bluuebunny/crossref_metadata_2025 huggingface dataset:
Commonalities in the lipid profile shift in ApoE ε4 risk variant and mild cognitive impairment highlight acyl chain remodeling
Authors: McIntire Laura Beth , Mares Jason , Costa Ana Paula , Lazarian Artur , Wartchow Krista Minéia , Dartora William , Nuriel Tal , Menon Vilas
Published: January 2025

Background

At least one‐third of the identified risk alleles from Genome Wide Association Studies of Alzheimer’s disease (AD) are involved in lipid metabolism, lipid transport, or direct lipid binding. BIN1 which is also known as Amphiphysin 2; and PICALM which are involved in phosphoinositide metabolism and binding rank just below the highest risk gene variant of Apolipoprotein E (ApoEε4), a cholesterol and phospholipid transporter. In addition to genetic variants, lipidomic studies have reported severe metabolic dysregulation in human autopsy brain tissue, CSF, blood and multiple mouse models of AD. We aimed to identify an overarching metabolic pathway in lipid metabolism by integrating analyses of transcriptomics and lipidomics in the Religious Order Study‐Memory Aging Project (ROS‐MAP) as well as models of disease.

Method

Lipidomic data in ROS‐MAP was generated using the Biocrates AbsoluteIDQ p180 platform, a multiplexed targeted metabolomic assay covering lipids and metabolites including acylcarnitines, glycerophospholipids and sphingolipids. We confirmed global lipid dysregulation of acyl chain remodeling using pharmacological inhibitors of lipid modifying enzymes in cell models overexpressing amyloid precursor protein (APP) and identified similarly dysregulated lipids in an animal model of AD overexpressing APP harboring the Swedish mutation in a targeted lipidomic panel of over 600 lipid species.

Result

Our analysis of transcriptomic data from ROS‐MAP lead to identification of multiple genes in the pathway for acyl chain remolding, Lands Cycle, which were associated with cognitive decline independently of amyloid and tau pathologies. Coordinate changes in lipids were found to be dysregulated in association with both mild cognitive impairment (MCI) and the ApoEe4 genotype which showed a correlated lipid profile shift. WGCNA analysis identified dysregulated lipids within a single module which are substrates and products in the Lands Cycle for acyl chain remodeling.

Conclusion

Our studies highlight the critical dysregulation of acyl chain remodeling in ApoEe4 carriers and MCI in human brain which could be modeled in mouse and cell models of disease. A coordinated lipid profile shift in both ApoEe4 carriers and MCI suggest pathological changes in lipid metabolism underly early disease and highlight lipid dyshomeostasis as a tractable target for early disease modifying intervention.
Carbonic anhydrase inhibitors (CAIs) decrease cardiac amyloid β pathology, mitigating neuro‐signaling maladaptive remodeling and improving cardiac function in Tg2676‐ AD mouse model
Authors: Elia Andrea , Parodi‐Rullan Rebecca M , Vazquez‐Torres Rafael , Carey Ashley M , Fossati Silvia
Published: January 2025

Background

FDA‐approved carbonic anhydrase inhibitors (CAIs) have been shown to attenuate Aβ pathology, neurodegeneration, and cerebrovascular dysfunction in models of Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), suggesting a key role for CAs as a novel and previously unexplored target for AD therapy. Amyloid β accumulation severely impairs the cerebral neuro‐signaling pathway with a progressive loss in neurotrophic factors (NTFs, i.e., NGF and BDNF), potentially also affecting the cardiac nervous system and culminating in lethal heart dysfunction. Yet, no studies have proposed the use of CAIs for treating and preventing the systemic and cardiac effects of amyloidosis and AD.

Methods

Here, we explored for the first time, the protective effects of a chronic CAIs therapeutic regimen against cardiac amyloid pathology, neuronal fibers’ loss, and heart neurotrophic dysregulation in Tg2576 mice, a widely used model of AD and cerebral amyloidosis.

Results

Cardiac fibrosis enhancement along with progressive Aβ deposition in the heart seriously affected the cardiac neuro‐signaling pathway culminating in a robust decline of BDNF expression associated with myocardial adrenergic nerve fibers and regenerated nerve endings impoverishment (stained with TH and GAP‐43 respectively) in 12‐month‐old Tg2576 mice compared to age‐matched WT littermates. These degenerative mechanisms severely compromised heart function, evidenced by a decline of both ejection fraction and fraction shortening percentage in Tg2576 animals. Accordingly, we observed that human Aβ40 or Aβ42 oligomers’ treatment drastically reduced BDNF and GAP‐43 expression in human neuronal cells and human cardiomyocytes. Notably, long‐term CAIs treatment in Tg2576 mice reduced Aβ accumulation in the heart tissue and reverted cardiac neuro‐signaling pathway adverse remodeling, thus ameliorating heart function, as evidenced through echocardiographic analysis. These in vivo results were validated by in vitro experiments both in neuronal and cardiac cells.

Conclusion

These findings suggest a new beneficial role of CAIs in preventing the Aβ‐induced cardiovascular remodeling and neuro‐signaling deregulation for the first time in the Tg2576 model of AD. Taken together with the positive effects of CAIs on cerebrovascular function and cognition, this study paves the way for future clinical trials aimed at repurposing FDA‐approved CAIs to prevent and correct both central and peripheral pathologies induced by AD and amyloidosis.
Specifically targeting toxic forms of tau modulates AD pathologies and inflammageing in very old triple‐transgenic mice
Authors: Sciortino Alessia , Senapati Sudipta , Al‐Shaebi Fadhl , Samples Madison , Kayed Rakez
Published: January 2025

Background

Rodent models have been proved pivotal in Alzheimer’s disease (AD) research. Nevertheless, the use of models that only recapitulate one aspect of AD neuropathology, and of early time points that might be excluding important features such as age‐dependent inflammation and senescence, could hinder the development of effective AD therapeutics. Several tau immunotherapies are currently undergoing clinical trial. Misfolding and accumulation of tau have been shown to correlate with Alzheimer’s disease (AD) progression and dementia stage. Numerous studies showed that tau removal is able to slow down AD pathology propagation and cognitive deterioration in different animal models.

