The olfactory molecular snapshot of Tg2576 mice at early stages of amyloid pathology
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ABSTRACT:
PROVIDER: PRJNA417496 | ENA |
REPOSITORIES: ENA
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Project description:Olfaction is often deregulated in Alzheimer's disease (AD) patients, being also impaired in transgenic Tg2576 AD mouse model, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of olfactory structures in Tg2576 mice. For that, we have applied proteome- and transcriptome-wide approaches to probe molecular disturbances in the olfactory bulb (OB) dissected from Tg2576 mice (2, and 6 months of age) respect to age-matched wild-type (WT) littermates.
2019-07-01 | GSE106643 | GEO
Project description:Olfaction is often deregulated in Alzheimer´s disease (AD) patients, being also impaired in transgenic Tg2576 AD mouse model, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of olfactory structures in Tg2576 mice. For that, we have applied proteome- and transcriptome-wide approaches to probe molecular disturbances in the olfactory bulb (OB) dissected from aged Tg2576 mice (18 months of age) respect to age matched wild-type (WT) littermates.
2018-02-14 | GSE103835 | GEO
Project description:Olfaction is often deregulated in Alzheimer´s disease (AD) patients, being also impaired in transgenic Tg2576 AD mouse model, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of olfactory structures in Tg2576 mice. For that, we have applied proteome- and transcriptome-wide approaches to probe molecular disturbances in the olfactory bulb (OB) dissected from aged Tg2576 mice (18 months of age) respect to age matched wild-type (WT) littermates
2017-11-02 | PXD007795 | Pride
Project description:Olfaction is often deregulated in Alzheimer´s disease (AD) patients, being also impaired in transgenic Tg2576 AD mouse model, which overexpress the Swedish mutated form of human amyloid precursor protein (APP). However, little is known about the molecular mechanisms that accompany the neurodegeneration of olfactory structures in Tg2576 mice. For that, we have applied proteome-wide approaches to probe molecular disturbances in the olfactory bulb (OB) dissected from Tg2576 mice respect to age matched wild-type littermates (2 and 6 months of age).
2019-06-28 | PXD007813 | Pride
Project description:Neuronal Idol deletion ameliorates amyloid pathology
| PRJNA1285258 | ENA
Project description:Earlier studies demonstrated that overexpression of the low-density lipoprotein receptor (LDLR) decreases apolipoprotein E (APOE) levels in the brain and alleviates amyloid-beta (Aβ) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL)- an E3 ubiquitin ligase that ubiquitinates LDLR for degradation- would increase endogenous LDLR levels and decrease amyloid pathology. Previously, we demonstrated that the deletion of Idol increased LDLR levels and reduced amyloid deposition in a transgenic mouse model of Aβ-amyloidosis. However, the cellular mechanisms underlying these beneficial effects were unknown. Here, we investigate the cell-type-specific contribution of Idol deletion to amyloid pathology by generating Idol conditional knock-out mouse models. We demonstrate that deletion of neuronal, but not microglial, Idol reduces amyloid accumulation in the 5XFAD transgenic mouse model. Furthermore, only neuronal Idol deletion alters brain LDLR and APOE levels, pointing to the critical role of the neuronal LDLR-APOE axis in modulating Aβ accumulation.
2025-12-16 | GSE301451 | GEO
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.
2024-09-30 | GSE235179 | GEO
Project description:Earlier studies demonstrated that overexpression of the low-density lipoprotein receptor (LDLR) decreases apolipoprotein E (APOE) levels in the brain and alleviates amyloid-beta (Abeta) pathology. We hypothesized that inhibiting the Inducible Degrader of LDLR (IDOL)- an E3 ubiquitin ligase that ubiquitinates LDLR for degradation- would increase endogenous LDLR levels and decrease amyloid pathology. Previously, we demonstrated that the deletion of Idol increased LDLR levels and reduced amyloid deposition in a transgenic mouse model of Abeta-amyloidosis. However, the cellular mechanisms underlying these beneficial effects were unknown. Here, we investigate the cell-type-specific contribution of Idol deletion to amyloid pathology by generating Idol conditional knock-out mouse models. We demonstrate that deletion of neuronal, but not microglial, Idol reduces amyloid accumulation in the 5XFAD transgenic mouse model. Furthermore, only neuronal Idol deletion alters brain LDLR and APOE levels, pointing to the critical role of the neuronal LDLR-APOE axis in modulating Abeta accumulation.
