APOE4 is the strongest genetic risk factor associated with late-onset Alzheimer's disease (AD). To address the underlying mechanism, we develop cerebral organoid models using induced pluripotent stem ...cells (iPSCs) with APOE ε3/ε3 or ε4/ε4 genotype from individuals with either normal cognition or AD dementia. Cerebral organoids from AD patients carrying APOE ε4/ε4 show greater apoptosis and decreased synaptic integrity. While AD patient-derived cerebral organoids have increased levels of Aβ and phosphorylated tau compared to healthy subject-derived cerebral organoids, APOE4 exacerbates tau pathology in both healthy subject-derived and AD patient-derived organoids. Transcriptomics analysis by RNA-sequencing reveals that cerebral organoids from AD patients are associated with an enhancement of stress granules and disrupted RNA metabolism. Importantly, isogenic conversion of APOE4 to APOE3 attenuates the APOE4-related phenotypes in cerebral organoids from AD patients. Together, our study using human iPSC-organoids recapitulates APOE4-related phenotypes and suggests APOE4-related degenerative pathways contributing to AD pathogenesis.
OBJECTIVE:The ε4 allele of the APOE gene (APOE4) is the strongest genetic risk factor for Alzheimer disease when compared with the common ε3 allele. Although there has been significant progress in ...understanding how apoE4 (apolipoprotein E4) drives amyloid pathology, its effects on amyloid-independent pathways, in particular cerebrovascular integrity and function, are less clear.
APPROACH AND RESULTS:Here, we show that brain pericytes, the mural cells of the capillary walls, differentially modulate endothelial cell phenotype in an apoE isoform-dependent manner. Extracellular matrix protein induction, tube-like structure formation, and barrier formation were lower with endothelial cells cocultured with pericytes isolated from apoE4-targeted replacement (TR) mice compared with those from apoE3-TR mice. Importantly, aged apoE4-targeted replacement mice had decreased extracellular matrix protein expression and increased plasma protein leakages compared with apoE3-TR mice.
CONCLUSIONS:ApoE4 impairs pericyte-mediated basement membrane formation, potentially contributing to the cerebrovascular effects of apoE4.
Carrying premature termination codons in 1 allele of the ABCA7 gene is associated with an increased risk for Alzheimer’s disease (AD). While the primary function of ABCA7 is to regulate the transport ...of phospholipids and cholesterol, ABCA7 is also involved in maintaining homeostasis of the immune system. Since inflammatory pathways causatively or consequently participate in AD pathogenesis, we studied the effects of Abca7 haplodeficiency in mice on brain immune responses under acute and chronic conditions. When acute inflammation was induced through peripheral lipopolysaccharide injection in control or heterozygous Abca7 knockout mice, partial ABCA7 deficiency diminished proinflammatory responses by impairing CD14 expression in the brain. On breeding to AppNL-G-F
knockin mice, we observed increased amyloid-β (Aβ) accumulation and abnormal endosomal morphology in microglia. Taken together, our results demonstrate that ABCA7 loss of function may contribute to AD pathogenesis by altering proper microglial responses to acute inflammatory challenges and during the development of amyloid pathology, providing insight into disease mechanisms and possible treatment strategies.
Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how ...microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.
The recent methodological advances in multi-omics approaches, including genomic, transcriptomic, metabolomic, lipidomic, and proteomic, have revolutionized the research field by generating “big data” ...which greatly enhanced our understanding of the molecular complexity of the brain and disease states. Network approaches have been routinely applied to single-omics data to provide critical insight into disease biology. Furthermore, multi-omics integration has emerged as both a vital need and a new direction to connect the different layers of information underlying disease mechanisms. In this review article, we summarize popular network analytic approaches for single-omics data and multi-omics integration and discuss how these approaches have been utilized in studying neurodegenerative diseases.