Method

We developed in‐house anti‐tau antibodies that target specific toxic tau conformations and evaluated immunotherapy impact on AD‐like pathology in very old triple‐transgenic AD mice (3xTg AD), in order to capture age‐dependent aspects often overlooked in other studies. Twenty‐three months old 3xTg AD mice, that reproduce both amyloid and tau pathology, and other cellular changes associated with AD, were injected in the tail vein with 120µg of anti‐toxic tau antibody or IgG isotype control. Behavioral tests to evaluate motor and cognitive performance were carried out one week post injection. Immunohistochemistry, immunofluorescence and western blot techniques were used to investigate brain neuropathology following toxic tau removal.

Result

Treatment with conformational antibodies targeting toxic forms of tau modulated the extent of AD pathology, in the form of tau and amyloid deposition, in hippocampus and cortex. Furthermore, immunotherapy modified markers of age‐related pathology, suggesting an interplay of toxic tau with the ageing process i.e. inflammation and senescence.

Conclusion

Our study contributes to the investigation of selective tau immunotherapy approaches for AD and tauopathies. Our results suggest that specifically targeting toxic forms of tau modulates AD pathology beyond pathological protein aggregation and could have beneficial effects even at later disease stages.
MR1‐ and MAIT cell‐dependent pathology in a mouse model of AD
Authors: Brutkiewicz Randy R
Published: January 2025

Background

We have found that the MHC class I‐like MR1 molecule and the innate‐like T cells that recognize them (MAIT—mucosal‐associated invariant T cells) contribute to the development of pathology in Alzheimer’s disease (AD). Moreover, we find elevated levels of MR1 expression and increased numbers of MAIT cells in the brains of 5XFAD mice overtime; these MAIT cells express high surface levels of the T cell activation markers, CD25 and CD69. Here, we are focused on how these two phenomena are connected in AD pathology.

Method

We will analyze mice (MAITCAST) that have up to 20X the normal level of MAIT cells crossed onto the 5XFAD background and/or those expressing transgenes that encode GFP or YFP under the control of various cytokine promoters. Flow cytometry will allow us to determine the fraction of MAIT cells producing proinflammatory cytokines and their numbers, as well as their level of T cell activation markers as compared to conventional T cells, in both brain and peripheral immune organs.

Result

In normal 5XFAD mice, we found that, not only are MAIT cell higher in the brain, but also in the liver. Moreover, we have found that MAITCAST mice have up to 20X the normal level of MAIT cells in the brain, as well in peripheral tissue, such as the liver.

Conclusion

Our studies have identified an important role for the MR1/MAIT cell axis in AD pathology, and its potential utility as a novel therapeutic target for AD patients.
Microglia and extracellular vesicle‐mediated spread of Tau pathology
Authors: Ikezu Tsuneya
Published: January 2025

Background

Extracellular vesicles (EVs) carry pathogenic molecules and play a role in the disease spread, including aggregated tau proteins. The Endosomal Sorting Complexes Required for Transport (ESCRT) machinery is responsible for the biogenesis of small EVs (exosomes), thus targeting critical ESCRT molecules can disrupt EV synthesis. We hypothesize that microglia‐specific targeting of ESCRT‐I molecule Tsg101 suppresses microglia‐derived EV‐mediated propagation of tau pathology, leading to amelioration of the disease phenotype of the tauopathy mouse model.

Methods

PS19 tau transgenic mouse line was crossed with Cx3cr1CreERT2/+:Tsg101fl/fl lines for tamoxifen‐inducible Cx3cr1‐specific deletion of Tsg101 (Tsg101 cKO) in PS19 mice to generate WT, Tsg101 cKO, PS19, and PS19:Tsg101cKO groups. The animals were treated with tamoxifen or corn oil at 2 months of age and subjected to comprehensive behavioral, neuropathological, biochemical, and molecular biological assessments at 6‐7 months of age. The microglia isolated from Cx3cr1CreERT2/+:Tsg101fl/fl pups were subjected to in vitro synaptosome uptake analysis with or without 4‐Hydroxytamoxifen treatment.

Results

PS19 mice develop cognitive impairment as determined by Y‐maze, forced alternation, novel object recognition and fear conditioning, which are reversed in PS19:Tsg101cKO mice. This is correlated with reduced Alz50+ tau accumulation, neurodegenerative microglial activation, neuroinflammation and complement pathway activation as determined by bulk RNA sequencing, ELISA and neuropathology. Primary cultured Cx3cr1CreERT2/+:Tsg101fl/fl microglia with 4‐Hydroxytamoxifen treatment show reduced phagocytosis of E. coli particles and synaptosome in C1q dependent manner. Tsg101 cKO microglia show reduced expression of C3aR1 and CD68, and secretion of total and Tau+ EVs in vivo.