2025-06-16 | MSV000098209 | MassIVE
Project description:Parkinson’s disease (PD) is characterized by multiple symptoms including olfactory dysfunction, whose underlying mechanisms remain unclear. Here, we explored pathologic changes in the olfactory pathway of transgenic (Tg) mice of both sexes expressing the human A30P mutant α-synuclein (α-syn; α-syn-Tg mice) at 6–7 and 12–14 months of age, representing early and late-stages of motor progression, respectively. α-Syn-Tg mice at late stages exhibited olfactory behavioral deficits, which correlated with severe α-syn pathology in projection neurons (PNs) of the olfactory pathway. In parallel, olfactory bulb (OB) neurogenesis in α-syn-Tg mice was reduced in the OB granule cells at six to seven months and OB periglomerular cells at 12–14 months, respectively, both of which could contribute to olfactory dysfunction. Proteomic analyses showed a disruption in endocytic and exocytic pathways in the OB during the early stages which appeared exacerbated at the synaptic terminals when the mice developed olfactory deficits at 12–14 months. Our data suggest that (1) the α-syn-Tg mice recapitulate the olfactory functional deficits seen in PD; (2) olfactory structures exhibit spatiotemporal disparities for vulnerability to α-syn pathology; (3) α-syn pathology is restricted to projection neurons in the olfactory pathway; (4) neurogenesis in adult α-syn-Tg mice is reduced in the OB; and (5) synaptic endocytosis and exocytosis defects in the OB may further explain olfactory deficits.
2023-01-13 | PXD039396 | Pride
Project description:The adenosine triphosphate–binding cassette transporter A7 (ABCA7) gene is ranked as one of the top susceptibility loci for Alzheimer’s disease (AD). While ABCA7 mediates lipid transport across cellular membranes, ABCA7 loss of function has been shown to exacerbate amyloid-β (Aβ) pathology and compromise microglial function. Our family-based study uncovered an extremely rare ABCA7 p.A696S variant that was substantially segregated with the development of AD in 3 African American families. Using the knockin mouse model, we investigated the effects of ABCA7-A696S substitution on amyloid pathology and brain immune response in 5xFAD transgenic mice. Importantly, our study demonstrated that ABCA7-A696S substitution reduces amyloid plaque–associated microgliosis and increases dystrophic neurites around amyloid deposits compared to control mice. We also found increased X-34–positive amyloid plaque burden in 5xFAD mice with ABCA7-A696S substitution, while there was no evident difference in insoluble Aβ levels between mouse groups. Thus, ABCA7-A696S substitution may disrupt amyloid compaction resulting in aggravated neuritic dystrophy due to insufficient microglia barrier function. In addition, we observed that ABCA7-A696S substitution disturbs the induction of proinflammatory cytokines interleukin 1β and interferon γ in the brains of 5xFAD mice, although some disease-associated microglia gene expression, including Trem2 and Tyrobp, are upregulated. Lipidomics also detected higher total lysophosphatidylethanolamine levels in the brains of 5xFAD mice with ABCA7-A696S substitution than controls. These results suggest that ABCA7-A696S substitution might compromise the adequate innate immune response to amyloid pathology in AD by modulating brain lipid metabolism, providing novel insight into the pathogenic mechanisms mediated by ABCA7.
2025-03-13 | GSE288170 | GEO