Project description:While mouse models of ß-amyloidopathy recapitulate aspects of Alzheimer's disease pathology, including plaque formation and synapse loss, most progress at a speed such that outcomes are studied in the mature mouse, rather than the aged mouse. Here we investigated Aß-dependent changes to astrocytes in a knock-in model of ß-amyloidopathy (APP NL-F) that is known to progress more slowly.
Project description:Bulk RNA-sequencing of astrocytes in the APP NL-F and APP PS1 models of ß-amyloidopathy, in which aspects of AD-related pathology progress at different speed, shows age-dependent gene expression changes. However, bulk RNA-seq does not provide insight into the heterogeneity of expression within this cell type, particularly relevant for such models, where reactive astrogliosis is most prominent in the vicinity of plaques. To investigate astrocyte heterogeneity in ß-amyloidopathy models, we thus performed single cell RNA-sequencing on astrocytes separated by FACS.
Project description:Alzheimer’s disease is known to alter astrocytes, but the effect of Aß and Tau pathology on these cells remains poorly understood. We investigated the transcriptomic behaviour of astrocytes (via translating ribosome affinity purification (TRAP)), and bulk brain tissue, in mouse models of APP/PS1 ß-amyloidopathy and MAPT-P301S tauopathy, in a mouse model overexpressing cytoprotective Nrf2 specifically in astrocytes (GFAP-Nrf2 model), and in crosses between the amyloidopathy and tauopathy models with the GFAP-Nrf2 mouse.
Project description:To investigate the effects of diabetic conditions on the development of AD pathology, we fed wild-type and Alzheimer's disease model (App[NL-F/NL-F]) mice with control or high fat diet from 6 months after birth for 12 months, then examined behavior, brain pathology and gene expression profiles. Both groups of mice fed with high fat diet exhibited diabetic conditions, and App[NL-F/NL-F] mice exhibited aggravated cognitive impairment with enhanced Alzheimer's disease pathology.
Project description:We performed a broad-spectrum microarray analysis using mRNA from 3 NL and 5 DS astrocyte cultures. The microarray output was validated for several genes To explore the relation between gene expression and potential oxidative stress in DS samples, we also evaluated the transcription profile in NL astrocytes subjected to mild oxidative stress (50µM H2O2 for 24 hr).
Project description:We performed a broad-spectrum microarray analysis using mRNA from 3 NL and 5 DS astrocyte cultures. The microarray output was validated for several genes To explore the relation between gene expression and potential oxidative stress in DS samples, we also evaluated the transcription profile in NL astrocytes subjected to mild oxidative stress (50µM H2O2 for 24 hr). Samples of total mRNA from NL cultures non treated (NT), normal cultures treated with H2O2 (T), DS cultures NT and DS cultures T were included in the arrays.
Project description:Remyelination failure contributes to axonal dysfunction in neurodegenerative disorders. But whether astrocytes, the most abundant glial cell type in demyelinated lesions, support or impede remyelination is controversial. Following focal demyelinated lesions of the mouse corpus callosum induced with the myelin toxin lysolecithin, we used TRAP (translational ribosome affinity purification) sequencing to isolate and sequence ribosome-associated mRNAs which are being actively translated in astrocytes, and studied how the responses and molecular mechanisms in astrocytes are linked to remyelination.
Project description:The APPSwe/PS1dE9 (APP/PS1) mouse ß-amyloidopathy mouse model exhibits extracellular Aß deposition, particularly in the neocortex and hippocampus, increasing steadily from about 6 months, with reactive astrogliosis and synapse loss occurring proximal to plaques. We crossed APP/PS1 mice onto genetically modified mice which lack microglia (Csf1r ∆FIRE/∆FIRE) to assess whether Aß plaque deposition and downstream events are altered in brains lacking microglia.
Project description:We analyzed the transcriptional profile of astrocytes from 1) WT mice infected with AAV-GFP, 2) reactive astrocytes from 9-month old APP/PSdE9 mice infected with AAV-GFP and 3) de-activated astrocytes from 9-month old APP/PSdE9 mice infected with AAV-SOCS3 We show SOCS3 normalizes the inflammatory profile of APP astrocytes