Conclusion

Microglia‐specific targeting of Tsg101 show beneficial effect for ameliorating the disease progression of tauopathy mouse model via suppression of EV secretion, microglial activation, tau accumulation and complement‐dependent synaptic pruning. Microglial Tsg101 is a potential therapeutic target of Alzheimer’s disease and related tauopathy.
Validation of an AAV gene therapy designed to complement the loss of TDP‐43 splicing repression for ALS‐FTD
Authors: Mallika Aswathy Peethambaran , Wong Philip C
Published: January 2025

Background

Emerging evidence support the notion that loss of splicing repression by TDP‐43, an RNA binding protein that was first implicated in ALS‐FTD, underlies their pathogenesis. Previously, we showed that delivery of an AAV9 vector at early postnatal day expressing a fusion protein, termed CTR comprised of the N‐terminal region of TDP‐43 and an unrelated splicing repressor termed RAVER1 complemented the loss of TDP‐43 in mice lacking TDP‐43 in spinal motor neurons (ChAT‐IRES‐Cre;tardbpF/F mice). To translate this potential therapeutic strategy to the clinic, it will be important to demonstrate benefit of such AAV delivery of CTR to motor neurons in adult mice. Here we validate a therapeutic approach using a recently developed AAV.PHP.eB vector that enables efficient transduction in central neurons, including motor neurons by an intra‐venous (IV) administrative route.

Method

Intra‐venous injection of AAV.PHP.eB.RAV1‐3’UTR (ChAT‐IRES‐Cre;TardbpF/F, n = 12 and ChAT‐IRES‐Cre;TardbpF/+, n = 8) and AAV.PHP.eB.GFP (ChAT‐IRES‐Cre;TardbpF/F, n = 10 and ChAT‐IRES‐Cre;TardbpF/+, n = 8) was carried out in 6 weeks old littermate animals. Histology and immunohistochemistry to show the infectivity, RT‐PCR and RNA in situ hybridization to show the rescue of splicing repression and the grip strength analysis to measure the motor strength were performed.

Result

We show that IV delivery of AAV.PHP.eB.RAV1‐3’UTR to adult ChAT‐IRES‐Cre;TardbpF/F mice efficiently transduced spinal motor neurons, repressed cryptic exon inclusion and attenuated muscle weakness.

Conclusion

These data support validation of our AAV gene therapeutic strategy to attenuate motor neuron disease, including ALS and potentially extended to other human disorders harboring TDP‐43 pathology. Other relevant results, including rescue of motor neurons and extension of life span will be presented.
Effects of APOE ε2 on different cognitive domains in the PUMCH dementia cohort
Authors: Shang Li , Dong Liling , Mao Chenhui , Huang Xinying , Chu Shanshan , Jin Wei , Wang Tianyi , LI Bo , Bao Jialu , Qiu Yuyue , Jiang Yuhan , Huang Yixuan , Gao Jing
Published: January 2025

Background

Previous studies on APOE have mostly focused on APOE ε4, while less attention has been paid to APOE ε2. The aim of this study was to clarify the effect of APOE ε2 on different cognitive domains in dementia patients.

Method

All subjects were from the Peking Union Medical College Hospital (PUMCH) dementia cohort and included clinical diagnoses of AD, VaD, FTLD, and LBD. All included individuals had completed the neuropsychological assessment. Genotypes were used to bin participants into five groups based on carrier status: ε2 carriers (ε2/ε2 or ε2/ε3), ε2/ε4 carriers, ε3/ε3 carriers, ε3/ε4 carriers, and ε4/ε4 carriers. The effect of APOE ε2 on different cognitive domains of the patients with dementia was assessed by using multivariate regression models.

Result

A total of 348 dementia patients were included in this study, with a mean age of 68.4± 9.8 years, 69.3% with AD, 14.4% with VaD, 10.1% with FTLD, and 6.3% with DLB. 19.5% were ε2 carriers, 3.4% were ε2/ε4 carriers, 30.7% were ε3/ε3 carriers, 32.3% were ε3/ε4 carriers, and 14.1% were ε4/ε4 carriers. Compared to ε3/ε3 carriers, ε2 carriers were more successful in MOCA (β = 1.93, P = 0.016), trail making test part A (β = 1.18, P = 0.025), nonverbal memory (β = 1.08, P = 0.003), AVLT 5 (β = 0.27, P = 0.039), episodic memory (β = 0.41, P = 0.005), calculation (β = 1.05, P = 0.045) and word fluency (β = 1.82, P = 0.03). Compared to ε4/ε4 carriers, ε2 carriers performed better in nonverbal memory (β = 1.59, P<0.001), AVLT 4 (β = 0.68, P<0.001), AVLT 5 (β = 0.62, P<0.001), associative learning test (β = 0.57, P<0.001), episodic memory (β = 0.46, P = 0.007) performed better. When adjusted for clinical diagnosis, the above significant differences remained statistically significant. While ε2/ε4 carriers performed better in associative learning (β = 1.38, P<0.001) compared to ε3/ε3, visuospatial (β = ‐1.94, P = 0.020) function was worse than ε3/ε3 carriers. Compared to ε4/ε4, ε2/ε4 carriers performed worse in similarity test and visuospatial function, while in verbal memory performed better

Conclusion

The present study found complex effects of APOE ε2 and APOE ε2/ε4 on cognitive domains that varied according to the selected control group, whereas different clinical diagnoses did not seem to influence their effects.
Mapping of Cognitive Pathways in Indian Ageing Population
Authors: Kushwaha Suman , Talwar Puneet , Agarwal Rachna , Sharma Vibha , Anthony Aldrin , Dhamija Rajinder
Published: January 2025

Background

Cognitive Reserve(CR) a concept based on the brain plasticity, is a mechanism that delays or minimizes clinical manifestations of brain changes due to aging. Prospective epidemiologic studies non‐demented individuals have shown that education, occupational duration and complexity, and greater lifetime engagement in cognitively stimulating activities are associated with a reduced risk of dementia. We study the cognitive reserve and its neuroimaging correlate.

