Modeling sporadic Alzheimer’s disease in human brain organoids under serum exposure
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE164089 | GEO | 2021/09/29
REPOSITORIES: GEO
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Project description:Our understanding of Alzheimer’s disease (AD) pathogenesis is currently limited by difficulties in obtaining live neurons from patients and the inability to model the sporadic form of AD. It may be possible to overcome these challenges by reprogramming primary cells from patients into induced pluripotent stem cells (iPSCs). We reprogrammed primary fibroblasts from two patients with familial AD (both caused by a duplication of APP1, APPDp), two with sporadic AD (sAD1, 2) and two non-demented control individuals (NDCs) into iPSC lines. Neurons from differentiated cultures were FACS-purified and characterized. Purified cultures contained >90% neurons, clustered with fetal brain mRNA samples by microarray criteria, and could form functional synaptic contacts. Virtually all cells exhibited normal electrophysiological activity. Relative to controls, iPSC-derived, purified neurons from the two APPDp patients and patient sAD2 exhibited significantly higher levels of secreted Aβ1-40, phospho-tauThr231 (pTau) and active GSK3β (aGSK3β). Neurons from APPDp and sAD2 patients also accumulated large Rab5-positive early endosomes compared to controls. Treatment of purified neurons with β-secretase inhibitors, but not g-secretase inhibitors, caused significant reductions in pTau and aGSK3β levels. These results suggest a direct relationship between APP proteolytic processing, but not Aβ, in GSK3β activation and tau phosphorylation in human neurons. Additionally, we observed that neurons with the genome of one sAD patient exhibited the phenotypes seen in familial AD samples. More generally, we demonstrate that iPSC technology can be used to observe phenotypes relevant to AD, even though it can take decades for overt disease to manifest in patients. Total RNA extracted from normal hIPSCs, Alzheimer's patient derived hIPSCs, neurons differentiated from hIPSCs, fetal brain, fetal heart, fetal liver and fetal lung
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Project description:The pathophysiology of Alzheimer’s disease (AD) is multifactorial with characteristic extracellular accumulation of amyloid-beta (Aβ) and intraneuronal aggregation of hyperphosphorylated tau in the brain. Development of disease-modifying treatment for AD has been challenging. Recent studies suggest that deleterious alterations in neurovascular cells happens in parallel with Aβ accumulation, inducing tau pathology and necroptosis. Therefore, therapies targeting cellular Aβ and tau pathologies may provide a more effective strategy of disease intervention. Tetramethylpyrazine nitrone (TBN) is a nitrone derivative of tetramethylpyrazine, an active ingredient from Ligusticum wallichii Franchat (Chuanxiong). We previously showed that TBN is a potent scavenger of free radicals with multi-targeted neuroprotective effects in rat and monkey models of ischemic stroke. The present study aimed to investigate the anti-AD properties of TBN. We employed AD-related cellular model (N2a/APPswe) and transgenic mouse model (3×Tg-AD mouse) for mechanistic and behavioral studies. Our results showed that TBN markedly improved cognitive functions and reduced Aβ and hyperphosphorylated tau levels in mouse model. Further investigation of the underlying mechanisms revealed that TBN promoted non amyloidogenic processing pathway of amyloid precursor protein (APP) in N2a/APPswe in vitro. Moreover, TBN preserved synapses from dendritic spine loss and upregulated synaptic protein expressions in 3×Tg-AD mice. Proteomic analysis of 3×Tg-AD mouse hippocampal and cortical tissues showed that TBN induced neuroprotective effects through modulating mitophagy, MAPK and mTOR pathways. In particular, TBN significantly upregulated PINK1, a key protein for mitochondrial homeostasis, implicating PINK1 as a potential therapeutic target for AD. In summary, TBN improved cognitive functions in AD-related mouse model, inhibited Aβ production and tau hyperphosphorylation, and rescued synaptic loss and neuronal damage. Multiple mechanisms underlie the anti-AD effects of TBN including the modulation of APP processing, mTOR signaling and PINK1-related mitophagy.
2023-05-10 | PXD039514 | Pride
Project description:The apolipoprotein E4 (APOE4) variant is the single greatest genetic risk factor for sporadic Alzheimer's disease (sAD). However, the cell-type-specific functions of APOE4 in relation to AD pathology remain understudied. Here, we utilize CRISPR/Cas9 and induced pluripotent stem cells (iPSCs) to examine APOE4 effects on human brain cell types. Transcriptional profiling identified hundreds of differentially expressed genes in each cell type, with the most affected involving synaptic function (neurons), lipid metabolism (astrocytes), and immune response (microglia-like cells). APOE4 neurons exhibited increased synapse number and elevated Ab42 secretion relative to isogenic APOE3 cells while APOE4 astrocytes displayed impaired Ab uptake and cholesterol accumulation. Notably, APOE4 microglia-like cells exhibited altered morphologies, which correlated with reduced Ab phagocytosis. Consistently, converting APOE4 to APOE3 in brain cell types from sAD iPSCs was sufficient to attenuate multiple AD-related pathologies. Our study establishes a reference for human cell-type-specific changes associated with the APOE4 variant.
