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. Familial AD is associated with the presence of APPswe and PS1dE9 mutations. However, it is still unknown whether these mutations cause deficits in CNS development of carriers. We studied genome-wide gene expression profiles of differentiated neural progenitor cells (NPCs) from wild-type and APPswe/PS1dE9 mouse embryo telencephalon. The occurrence of strong innate immune and glial cell responses in APPswe/PS1dE9 neurospheres mainly involves microglial activation, inflammatory mediators and chemokines. APPswe/PS1dE9 neurospheres augmented up to 100-fold CCL12, CCL5, CCL3, C3, CX3CR1, TLR2 and TNF-alpha expression levels, when compared to WT neurospheres. Expression levels of the glia cell marker GFAP and microglia marker Iba-1 were up to 20-fold upregulated in APPswe/PS1dE9 neurospheres. The secretome of differentiated APPswe/PS1dE9 NPCs revealed enhanced chemoattraction of peripheral blood mononuclear cells. When evaluating the inferred protein interaction networks constructed from the array data, an improvement in astrocyte differentiation in APPswe/PS1dE9 neurosphereswas evident in view ofincreased GFAPexpression. Transgenic NPCs differentiated into neural phenotypes presented expression patterns of cytokine, glial cells, and inflammatory mediators characteristic of APPswe/PS1dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 neurospheres spontaneously presents several alterations observed in adult ADbrains. Finally, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.