APOE4
is a strong genetic risk factor for Alzheimer’s disease and Dementia with Lewy bodies; however, how its expression impacts pathogenic pathways in a human-relevant system is not clear. Here ...using human iPSC-derived cerebral organoid models, we find that
APOE
deletion increases α-synuclein (αSyn) accumulation accompanied with synaptic loss, reduction of GBA levels, lipid droplet accumulation and dysregulation of intracellular organelles. These phenotypes are partially rescued by exogenous apoE2 and apoE3, but not apoE4. Lipidomics analysis detects the increased fatty acid utilization and cholesterol ester accumulation in apoE-deficient cerebral organoids. Furthermore,
APOE4
cerebral organoids have increased αSyn accumulation compared to those with
APOE3
. Carrying
APOE4
also increases apoE association with Lewy bodies in postmortem brains from patients with Lewy body disease. Our findings reveal the predominant role of apoE in lipid metabolism and αSyn pathology in iPSC-derived cerebral organoids, providing mechanistic insights into how
APOE4
drives the risk for synucleinopathies.
Mounting evidence highlights the crucial role of aging in the pathogenesis of Alzheimer's disease (AD). We have previously explored human apoE-targeted replacement mice across different ages and ...identified distinct molecular pathways driven by aging. However, the specific contribution of different brain cell types to the gene modules underlying these pathways remained elusive. To bridge this knowledge gap, we employed a computational deconvolution approach to examine cell-type-specific gene expression profiles in major brain cell types, including astrocytes (AS), microglia (MG), oligodendroglia (OG), neurons (NEU), and vascular cells (VC). Our findings revealed that immune module genes were predominantly expressed in MG, OG, and VC. The lipid metabolism module genes were primarily expressed in AS, MG, and OG. The mitochondria module genes showed prominent expression in VC, and the synapse module genes were primarily expressed in NEU and VC. Furthermore, we identified intra- and inter-cell-type interactions among these module genes and validated their aging-associated expression changes using published single cell studies. Our study dissected bulk brain transcriptomics data at the cellular level, providing a closer examination of the cell-type contributions to the molecular pathways driven by aging.
Aging is a growing issue nowadays, and active aging is not only about the health of the elderly but also about social participation. The gap between the elderly and the digital age has to some extent ...reduced their motivation to participate in social activities. To explore the smartphone use behavior of the elderly, this study developed an extended model based on the technology acceptance model. A hybrid survey was carried out with data collection both online and offline. A total of 271 valid questionnaires were collected through offline field interviews and online distribution of questionnaire links, and hypothesis testing was conducted using path analysis. The results showed that both perceived usefulness and attitude toward using could directly, positively and significantly influence the intention to use. Moreover, perceived playfulness and perceived ease of use showed positive and significant relationships with perceived usefulness and attitude toward using, respectively. Therefore, we suggest that smartphone companies focus on improving perceived playfulness when designing and developing product features or applications for the elderly to increase their competitiveness based on ensuring basic technical features.
The ATP binding cassette subfamily A member 7 (
) gene is one of the significant susceptibility loci for Alzheimer's disease (AD). Furthermore, ABCA7 loss of function variants resulting from ...premature termination codon in the gene are associated with increased risk for AD. ABCA7 belongs to the ABC transporter family, which mediates the transport of diverse metabolites across the cell membrane. ABCA7 is also involved in modulating immune responses. Because the immune system and lipid metabolism causatively engage in the pathogenesis of AD, we investigated how ABCA7 haplodeficiency modulates the metabolic profile in mouse brains during acute immune response using a metabolomics approach through LC/Q-TOF-MS. Peripheral lipopolysaccharide (LPS) stimulation substantially influenced the metabolite content in the cortex, however, the effect on metabolic profiles in
heterozygous knockout mice (
) was modest compared to that in the control wild-type mice. Weighted gene co-expression network analysis (WGCNA) of the metabolomics dataset identified two modules influenced by LPS administration and ABCA7 haplodeficiency, in which glycerophospholipid metabolism, linoleic acid metabolism, and α-linolenic acid metabolism were identified as major pathways. Consistent with these findings, we also found that LPS stimulation increased the brain levels of eicosapentaenoic acid, oleic acid, and palmitic acid in
mice, but not control mice. Together, our results indicate that ABCA7 is involved in the crosstalk between fatty acid metabolism and inflammation in the brain, and disturbances in these pathways may contribute to the risk for AD.
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