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Differentiated embryonic neurospheres from familial Alzheimer’s disease model show Innate Immune and Glial Cell Responses

ABSTRACT: Proteins involved in the Alzheimer’s disease (AD), such as amyloid precursor protein (APP) and presenilin-1 (PS1), play critical roles in early development of the central nervous system (CNS), as well as in innate immune and glial cell responses. However, it is unknown whether these alterations start on development of the CNS of carriers of APPswe and PS1dE9 mutations , associated with familial AD. Using microarray technology we studied the genome-wide gene expression profiles in the differentiated neural progenitor cells (NPCs) from wild-type (WT) and APPswe/PS1dE9 embryo telencephalon. Differential gene expression analysis indicated the occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres, involving mainly microglial cells, inflammatory mediators and chemokines. APPswe/PS1dE9 cells expressed up to 100-fold more CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha, which was confirmed by real time PCR. The expression of activated microglia marker Iba-1 was also 20-fold upregulated in APPswe/PS1dE9 cells. The secretome of APPswe/PSldE9 differentiated NPCs increased the chemoattraction of peripheral blood mononuclear cells (PBMCs) compared to the secretome of WT cells. Taken together, our results demonstrated that neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres is an excellent model for AD in vitro, since this culture spontaneously presents several alterations observed in the adult-brain with this pathology. Moreover, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.

ORGANISM(S): Mus musculus

PROVIDER: GSE227002 | GEO | 2023/09/30

REPOSITORIES: GEO

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Project description:GFAP and vimentin deficiency alters gene expression in astrocytes and microglia in wild-type mice and changes the transcriptional response of reactive glia in mouse model for Alzheimer's disease. Reactive astrocytes with an increased expression of intermediate filament (IF) proteins Glial Fibrillary Acidic Protein (GFAP) and Vimentin (VIM) surround amyloid plaques in Alzheimer's disease (AD). The functional consequences of this upregulation are unclear. To identify molecular pathways coupled to IF regulation in reactive astrocytes, and to study the interaction with microglia, we examined WT and APPswe/PS1dE9 (AD) mice lacking either GFAP, or both VIM and GFAP, and determined the transcriptome of cortical astrocytes and microglia from 15- to 18-month-old mice. Genes involved in lysosomal degradation (including several cathepsins) and in inflammatory response (including Cxcl5, Tlr6, Tnf, Il1b) exhibited a higher AD-induced increase when GFAP, or VIM and GFAP, were absent. The expression of Aqp4 and Gja1 displayed the same pattern. The downregulation of neuronal support genes in astrocytes from AD mice was absent in GFAP/VIM null mice. In contrast, the absence of IFs did not affect the transcriptional alterations induced by AD in microglia, nor was the cortical plaque load altered. Visualizing astrocyte morphology in GFAP-eGFP mice showed no clear structural differences in GFAP/VIM null mice, but did show diminished interaction of astrocyte processes with plaques. Microglial proliferation increased similarly in all AD groups. In conclusion, absence of GFAP, or both GFAP and VIM, alters AD-induced changes in gene expression profile of astrocytes, showing a compensation of the decrease of neuronal support genes and a trend for a slightly higher inflammatory expression profile. However, this has no consequences for the development of plaque load, microglial proliferation, or microglial activation. 2 cell types from 6 conditions: cortical microglia and cortical astrocytes from 15-18 month old APPswe/PS1dE9 mice compared to wildtype littermates. Biological replicates: microglia from APPswe/PS1dE9, N=7, microglia from WT, N=7, astrocytes from APPswe/PS1dE9, N=4, microglia from WT, N=4

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Differentiated embryonic neurospheres from familial Alzheimer’s disease model show Innate Immune and Glial Cell Responses

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