| 1. |
- Balusu, Sriram, et al.
(författare)
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MEG3 activates necroptosis in human neuron xenografts modeling Alzheimer's disease.
- 2023
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Ingår i: Science (New York, N.Y.). - 1095-9203. ; 381:6663, s. 1176-1182
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal cell loss is a defining feature of Alzheimer's disease (AD), but the underlying mechanisms remain unclear. We xenografted human or mouse neurons into the brain of a mouse model of AD. Only human neurons displayed tangles, Gallyas silver staining, granulovacuolar neurodegeneration (GVD), phosphorylated tau blood biomarkers, and considerable neuronal cell loss. The long noncoding RNA MEG3 was strongly up-regulated in human neurons. This neuron-specific long noncoding RNA is also up-regulated in AD patients. MEG3 expression alone was sufficient to induce necroptosis in human neurons in vitro. Down-regulation of MEG3 and inhibition of necroptosis using pharmacological or genetic manipulation of receptor-interacting protein kinase 1 (RIPK1), RIPK3, or mixed lineage kinase domain-like protein (MLKL) rescued neuronal cell loss in xenografted human neurons. This model suggests potential therapeutic approaches for AD and reveals a human-specific vulnerability to AD.
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| 2. |
- Chen, Wei-Ting, et al.
(författare)
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Spatial Transcriptomics and In Situ Sequencing to Study Alzheimer's Disease
- 2020
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Ingår i: Cell. - : Elsevier BV. - 0092-8674 .- 1097-4172. ; 182:4, s. 976-
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Tidskriftsartikel (refereegranskat)abstract
- Although complex inflammatory-like alterations are observed around the amyloid plaques of Alzheimer's disease (AD), little is known about the molecular changes and cellular interactions that characterize this response, We investigate here, in an AD mouse model, the transcriptional changes occurring in tissue domains in a 100-mu m diameter around amyloid plaques using spatial transcriptomics. We demonstrate early alterations in a gene co-expression network enriched for myelin and oligodendrocyte genes (OLIGs), whereas a multicellular gene co-expression network of plaque-induced genes (PIGs) involving the complement system, oxidative stress, lysosomes, and inflammation is prominent in the later phase of the disease. We confirm the majority of the observed alterations at the cellular level using in situ sequencing on mouse and human brain sections. Genome-wide spatial transcriptomics analysis provides an unprecedented approach to untangle the dysregulated cellular network in the vicinity of pathogenic hallmarks of AD and other brain diseases.
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| 3. |
- Sala Frigerio, Carlo, et al.
(författare)
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Reduced expression of hsa-miR-27a-3p in CSF of patients with Alzheimer disease.
- 2013
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 81:24, s. 2103-2106
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Tidskriftsartikel (refereegranskat)abstract
- We evaluated microRNAs (miRNAs) as potential biomarkers for Alzheimer disease (AD) by analyzing the expression level of miRNAs in CSF of patients with AD dementia and nonaffected control subjects.
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| 4. |
- Walgrave, Hannah, et al.
(författare)
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Restoring miR-132 expression rescues adult hippocampal neurogenesis and memory deficits in Alzheimer's disease.
- 2021
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Ingår i: Cell stem cell. - : Elsevier BV. - 1875-9777 .- 1934-5909. ; 28:10
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Tidskriftsartikel (refereegranskat)abstract
- Neural stem cells residing in the hippocampal neurogenic niche sustain lifelong neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer's disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous proneurogenic effects in adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly affected by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in mouse models of AD and reveal the possible therapeutic potential of targeting miR-132 in neurodegeneration.
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