Methods

Prospective cross‐sectional study. 500 subjects were screened, Recruitment of subjects with inclusion criteria of age 40‐80 yr without neurodegenerative or psychiatric disorder. Clinical History and presence of CVD risk factors were investigated. MMSE, MOCA, Selected neuropsychology tests were done to evaluate cognitive status, CR assessed by CRIq scale. Biochemical and MRI(volumetry) and DTI(FA, Diffusivity.

Result

252 pts were recruited, Mean age ‐53 yrs. 33% female. Diabetes(17%) and hypertension(24%). Mean MOCA score 24.CRIq was high in 10 subjects and majority had medium score. Significant association was found between Verbal and Category fluency with low CRIq and Serum ferritin with brain volume. Fractional isotropy(FA) values were reduced in central part of corpous callosum corelated with verbal fluency.

Conclusion

Cognitive reserve can play a significant modifiable risk factor for cognitive decline. Neuroimaging can play an important biomarker to diagnose and in prognosis of cognitive impairment.
Influence of liver function on Alzheimer’s brain pathologies: A longitudinal study
Authors: Kim Jee Wook , Byun Min Soo , Yi Dahyun , Jung Joon Hyung , Kong Nayeong , Chang Yoon Young , Jung Gijung , Ahn Hyejin , Lee Jun‐Young , Kang Koung Mi , Sohn Chul‐Ho , Lee Yun‐Sang , Kim Yu Kyeong , Lee Dong Young ,   KBASE Research Group
Published: January 2025

Background

Numerous studies have demonstrated an association between altered liver function and Alzheimer’s disease (AD) or related dementia. Nevertheless, the neuropathological substrates underlying the association remains unclear. Our aim was to investigate the association between liver function markers and the longitudinal changes of in vivo AD pathologies.

Methods

We utilized a longitudinal study designs using data from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer’s Disease, an ongoing prospective cohort study that began in 2014. Total 347 older adults between 55 and 90 years of age assessed at both baseline and 2‐year follow‐up were included in community and memory clinic setting. We used four liver function markers (alanine aminotransferase [ALT], aspartate aminotransferase [AST], AST to ALT ratio, and total bilirubin) as exposure variables. Participants underwent comprehensive clinical assessments and multimodal brain imaging, including Pittsburgh compound‐B positron emission tomography (PET), AV‐1451 PET, fluorodeoxyglucose (FDG)‐PET, and MRI at both baseline and the 2‐year follow‐up.

Results

A higher ALT level and lower AST to ALT ratio at baseline were associated with greater amyloid deposition over a 2‐year period (ALT: β, 0.151 [95% CI, 0.007 to 0.033], P = 0.004; AST to ALT ratio: β, ‐0.153 [95% CI, ‐0.050 to ‐0.010], P = 0.004), but not with the change of other neuroimaging markers. A lower total bilirubin level was associated with greater tau deposition over a 2‐year period (β, ‐0.442 [95% CI, ‐0.385 to ‐0.106], P < 0.001), but not with the change of other neuroimaging markers. In contrast, AST alone was not associated with any neuroimaging marker change.

Conclusions

The present findings, based on longitudinal observation for older adults, suggest that lower liver function may accelerate the accumulation of AD pathology in the brain. These results also support the possibility that the liver‐brain axis could be a potential target for therapeutic or preventive strategies against AD.
Associations between AD polygenic risk scores and global amyloid deposition in the European AMYPAD consortium
Authors: Luckett Emma S. , Abakkouy Yasmina , Collij Lyduine E. , García David Vállez , Alves Isadora Lopes , Lorenzini Luigi , Gispert Juan Domingo , Visser Pieter Jelle , den Braber Anouk , Ritchie Craig W , Vandenberghe Rik , Wolz Robin , Shekari Mahnaz , Vilor‐Tejedor Natalia , Farrar Gill , Barkhof Frederik , Cleynen Isabelle ,   the AMYPAD consortium
Published: January 2025

Background

Published data have highlighted associations between Alzheimer’s disease (AD) susceptibility loci and AD‐related brain changes. The amyloid imaging to prevent AD (AMYPAD) consortium is a European collaboration consisting of several parent cohorts, four of which had raw genotype array data available. We sought to integrate and harmonise the genetic data, calculate AD polygenic risk scores (PRS), and investigate their association with global amyloid deposition.

Method

Raw genetic data (GRCh37) was available for 753 non‐demented participants, which underwent standard pre‐imputation quality control (QC) using PLINK. Imputation was performed using the Michigan Imputation server and HRC reference panel, and standard post‐imputation QC was done prior to the final merging of cohorts. PRSice was used for PRS calculations with Stage 1 summary statistics from Kunkle et al. (2019) as base file and European individuals from 1000 Genomes as reference for clumping. We calculated several builds of PRS at three p‐value thresholds for SNP inclusion: 5 × 10‐8, 1 × 10‐5, and 0.1. These included PRSall, PRSAPOEonly (Chr19:45‐48.8Mb), APOEε2+
ε4 (the weighted sum of the two major APOE SNPs rs429358 and rs7412), PRSnoAPOE (all SNPs excluding Chr19:45‐48.8Mb), and a composite PRSnoAPOE+APOEε2+
ε4. All were corrected for genetic principal components 1‐5 and standardised against 1000 Genomes. Cross‐sectional global amyloid burden (expressed in Centiloids) was available for everyone. Linear regression models determined if PRS were associated with amyloid deposition (age, sex, and education as covariates). Significance was based on an uncorrected p<0.05 divided by the number of SNP inclusion thresholds (N = 3).

