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APOE and Trem2 are major genetic risk factors for Alzheimer’s disease (AD), but how they affect microglia response to Aβ remains unclear. Here we report an APOE isoform-specific phospholipid signature with correlation between human APOEε3/3 and APOEε4/4 AD brain and lipoproteins from astrocyte conditioned media of APOE3 and APOE4 mice. Using preclinical AD mouse models, we show that APOE3 lipoproteins, unlike APOE4, induce faster microglial migration towards injected Aβ, facilitate Aβ uptake, and ameliorate Aβ effects on cognition. Bulk and single-cell RNA-seq demonstrate that, compared to APOE4, cortical infusion of APOE3 lipoproteins upregulates a higher proportion of genes linked to an activated microglia response, and this trend is augmented by TREM2 deficiency. In vitro, lack of TREM2 decreases Aβ uptake by APOE4-treated microglia only, suggesting TREM2-APOE interaction. Our study elucidates phenotypic and transcriptional differences in microglial response to Aβ mediated by APOE3 or APOE4 lipoproteins in preclinical models of AD. Microglia can clear amyloid plaques in Alzheimer’s disease. Here, the authors show that specific isoforms of the phospholipid forming APOE lipoproteins activate microglia in pre-clinical mouse models of Alzheimer’s disease.

Neuromuscular electrical stimulation (NMES) has been shown to improve motor activities and daily living. Prior studies indicated extracellular vesicles (EVs) play a role in cellular communication. Here, we evaluated transcriptomic profiles of tibialis muscle, brain, and plasma-derived EVs following NMES in wild type (WT) and Klotho heterozygous (KlHET) mice. Muscle RNA-seq data demonstrated that, in both genotypes, the most upregulated functional categories were related to glucose metabolism and response to insulin, with pathways uniquely affected in each genotype. There was a similarity of the non-coding RNA transcriptome of plasma EVs, with functional patterns suggesting response to oxygen and insulin and long-term synaptic potentiation. The brain transcriptome showed little functional overlap between WT and KlHET mice. In WT, brain upregulation of genes was related to blood flow and cell adhesion processes, while KlHET showed upregulation of immune function. The results indicate that similar metabolic function is impacted in the location of stimulation, but the distal impact of stimulation on the brain is associated with Klotho deficiency.

Pharmacological activation of brain Retinoid X Receptors (RXRs) enhances cognition and facilitates amyloid-beta (Aβ) clearance in Alzheimer’s disease (AD) mouse models, partly by upregulating apolipoprotein E (Apoe), a major AD genetic risk factor. However, the specific cellular contributions to these effects are unclear. Here, we used single-cell transcriptomic profiling to investigate cell subpopulation-specific responses to bexarotene, an RXR agonist, in APP/PS1 mice. Our analysis revealed that bexarotene activated cholesterol biosynthesis and lipid metabolism transcriptional programs in homeostatic astrocytes and oligodendrocytes. Astrocytes also upregulated neurodevelopmental genes, while oligodendrocytes and endothelial cells showed enhanced protein folding and cellular growth pathways. Bexarotene further modulated immune responses, promoting Aβ-responsive signatures in disease-associated microglia and reactive astrocytes while dampening pro-inflammatory responses in homeostatic microglia and endothelial cells. Furthermore, Apoe expression was significantly elevated across multiple cell types, especially in microglia and oligodendrocytes. Cell–cell communication analysis highlighted increased astrocyte-centered signaling, with APOE-driven pathways emerging as a prominent mediator. These findings clarify the molecular complexity of RXR-mediated regulation, revealing the cellular origins of bexarotene’s known effects as well as novel, cell-type-specific responses. This study provides mechanistic insights into RXR-targeted interventions and supports APOE-associated pathways as promising therapeutic targets in AD.

The inheritance of Apolipoprotein E4 ( APOEε4 ) brings the highest genetic risk of Alzheimer’s disease (AD), arguably the highest genetic risk in human pathology. Since the discovery of the association, APOE protein isoforms have been at the center of tens of thousands of studies and reports. While, without a doubt, our knowledge about the normal physiological function of APOE isoforms in the brain has increased tremendously, the questions of how the inheritance of the APOEε4 allele translates into a risk of AD, and the risk is materialized, remain unanswered. Moreover, the knowledge about the risk associated with APOEε4 has not helped design a meaningful preventative or therapeutic strategy. Animal models with targeted replacement of Apoe have been generated and, thanks to the recent NIH/NIA/Alzheimer’s disease Association initiative, are now freely available to AD researchers. While helpful in many aspects, none of the available models recapitulates normal physiological transcriptional regulation of the human APOE gene cluster. Changes in epigenetic regulation of APOE alleles in animal models in response to external insults have rarely been if ever, addressed. However, these animal models provide a useful tool to handle questions and investigate protein–protein interactions with proteins expressed by other recently discovered genes and gene variants considered genetic risk factors of AD, like Triggering Receptor expressed on Myeloid cells 2 ( TREM2 ). In this review, we discuss genetic and epigenetic regulatory mechanisms controlling and influencing APOE expression and focus on interactions of APOE and TREM2 in the context of microglia and astrocytes’ role in AD-like pathology in animal models.

