xFAD) and the autoimmune‐mediated, primary astrocytopathy (neuromyelitis optica, NMO) hallmarked by CHI3L1 induction.

Result

We first confirmed the induction of CHI3L1 and neuroinflammatory features in cultured astrocytes activated by well‐characterized pro‐inflammatory stimuli, including the cytokine IL‐1b, amyloid‐b peptides (Ab42) and the autoantibody targeting astroglial protein aquaporin 4 (AQP4 IgG, as in NMO). Strikingly, astrocyte‐secreted CHI3L1 inhibited proliferation and neuronal differentiation of NSCs, and enhanced Ab production, tau phosphorylation and apoptosis in differentiated neurons in vitro. In vivo, we analyzed brain tissues from mice overexpressing CHI3L1 or receiving stereotaxic transfer of AQP4 IgG, and observed a significant reduction in adult hippocampal neurogenesis and defective learning behaviors as in 5XFAD mice; such in‐vivo defects, of note, can be rescued by CHI3L1 depletion in astrocytes, as demonstrated in our compound AD transgenic mice of astrocyte‐specific CHI3L1 knockout. We further characterized the molecular mechanism of CHI3L1 by identifying the receptor and downstream pathway in NSCs. Mechanistically, CHI3L1 engages the CRTH2 receptor and dampens β‐catenin signaling, which is critical for neurogenesis. Finally, we showed that this CHI3L1/CRTH2/β‐catenin cascade can be targeted to restore neurogenesis and ameliorate cognitive deficits resulting from neuroinflammation.

Conclusion

Our findings provide the pioneering evidence for the biological role of CHI3L1 in the brain, departing from its long‐regarded role as merely a biomarker. The discoveries we made here would be highly advantageous for the development of much‐needed therapeutics to prevent neuroinflammatory toxicity in AD and relevant brain disorders.
Microglial Activation Alters Chromatin Accessibility of AD‐Associated Transcription Factors
Authors: Chatila Zena K , Mares Jason , Vardarajan Badri N. , Elyaman Wassim , Menon Vilas , Bradshaw Elizabeth M
Published: January 2025

Background

While dysregulated local innate immunity and microglial dysfunction are thought to play a pathogenic role in Alzheimer’s disease (AD), the underlying mechanisms remain unclear. Importantly, activation of immune and metabolic pathways in myeloid cells can lead to a functional reprogramming process, termed innate immune memory (IIM), in which the response to an initial stimulus shapes long‐lasting epigenetic modifications that alter the response to future inflammatory stimuli. This epigenetic imprinting process has been minimally studied in microglia. We posit that immune activation may result in epigenetic reprogramming which contributes to sustained microglial dysfunction as a pathogenic mechanism in AD.

Method

We treated an in vitro primary monocyte‐derived microglial model with a range of activators of specific innate immune receptors, disease‐associated stimuli, and pathogens. We investigated whether any of these stimuli induce epigenetic remodeling using single nucleus RNA‐and ATAC‐sequencing after a washout and seven‐day rest period, and probed for alterations in AD‐associated molecular pathways. We compared the rewired epigenetic signatures we observed to ATAC‐sequencing data from human microglia from post‐mortem AD brain tissue.

Result

We found that three stimuli in particular resulted in unique remodeled chromatin signatures: E. coli LPS (TLR4 activator), CpG ODNs (TLR9 activator), and HSV‐1 infection. Motif enrichment identified binding sites of AD‐associated transcription factors within the differential chromatin peaks remodeled by these stimuli. For example, TLR9 activation with CpG ODNs altered chromatin accessibility of MEF2A and MEF2C binding sites, transcription factors that have been genetically associated with AD. We identified that features of the unique chromatin signatures associated with these stimuli overlap with post‐mortem microglial chromatin configuration from human AD brain tissues. Lastly, we identified the functional consequences of microglial IIM induced by these three primary stimuli upon delayed secondary stimulation, including altered cytokine response.

Conclusion

Microglial activation by specific inflammatory stimuli causes epigenetic rewiring, resulting in differential accessibility of AD‐associated transcription factors and altered response to future stimuli. In this way, microglial activation and IIM may later contribute to microglial dysfunction in AD pathogenesis.