Result

Participants were 66.9±7.6 years, 58.6% female, and 207 (27%) considered amyloid positive (CL>21). In this preliminary analysis, we found that most PRS builds were significantly associated with amyloid at all SNP inclusion thresholds assessed (Table 1, representative plots Fig. 1A,1B), except for PRSnoAPOE (Table 1, representative plot Fig. 1C).

Conclusion

We highlight the significant influence of APOE in determining AD genetic predisposition, and that AD PRS are associated with amyloid deposition. Our results show that AMYPAD is a suitable cohort for studying genetic factors driving amyloid deposition before clinical onset, which we aim to extend with the inclusion of more parent cohorts, and regional and longitudinal amyloid data.
Reduced plasma nicotinamide level and altered NAD+ metabolism in glial cells surrounding Aβ plaques in the mouse model of Alzheimer’s disease
Authors: Sekiya Michiko , Sakakibara Yasufumi , Hirota Yu , Ito Naoki , Takei Kimi , Chikamatsu Sachie , Nishijima Risa , Iijima Koichi M.
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disease and a leading cause of senile dementia. Accumulation of amyloid‐β (Aβ) in the brains causes chronic neuroinflammation, synaptic loss, and neurovascular damage, which is thought to initiate decades‐long AD pathogenesis. Recent clinical trials for anti‐Aβ immunotherapy highlights the utility of biomarkers that faithfully reflect Aβ‐related brain pathology to diagnose AD at the preclinical stage, to predict the onset and progression of the disease, and to assess the therapeutic efficacy of drugs.

Method

To search for plasma metabolites reflecting neuroinflammation due to Aβ accumulation, we conducted untargeted metabolomics in plasma and analyzed potential roles of metabolic changes in neuroinflammatory response in brains using Appknock‐in (AppNLGF) mouse model of brain parenchymal Aβ amyloidosis.

Result

The capillary electrophoresis‐time‐of‐flight mass spectrometry analysis on plasma samples from wild‐type and AppNLGF mice revealed that plasma nicotinamide levels were significantly reduced in AppNLGF mice, and “nicotinate and nicotinamide metabolism” was the most enriched pathway of altered metabolite profiles. Nicotinamide is a precursor of nicotinamide adenine dinucleotide (NAD+). In AppNLGF mouse brains, while NAD+ levels were unaltered, mRNA levels of NAD+‐synthesizing and NAD+‐degrading genes were increased, and these enzymes were expressed in reactive astrocytes and microglia surrounding Aβ plaques.

Conclusion

This study suggests that alterations in plasma nicotinamide levels may be a potential biomarker to assess neuroinflammatory response against Aβ pathology and “nicotinate and nicotinamide metabolism” may be a potential therapeutic target to prevent the onset of AD by targeting both neuroinflammation and neuroprotection.
Lewy body pathology in autosomal dominant and sporadic Alzheimer’s disease – neuropathological distribution patterns and associated survival and genetic findings
Authors: Vöglein Jonathan , Ryan Natalie S , Cruchaga Carlos , Gorijala Priyanka , Bateman Randall J. , McDade Eric , Paumier Katrina L. , Cairns Nigel J , Franklin Erin E. , Xiong Chengjie , Jucker Mathias , Lashley Tammaryn , Arzberger Thomas , Herms Jochen , Perrin Richard J. , Danek Adrian , Höglinger Günter , Morris John C. , Fox Nick C , Levin Johannes
Published: January 2025

Background

Lewy body pathology (LBP) is common in autosomal dominant (ADAD) or sporadic Alzheimer disease (sAD). LBP seems to be the most frequent co‐pathology in sAD and even in the relatively young ADAD population, where other co‐pathologies are rare. Knowledge of neuropathological distribution patterns of LBP and associated survival and genetic characteristics in both AD variants is incomplete.

Methods

Data from the National Alzheimer’s Coordinating Center, the Dominantly Inherited Alzheimer Network, the Queen Square Brain Bank at University College London and the Neurobiobank Munich were used to correlate widespread (neocortical, limbic) and focal (amygdala‐predominant, brainstem‐predominant, olfactory system‐predominant) LBP distribution patterns with survival (time from symptom onset to death) and genetic findings in individuals with ADAD or neuropathologically diagnosed sAD. T‐test or chi‐squared test were used for comparison of continuous or categorical variables.

Results

In 134 ADAD cases, widespread LBP was found in 20.9% and focal LBP in 41.0%. LBP was absent in 38.1%. In 3706 sAD cases, widespread LBP was present in 14.0% and focal LBP in 11.2%. The remaining 74.9% had no LBP. In both AD variants individuals with focal LBP survived longer compared to individuals without LBP, whereas no differences in survival were observed when comparing patients with widespread and no LBP. In both AD forms both focal and widespread distribution patterns were associated with APOE4 positivity. While there was no difference in Parkinson’s disease polygenic risk scores (PD‐PRS) between ADAD LBP distribution groups, PD‐PRS were statistically significantly higher in individuals with sAD with widespread LBP, both compared to sAD with focal LBP and to sAD without LBP (Table).

