Histone acetylation in an Alzheimer’s disease cell model promotes homeostatic amyloid-reducing pathways
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1054539 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR27291800_1.fastq.gz | Fastqsanger.gz | |||
| SRR27291800_2.fastq.gz | Fastqsanger.gz | |||
| SRR27291801_1.fastq.gz | Fastqsanger.gz | |||
| SRR27291801_2.fastq.gz | Fastqsanger.gz | |||
| SRR27291802_1.fastq.gz | Fastqsanger.gz |
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Project description:Defining how amyloid-β and pTau together lead to neurodegeneration is fundamental to understanding Alzheimer’s disease (AD). We used imaging mass cytometry to identify neocortical neuronal subtypes lost with AD in post-mortem brain middle temporal gyri from non-diseased and AD donors. Here we showed that L5,6 RORB+FOXP2+ and L3,5,6 GAD1+FOXP2+ neurons, which accumulate amyloid-β intracellularly from early Braak stages, are selectively vulnerable to degeneration in AD, while L3 RORB+GPC5+ neurons, which accumulate pTau but not amyloid-β, are not lost even at late Braak stages. We discovered spatial associations between activated microglia and these vulnerable neurons and found that vulnerable RORB+FOXP2+ neuronal transcriptomes are enriched selectively for pathways involved in inflammation and glycosylation and, with progression to AD, also protein degradation. Our results suggest that the accumulation of intraneuronal amyloid-β, which is associated with glial inflammatory pathology, may contribute to the initiation of degeneration of these vulnerable neurons.
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Project description:Alzheimer’s Disease (AD) is the most common form of dementia and a leading global cause of human mortality and morbidity. Amyloid plaques of the amyloid beta (Aß) peptide are a universal pathological hallmark of AD and rare mutations in Aß can cause familial forms of AD (fAD). However, hundreds of additional mutations in Aß of uncertain significance are likely to exist in the human population, making clinical interpretation of genetic variation a difficult challenge even in this short peptide. Here, we use deep mutagenesis to quantify the effects of all possible single nucleotide variants and thousands of double mutations on the ability of Aß to nucleate amyloid fibrils in vivo. This data provides the first comprehensive view of how mutations alter the nucleation of an amyloid, reveals a modular organisation of mutational effects in Aß, and demonstrates the importance of charge in preventing nucleation. Moreover, the in vivo nucleation data, unlike computational predictors, accurately discriminates the known dominant fAD mutations. These results illustrate how deep mutagenesis can be used to genetically validate assays as discovery platforms. They also further prioritize nucleation as the critical biochemical event to target in order to prevent and treat AD.
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2024-12-06 | PXD058639 |
Project description:Background: ABCA1 has recently been identified as a novel genetic risk factor for Alzheimer’s disease. The major known role of ABCA1 in the brain is to transfer lipids onto lipid poor APOE. Given that APOEε4 is the strongest genetic risk factor for developing late onset Alzheimer’s disease, this recent finding implicates the cholesterol homeostatic pathway in the onset/progression of Alzheimer’s disease. microRNAs (miRs) are small RNA species that negatively regulate expression of their target genes. ABCA1 is regulated by miR-33, and loss of this miR significantly increases protein levels of ABCA1 and increases the lipidation of APOE. However, it is unknown if loss of miR-33 and subsequent increase in ABCA1 protein levels ameliorates amyloid pathology. Methods: We generated miR-33+/+;APP/PS1 and miR-33-/-;APP/PS1 mice to determine changes in amyloid-beta (Aβ) peptides and amyloid plaque formation utilizing biochemical and histological analyses. In addition to amyloid pathology, we assessed if deletion of miR-33 altered the activation of glial cells in the brains of these mice. We utilized in vitro methods to determine if miR-33 alters the phagocytosis of Aβ aggregates. We utilized RNA-sequencing and mass spectrometry to identify the transcriptome and proteome regulation by miR-33 in the context of amyloid pathology. Results: Deletion of miR-33 dramatically reduces insoluble Aβ peptide levels and the deposition of amyloid plaques in APP/PS1 mice. In addition, we identified that astrocyte and microglial activation is markedly decreased in miR-33-/-;APP/PS1 mice through histological analyses. Intriguingly, we show that loss of miR-33 results in amyloid plaques that are more compact, potentially implicating enhanced microglial phagocytosis. We confirm in vitro that loss of miR-33 significantly increases microglial phagocytosis of Aβ aggregates. Our multi-omics analyses reveal that deletion of miR-33 regulates immune response in the context of amyloid pathology. Interestingly, we identified that WNT/Beta-catenin signaling is significantly upregulated in miR-33-/-;APP/PS1 mice. Conclusion: We confirm that the deletion of miR-33 increases APOE lipidation and significantly reduces amyloid pathology as well as glial activation in APP/PS1 mice. Our results agree with previous work identifying APOE lipidation as an important modulator of amyloid pathology. We show, for the first time, that loss of miR-33 increases the phagocytosis of Aβ by microglia. In total, we identify miR-33 as a promising target for the amelioration of amyloid pathology.
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Project description:Background: The p38 alpha mitogen-activated protein kinase (p38a) pathway is linked to both innate and adaptive immune responses, and as such, is currently under active investigation as a target for drug development in the context of Alzheimer’s disease (AD) and other conditions with neuroinflammatory dysfunction. While preclinical data has shown that p38a inhibition can protect against AD-associated neuropathology, the underlying mechanisms are only partially elucidated. Inhibitors of p38a may provide benefit via modulation of microglial-associated neuroinflammatory responses that contribute to the development of AD pathology. The present study tests this hypothesis by knocking out microglial p38a and assessing early-stage pathological changes. Materials and methods: Conditional knockout of microglial p38a was accomplished in 5-month-old C57BL/6J wild-type and amyloidogenic AD model (APPswe/PS1dE9) mice using a tamoxifen-inducible Cre/loxP system. Beginning at 7.5 months of age, animals underwent behavioral assessment on the open field and radial arm water maze tests, followed by collection of cortical and hippocampal tissues at 11 months. Additional endpoint measures included microglial RNA-seq analysis, quantification of pro-inflammatory cytokines, assessment of amyloid burden and plaque deposition, and characterization of microglia-plaque dynamics using a combination of ELISA, immunohistochemical, and immunofluorescent techniques. Results: Loss of microglial p38a did not alter behavioral outcomes, pro-inflammatory cytokine levels, or overall amyloid plaque burden. However, this manipulation did significantly increase hippocampal levels of soluble Abeta42 and reduce colocalization of Iba1 and 6E10 in a subset microglia in close proximity to plaques, indicating that p38a suppression may alter microglial phagocytosis. Conclusion: The data presented here suggest that rather than reducing inflammation per se, the net effect of microglial p38a inhibition in the context of AD-type amyloid pathology could be an alteration of phagocytosis and/or plaque deposition. Additionally, these results support future investigations of microglial p38a signaling at different stages of disease, as well as its relationship to phagocytic processes in this particular cell-type.
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