Ligand-activated Retinoid X Receptors (RXRs) regulate gene networks essential for neural development, neuroinflammation, and metabolism. Understanding how RXR activation influences chromatin architecture and gene expression may reveal mechanisms relevant to neurodegenerative diseases. We used Bexarotene-treated APP/PS1ΔE9 mice to study RXR-mediated regulatory mechanisms by integrating single-nucleus ATAC-seq (snATAC-seq) with single-cell RNA-seq (scRNA-seq) and validating differentially accessible chromatin peaks using RXR ChIP-seq. Transcription factor (TF) footprinting analysis mapped regulatory networks activated by ligand-bound RXR. Our integrated analyses revealed a multilayered transcriptional cascade initiated by RXR signaling. We identified RXR-centered regulatory circuits involving heterodimer activation, upregulation of downstream TFs, and induction of metabolic pathways relevant to neural function. Detailed analysis of neuronal TF networks revealed that Bexarotene modulates RXR's role through existing regulatory scaffolds rather than creating new ones. This study demonstrates that combining scRNA-seq, snATAC-seq, and ChIP-seq enables comprehensive analysis of RXR-mediated transcriptional regulation. RXR activation orchestrates cell-type-specific chromatin remodeling of gene networks controlling neuroinflammation, lipid metabolism, and synaptic signaling, providing mechanistic insights into RXR-dependent transcriptional programs in Alzheimer's disease pathology.

Background Alzheimer’s Disease (AD) is a neurodegenerative disorder influenced by aging and genetic risk factors. The inheritance of APOE ε4 and variants of Triggering Receptor Expressed on Myeloid cells 2 ( TREM2 ) are major genetic risk factors for AD. Recent studies showed that APOE binds to TREM2, thus raising the possibility of an APOE-TREM2 interaction that can modulate AD pathology. Methods The aim of this study was to investigate this interaction using complex AD model mice - a crossbreed of Trem2 ko and APP/PSEN1dE9 mice expressing human APOE3 or APOE4 isoforms (APP/E3 and APP/E4 respectively), and their WT littermates (E3 and E4), and evaluate cognition, steady-state amyloid load, plaque compaction, plaque growth rate, glial response, and brain transcriptome. Results In both, APP/E3 and APP/E4 mice, Trem2 deletion reduced plaque compaction but did not significantly affect steady-state plaque load. Importantly, the lack of TREM2 increased plaque growth that negatively correlated to the diminished microglia barrier, an effect most pronounced at earlier stages of amyloid deposition. We also found that Trem2 deficiency significantly decreased plaque-associated APOE protein in APP/E4 but not in APP/E3 mice in agreement with RNA-seq data. Interestingly, we observed a significant decrease of Apoe mRNA expression in plaque-associated microglia of APP/E4/Trem2 ko vs APP/E4 mice. The absence of TREM2, worsened cognitive performance in APP transgenic mice but not their WT littermates. Gene expression analysis identified Trem2 signature - a cluster of highly connected immune response genes, commonly downregulated as a result of Trem2 deletion in all genotypes including APP and WT littermates. Furthermore, we identified sets of genes that were affected in TREM2- and APOE isoform-dependent manner. Among them were Clec7a and Csf1r upregulated in APP/E4 vs APP/E3 mice, a result further validated by in situ hybridization analysis. In contrast, Tyrobp and several genes involved in the C1Q complement cascade had a higher expression level in APP/E3 versus their APP/E4 counterparts. Conclusions Our data demonstrate that lack of Trem2 differentially impacts the phenotype and brain transcriptome of APP mice expressing human APOE isoforms. The changes probably reflect the different effect of APOE isoforms on amyloid deposition.