Conclusion

Distribution of LBP is focal in two‐thirds of ADAD with LBP and a little less than half of sAD patients with LBP. The longer survival in ADAD and sAD patients with focal but not widespread LBP may suggest that spreading of LBP in AD does not follow the same spatial evolution as described by Braak stages, but exhibits a unique, AD‐specific pattern. The association of APOE4 positivity with both focal and widespread LBP in AD and of PD‐PRS with widespread LBP in sAD indicates a genetic component that influences occurrence and distribution of LBP in AD.
Sex‐specific role of integrins in influencing tauopathy onset in htau mice
Authors: Bretland Katie , Lin Li , Terrill Sarah J , Dengler‐Crish Christine M.
Published: January 2025

Background

Integrins are essential mediators of numerous critical cellular processes. Increasing evidence indicates that aberrant function of αVβ1 integrins contributes to the onset and progression of tauopathy. Previously, our group showed that the neuroprotective exercise hormone irisin—a known αVβ integrin modulator, prevented age‐related increases in phosphorylated tau and inflammation in hippocampus of presymptomatic‐age female but not male htau tauopathy‐model mice (Bretland et al., 2021). Here, we investigated whether presymptomatic‐age female and male htau mice exhibited intrinsic differences in hippocampal αVβ integrins and whether irisin treatment impacted integrin expression and downstream signaling related to tauopathy disease mechanisms (i.e. PI3K/Akt/GSKβ pathway).

Methods

Presymptomatic age (4‐month old) htau mice were administered 1 month of irisin (100 ug/kg i.p.) or vehicle control injections. Age‐ and sex‐ matched C57BL/6J mice were used as controls. An additional cohort of presymptomatic age ovariectomized and surgical sham female htau and C57BL/6J mice also underwent 1 month of irisin/vehicle treatment. Mice were sacrificed at 5 months of age, hippocampi were fresh dissected, and automated capillary‐based protein quantitation via Protein Simple Wes/Jess platform was used to measure hippocampal levels of αVβ1 integrins, relevant pathway targets, and neuropathology.

Results

Presymptomatic female htau mice had endogenously dysregulated β1 integrin expression compared to female controls; no such differences were found among males. Irisin treatment significantly reduced hippocampal αV integrin expression and trended towards decreasing β1 integrin expression in female mice while having no impact on integrin expression in males. Irisin treatment also significantly reduced intrinsically upregulated PI3K/Akt/GSKβ pathway signaling in female htau mice, but had no impact on this signaling in males. Ovariectomy prevented irisin’s neuroprotective effects against hippocampal ptau and inflammation in female htau mice; notably, irisin triggered an upregulation of β1 integrin expression in hippocampus of ovariectomized female htau mice.

Conclusions

Alterations in αVβ integrin function may influence early tauopathy disease mechanisms in a sex‐specific manner. These findings emphasize a need to understand the role of integrins in dementia and emphasize the importance of identifying sex‐specific disease etiologies.
Clinical and neuropsychological variables associated with subjective cognitive decline and its progression
Authors: Villino‐Rodríguez Rafael Angel , Ríos‐Rivera Mirla , Imaz Laura , Espinoza‐Vinces Christian , Pérez‐Prol Cristina , Montoya‐Murillo Genoveva , Arrondo Carlota , Riverol Mario
Published: January 2025

Background

This study focused on comparing clinical and neuropsychological aspects in individuals with subjective cognitive decline (SCD) versus healthy controls (HCs) in a memory clinic, aiming to identify factors linked to the progression towards mild cognitive impairment (MCI) or dementia.

Method

We retrospectively analysed data from 945 SCD patients and 68 HCs at Clínica Universidad de Navarra memory clinic between 2001 and 2017, with 450 followed up until January 2020, the study involved various assessments including medical interviews, lab tests, neuropsychological evaluations (during the first interview and follow‐ups), and brain imaging. All the neuropsychological variables were adjusted for age, sex and education.

Result

Among the participants with SCD, 131 progressed to MCI or dementia. SCD individuals were younger, and had higher educated, and more vascular risk factors compared to HCs. Factors associated with MCI or dementia encompassed age at diagnosis, years of education, and hypercholesterolemia. Neuropsychologically, SCD individuals exhibited weaker global cognition, verbal memory, fluency in language, and increased depressive symptoms. Poorer performance in episodic verbal memory tests correlated with a higher likelihood of transitioning to MCI or dementia.

Conclusion

The study’s discussion emphasized the complex nature of SCD development and progression, involving both clinical and neuropsychological factors. Younger age and increased vascular risk were characteristic of SCD individuals, who also showed deficiencies in global cognition, language fluency, verbal memory, and executive functions. Key indicators of disease progression included age at diagnosis, hypercholesterolemia, and poorer performance in tests assessing language fluency, verbal and visual memory, and executive functions.
Nanoscale imaging of pT217‐tau in aged rhesus macaque entorhinal and dorsolateral prefrontal cortex: Evidence of interneuronal trafficking and early‐stage neurodegeneration
Authors: Datta Dibyadeep
Published: January 2025

Background

Advances in Alzheimer’s disease (AD) have revealed a novel fluid biomarker, tau phosphorylated at T217 (pT217‐tau), in CSF and plasma, that predicts AD prior to cognitive deficits. Understanding the role of pT217‐tau is important in assessing efficacy of novel treatments aimed at early‐stage disease. However, it is unknown why pT217‐tau is effective in predicting brain pathology, as little is known about early, soluble pT217‐tau brain expression. These questions are difficult to address in humans, as soluble p‐tau is rapidly dephosphorylated postmortem, and PET scans detect late‐stage, fibrillated tau. However, the etiology of pT217‐tau in aging brains can be probed in rhesus macaques, where perfusion fixation allows capture of phosphorylated proteins in their native state. Aging macaques naturally develop tau pathology with the same qualitative pattern and sequence as humans, including initial cortical pathology in layer II of the entorhinal cortex (ERC) evident early in aging, and later in layer III of the dorsolateral prefrontal cortex (dlPFC).