2018-05-31 | GSE102956 | GEO
Project description:Communication within the glial cell ecosystem is essential for neuronal and brain health1–3. The influence of glial cells on the accumulation and clearance of β-amyloid (Aβ) and neurofibrillary tau in the brains of individuals with Alzheimer’s disease (AD) is poorly understood, despite growing awareness that these are therapeutically important interactions4,5. Here we show, in humans and mice, that astrocyte-sourced interleukin-3 (IL-3) programs microglia to ameliorate the pathology of AD. Upon recognition of Aβ deposits, microglia increase their expression of IL-3Rα—the specific receptor for IL-3 (also known as CD123)—making them responsive to IL-3. Astrocytes constitutively produce IL-3, which elicits transcriptional, morphological, and functional programming of microglia to endow them with an acute immune response program, enhanced motility, and the capacity to cluster and clear aggregates of Aβ and tau. These changes restrict AD pathology and cognitive decline. Our findings identify IL-3 as a key mediator of astrocyte–microglia cross-talk and a node for therapeutic intervention in AD.
2021-06-02 | GSE163289 | GEO
Project description:Amyloid-beta (Aβ) deposition in the brain, is closely linked to development of Alzheimer’s disease (AD). Unfortunately, therapies specifically targeting Aβ deposition have failed to reach their primary clinical endpoints, emphasizing the need to broaden the search strategy for identification of alternative therapeutic targets/mechanisms. Transglutaminase (TG2) catalyses posttranslational modifications, is present in characteristic AD lesions and has AD-associated proteins, including Aβ, tau and apolipoprotein E. However, an unbiased overview of TG2 interactors (TG2 interactome) and the cellular pathways of which these interactors are part in control and AD brain is lacking. Here, anticipating future studies in AD brain, we aimed to identify these interactors and their pathways using a crossbred of the AD-mimicking APP23 mouse model with wildtype and TG2-/- mice. We found that absence of TG2 had no (statistically) significant effect on Aβ pathology, soluble brain levels of Aβ1-40, Aβ1-42, and mRNA levels of TG2 family members compared to APP23 mice. Quantitative proteomics and network analysis revealed a large cluster of TG2 interactors with synaptic transmission/assembly and cell adhesion typical of AD in the APP23 brain. Comparative proteomics were in line with these observations as it also revealed association of proteins of both pathways to be linked to TG2 in APP23 brains Together, our data showed that TG2 deletion led to considerable network alterations consistent with a role of TG2 in (dys)regulation of synaptic transmission and cell adhesion in APP23 brains.
2022-02-22 | PXD030354 | Pride
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2024-03-22 | GSE169347 | GEO
Project description:Alzheimer’s Disease (AD) is the most common cause of age-related dementia and the sixth leading cause of death in the United States. AD neuropathology is primarily characterized by the accumulation of extracellular beta-amyloid (Aβ) plaques and intraneuronal neurofibrillary tau tangles. In addition to these hallmark AD pathologies, many other important pathological changes occur in the brains of AD patients, including synaptic and neuronal loss and neuroinflammation. Most recently, genome-wide association studies (GWAS) have provided substantial new evidence that immune dysfunction may contribute to the development and progression of AD. To date over 60 GWAS loci have been identified and almost two thirds of these genes are highly expressed in microglia, the resident innate immune cell of the brain. These genetic discoveries have in turn inspired many new studies of microglial biology and the role of these cells in AD. In contrast, the role of the adaptive immunity in AD remains understudied, despite evidence that many of AD risk genes are also highly expressed in T and B cells. To investigate the role of T cell infiltration in AD, we examined T cells from immune-deficient AD mice via bone marrow transplantation studies using flow cytometry and immunohistochemistry; and from immune-intact transgenic AD model mice using flow cytometry, immunohistochemistry, and single-cell RNA sequencing. Our experiments demonstrate that multiple T cell subtypes infiltrate the AD brain, and that effector memory CD8 T cells are specifically enriched in response to Aβ pathology or a combination of Aβ and tau pathologies. Single-cell sequencing analysis revealed high expression of over 40 AD risk genes between several T cell sub-populations, implying a need for more research of these T cell phenotypes in AD development. Additionally, T-cell receptor (TCR) sequencing revealed increased clonal expansion of T cells from mice that developed Aβ pathology or Aβ and tau pathology, suggesting amyloid-driven recruitment and clonal expansion of T cells in these mice. Ultimately, this study demonstrates the crucial importance of investigating the role of T cells in AD and provides a guide for future experiments to continue to enhance our understanding of AD immunology.
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Project description:Alzheimer's disease (AD) is one of the neurodegenerative diseases and characterized by the appearance and accumulation of amyloid-β (Aβ) aggregates and phosphorylated tau with aging. We performed scRNAseq of immene cells in the brain from WT and AD mice.
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Project description:The two hallmarks of Alzheimer’s disease (AD) are A-amyloid- (A) plaques and neurofibrillary tangles marked by phosphorylated tau. There is compelling evidence that aggregating A drives tau accumulation, a process that involves synaptic degeneration leading to cognitive impairment. Conversely there is a growing realization that non-fibrillar (oligomeric) forms of Aβ mediate toxicity in AD. Using quantitative proteomics, we find that AD brain sarkosyl-insoluble pellets are greatly enriched with A at almost equimolar levels to N-terminal truncated microtubule binding region (MTBR) isoforms of tau with multiple post-translational modifications (PTMs). The extracted R3-R4 tau peptides are 100-fold higher compared to N-terminus intact tau peptides. Substantial proportions of site-specific phosphorylation at T181 (~ 22 %) and T217 (~ 16 %) along with other PTMs in the proline rich region (PRR) and MTBR indicate a regional susceptibility of PTMs in aggregated tau. Immuno-electron microscopy reveals that co-purified A and tau co-localize to globular non-filamentous aggregates.
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