Tauopathies, including Alzheimer's disease, involve progressive neurodegeneration and sustained neuroinflammation. We present a multi-compartment transcriptomic atlas of 9.6-month-old PS19 tauopathy mice compared with wild-type (WT) controls ( = 8/group), profiling cortical mRNA, cortical non-coding RNA (ncRNA), and plasma small extracellular vesicle (pEV) ncRNA. In the PS19 cortex, mRNA sequencing identified 917 differentially expressed genes (DEGs), with microglial deconvolution revealing an association toward disease-associated microglia (DAM) gene signature and downregulation of genes involved in oxidative phosphorylation and cholesterol biosynthesis relative to WT. Cortical ncRNA profiling identified 466 differentially expressed ncRNAs, primarily circular RNAs (circRNAs; = 331). In pEVs, 822 ncRNAs were differentially abundant, of which 657 circRNAs were identified in PS19 compared to WT mice. Cross-compartment integration suggest that pEV miRNA gene targets functionally mirrored genes involved in the brain's inflammatory and metabolic failure. We identified a preliminary candidate signature of 33 ncRNAs, including miR-5114 (up in brain, down in pEV), circ_0008242 and circ_0002153 (up in brain and pEV), and circ_0007688 (down in brain and pEV), differentially enriched across both brain and periphery in PS19 compared to WT mice. These results suggest that the pEV non-coding landscape may partially reflect central tau-mediated changes in the brain transcriptional response. This study identifies circRNAs as the most numerically perturbed ncRNA class and provides a foundation for potential peripheral indicators of central brain tau pathology.

We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition of 12-months old APP23 mice, and correlated the phenotype to brain transcriptome and lipidome. HFD significantly increased amyloid plaques and worsened cognitive performance compared to mice on normal diet (ND). RNA-seq results revealed that in HFD mice there was an increased expression of genes related to immune response, such as Trem2 and Tyrobp . We found a significant increase of TREM2 immunoreactivity in the cortex in response to HFD, most pronounced in female mice that correlated to the amyloid pathology. Down-regulated by HFD were genes related to neuron projections and synaptic transmission in agreement to the significantly deteriorated neurite morphology and cognition in these mice. To examine the effect of the diet on the brain lipidome, we performed Shotgun Lipidomics. While there was no difference in the total amounts of phospholipids of each class, we revealed that the levels of 24 lipid sub-species in the brain were significantly modulated by HFD. Network visualization of correlated lipids demonstrated overall imbalance with most prominent effect on cardiolipin molecular sub-species. This integrative approach demonstrates that HFD elicits a complex response at molecular, cellular and system levels in the CNS.

Background The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer’s disease (AD) brain. The results so far have prompted further research using “multi-omics” approaches. These approaches become particularly relevant, considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, disease protective effect of APOEε2 allele, and a major role of APOE in brain lipid metabolism. Methods Postmortem brain samples from inferior parietal lobule genotyped as APOEε2/c ( APOEε2 /carriers), APOEε3/3 , and APOEε4/c (APOEε4/ carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. Results Significantly affected GO terms and pathways were determined based on the comparisons of APOEε2/c datasets to those of APOEε3/3 and APOEε4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOEε2/c brain samples compared to both APOEε3/3 and APOEε4/c . The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOEε4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. Conclusions The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy—canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOEε2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.

ATP-binding cassette transporter A1 (ABCA1) controls cholesterol and phospholipid efflux to lipid-poor apolipoprotein E (APOE) and is transcriptionally controlled by Liver X receptors (LXRs) and Retinoic X Receptors (RXRs). In APP transgenic mice, lack of Abca1 increased Aβ deposition and cognitive deficits. Abca1 haplo-deficiency in mice expressing human APOE isoforms, increased level of Aβ oligomers and worsened memory deficits, preferentially in APOE4 mice. In contrast upregulation of Abca1 by LXR/RXR agonists significantly ameliorated pathological phenotype of those mice. The goal of this study was to examine the effect of LXR agonist T0901317 (T0) on the phenotype and brain transcriptome of APP/E3 and APP/E4 Abca1 haplo-deficient (APP/E3/Abca1+/- and APP/E4/Abca1+/-) mice. Our data demonstrate that activated LXRs/RXR ameliorated APOE4-driven pathological phenotype and significantly affected brain transcriptome. We show that in mice expressing either APOE isoform, T0 treatment increased mRNA level of genes known to affect brain APOE lipidation such as Abca1 and Abcg1. In both APP/E3/Abca1+/- and APP/E4/Abca1+/- mice, the application of LXR agonist significantly increased ABCA1 protein level accompanied by an increased APOE lipidation, and was associated with restoration of APOE4 cognitive deficits, reduced levels of Aβ oligomers, but unchanged amyloid load. Finally, using Gene set enrichment analysis we show a significant APOE isoform specific response to LXR agonist treatment: Gene Ontology categories \"Microtubule Based Process\" and \"Synapse Organization\" were differentially affected in T0-treated APP/E4/Abca1+/- mice. Altogether, the results are suggesting that treatment of APP/E4/Abca1+/- mice with LXR agonist T0 ameliorates APOE4-induced AD-like pathology and therefore targeting the LXR-ABCA1-APOE regulatory axis could be effective as a potential therapeutic approach in AD patients, carriers of APOEε4.