Method

We utilized multi‐label immunofluorescence and immunoelectron‐microscopy to examine the subcellular localization of early‐stage pT217‐tau in ERC and dlPFC of aged macaques with naturally occurring tau pathology and assayed pT217‐tau levels in plasma.

Result

Our results show that pT217‐tau labeling is primarily observed in postsynaptic compartments, accumulating in: 1) dendritic spines on the calcium‐storing smooth endoplasmic reticulum spine apparatus near asymmetric glutamatergic‐like synapses, and 2) in dendritic shafts, where it aggregated on microtubules, often “trapping” endosomes associated with Aβ42. The dendrites expressing pT217‐tau were associated with autophagic vacuoles and dysmorphic mitochondria, indicative of early neurite degeneration. We observed trans‐synaptic pT217‐tau trafficking between neurons within omega‐shaped bodies and endosomes, specifically near excitatory, but not inhibitory synapses. We also examined pT217‐tau in blood plasma in macaques across age‐span and observed a statistically significant age‐related increase in pT217‐tau.

Conclusion

These data provide the first direct evidence of pT217‐tau trafficking between neurons near synapses to “seed” tau pathology in higher brain circuits, interfacing with the extracellular space to become accessible to CSF and blood. The expression of pT217‐tau in dendrites with early signs of degeneration may help to explain why this tau species can herald future disease.
Sphingomyelin 14:0 ‐ a driver of neuroinflammation
Authors: McManus Roisin M.
Published: January 2025

Background

Western‐diet (WD) can induce sterile inflammation and epigenetic reprogramming of myeloid cells, affecting their immune response (Christ et al., 2018). However, the molecular signaling mediating these changes was unknown. We recently identified that WD increases circulating sphingomyelin 14:0 (S14), which was associated with peripheral inflammation and atherosclerosis. As atherosclerosis, inflammation and WD are risk factors for dementia and Alzheimer’s disease (AD), our goal was to determine whether S14 was the precise signaling factor driving neuroinflammation leading to AD.

Method

Wild‐type and Apoe‐/‐ mice (mouse model of atherosclerosis) were fed a high‐fat diet mimicking WD for 8 weeks, before samples were obtained for lipidomics. Microglia were isolated ex vivo for either RNA sequencing or to determine their metabolic profile. In a separate series of experiments, microglia were prepared from wild‐type mice and treated with various TLR inhibitors to assess whether these cells can recognize S14, and the exact molecular pathways induced by the lipid. Wild‐type microglia were prepared for RNA sequencing, to determine the genes and networks induced by S14, which were compared with the microglia enriched ex vivo. Pathways were confirmed at a protein and functional level.

Result

Lipidomic analysis confirmed that WD increased S14 in the circulation of wild‐type and Apoe‐/‐ mice. Patients with obesity also had greater levels of S14, which was associated with heart disease. We found that S14 triggers an extensive increase in pro‐inflammatory genes and pathways in microglia. We confirmed that S14 utilizes TLR4 to signal in vitro, inducing NFkB activation and ultimately the release of TNFα from microglial cells. S14 also affected microglial metabolic function and reduced phagocytic capacity ex vivo and in vitro.

Conclusion

We found that S14 is a lipid significantly increased in both human and murine models of obesity or heart disease. S14 is a novel TLR4 agonist that can activate microglia and trigger extensive inflammation. Critically, S14 affects microglial function both ex vivo and in vitro. Together, our data shows that S14 is an endogenous immune stimulus, capable of triggering various innate immune responses and microglial changes that are associated with neuroinflammation and the development of dementia.
In depth comparisons of neuropsychological & neuroimaging profile of primary psychiatric disorders and behavioral variant FTD
Authors: Denève Agnès , Lebouvier Thibaud , Lopes Renaud , Kuchcinski Gregory , Pasquier Florence , Amad Ali , Bertoux Maxime
Published: January 2025

Background

Over the past years, social cognition has been envisaged as a promising domain to distinguish behavioral variant frontotemporal degeneration (bvFTD) from its main differential diagnoses that is primary psychiatric disorders (PPD). The core‐processes approach, which has emphasized the importance of emotion recognition and mentalizing, has been particularly useful to better characterize each condition and enhance the earliness of FTD’s diagnosis. However, new findings evidencing conflicting results regarding the ability of social cognition to distinguish bvFTD from PPD have underlined the importance of moving beyond the core processes approach.

Method

We reviewed all cases with a suspission of bvFTD in the last 8 years in the Lille memory clinic, at least followed‐up for 24 months with a neuropsychological assessment and an MRI and/or PET‐scan. We then applied a quantitative comparison approach based on total scores, then a qualitative approach, based on responses and errors types. Then, neuroimaging analyses were run, and biomarkers were analyzed.

Result

Data of 56 patients with a probable to certain bvFTD and 47 patients with a primary psychiatric disorders (late major depression, bipolar disorders, schizophrenia…) were analyzed at classical and social cognitive (mini‐SEA) tests. Overall, clinical groups were not different on executive functionning, attention, motor & perceptual functions. Minor differences were retrieved in memory and langage processing. Important differences were retrieved in social cognition. Qualitative differences were retrieved in facial emotion recognition (inter & intra valence errors) and mentalizing (type of mental inference, emotional labelling), as well as memory functioning (primacy/recency ratio, intrusions). Anatomical and functional brain networks involved showed a combination of overlaping and distincts areas. Regarding biomarkers, NFLs showed promising results with AUC = 0.88).

Conclusion

While the usual approach (considering general or subscores scores) may not be the more efficient way, a more qualitative neuropsychological approach has the potential to provide relevant cognitive markers for the clinical distinction between bvFTD and PPD, particularly regarding social cognition.
Diverse Patterns and Impact of Mitochondrial DNA Alteration in Parietal Cortex of Diabetic and Non‐diabetic Alzheimer’s Disease
Authors: Shi Anqi , Kaikini Aakruti , Hodgkinson Alan , Malik Afshan N
Published: January 2025

Background

Diabetes increases the risk of Alzheimer’s disease (AD), and mitochondrial dysfunction is implicated in both diseases. We previously detected mitochondrial DNA copy number (MtDNA‐CN) changes in human parietal cortex that differed between diabetic AD and non‐diabetic AD. We hypothesize that MtDNA‐CN changes may be indicative of different underlying mechanisms. In the current study, we aim to evaluate the impact of MtDNA‐CN changes on MtDNA damage and proteins involved in energy production in the mitochondria.

Method

Total DNA and protein were isolated from human post‐mortem parietal cortex (n = 24). MtDNA‐CN was determined as the ratio of MtDNA to nuclear DNA using qPCR. MtDNA damage was measured using the surveyor nuclease method in 11 overlapping mitochondrial genome regions, and next generation sequencing (NGS) after removing the nuclear DNA using exonuclease V.

NDUFB8(I), SDHB(II), UQCRC2(III), MTCO1(IV), and ATP5A(V) expression were measured as the representatives of 5 complexes in OXPHOS chain by western blotting. Data were compared as 4 groups: non‐cognitive impairment (NCI) and AD, ± diabetes using ANOVA.

Result

In AD groups, MtDNA‐CN was reduced in cases without diabetes (P<0.05), however, no reduction was seen in diabetic AD. In diabetic groups, irrespective of cognitive status, higher MtDNA‐CN were found compared to non‐diabetic groups. Putative mutations with various intensities and patterns were observed, especially in the displacement loop area in AD and diabetic AD groups. Among 4 groups, the expression of 2 nuclear‐encoded subunits NDUFB8 and ATP5A were higher than the level of other 2 nuclear‐encoded subunits (SDHB and UQCRC2) and 1 mitochondrial‐encoded subunit MTCO1. However, no significant difference was found in the expression of these 5 subunits between diabetic and non‐diabetic groups in parietal cortex.

Conclusion

Our data show that in human parietal cortex, the MtDNA‐CN changes differently in diabetic and non‐diabetic AD suggesting of different underlying mechanisms. The presence of MtDNA changes without any impact on levels of OXPHOS subunits indicates an MtDNA‐based pathology. We propose that different patterns of MtDNA damage may impact energy production in specific brain regions and contribute to disease progression. The level of MtDNA heteroplasmy in the groups determined by NGS and its potential impact will be presented.
Identification of regulators of microglia lipotoxicity
Authors: Therrien Martine , Weider Nicolas , Monti Giulia , Meyer Daniel , Atkeson Trevor , McCarroll Steven , Greka Anna , Stevens Beth
Published: January 2025

Background

Emerging studies have identified changes in lipid processing in Alzheimer’s disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer’s disease risk genes are expressed in microglia and involved in lipid sensing and processing.

Method

In this project, we assessed unbiasedly how various fatty acids impact microglia states and functions. Using the iPSC‐derived microglia platform, our lab has recently developed (Dolan*, Therrien* et al. Nature Immunology 2023), we characterized the impact of 48 different fatty acids on human microglia.

Result

We identified 5 distinct transcriptional signatures produced in response to various lipids, including a toxic lipotoxicity signature independent of TREM2 signaling. Using microglia villages, we assessed the toxicity across 25 iPSC donors and identified genetic modifiers of microglia lipotoxicity.

Conclusion

Together, our data identifies genetic regulators of microglia states and presents new insight into understanding how to protect synapses in Alzheimer’s that could lead to new therapies and biomarkers for early diagnoses.
Signatures of resolution reprogramming in amyloid‐challenged microglia
Authors: Kondrikova Galina , Hamlett Eric D , Pytel Dariusz
Published: January 2025

Background

Specialized pro‐resolving mediators (SPMs) promote inflammatory resolution and homeostasis and are thought to have specific reprogramming effects on hman microglia. Decreased SPM levels have been correlated with chronic neuroinflammation, late‐stage Alzheimer’s disease (AD) and neuropathology in humans, yet few studies have explored the cellular signatures of resolution. Amyloid is though to bind one target resolution receptor, ChemR23, leading to internalization. In this study we explore if internalized ChemR23 receptor is part of a signaling endosome in microglial cells and how this interfaces with amyloid challenge and/or SPM mitigation.

Method

We then challenged human microglial cell culture models (HMC3) with amyloid‐beta oligomer activation and/or administered RvE1 to promote resolution. We quantified resolution signaling responses using standard immunoblot. We measured microglial activation using immunofluorescence and cell characterization software. We examined the occurrence of ChemR23 receptor internalization and several endosomal markers by super‐resolution immunofluorescence microscopy.

Result

RvE1 significantly reduces microglial activation and cytokine expression under amyloid challenge. We discovered that RvE1 leads to compensatory response in specific G protein coupled receptors within the resolution family 2) specific signaling events 3) unique endosome signatures, We are quantifying functionality of endosomes and other objectives to share at the poster at AAIC.

Conclusion

We have demonstrated that RvE1 modulates inflammation in a mouse model and in a microglial cell line. Understanding the molecular signatures of resolution reprogramming in cells will be key to identifying prognostic indicators and molecular mechanisms of this unique understudied GPCR system and response in the brain.