Differentiated Embryonic Neurospheres from Familial Alzheimer's Disease Model Show Innate Immune and Glial Cell Responses.

Autor: Pillat MM; Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil. micheli.pillat@ufsm.br., Ayupe AC; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil., Juvenal G; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil., Meinerz C; Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil., Glaser T; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil., da Silva Pellegrina DV; Interunit Graduate Program in Bioinformatics, University of São Paulo, Sao Paulo, SP, Brazil., Paiva DS; Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil., Mello CF; Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil., Longo BM; Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil., Reis EM; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil., Ulrich H; Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil. henning@iq.usp.br.
Jazyk: angličtina
Zdroj: Stem cell reviews and reports [Stem Cell Rev Rep] 2023 Aug; Vol. 19 (6), pp. 1800-1811. Date of Electronic Publication: 2023 May 02.
DOI: 10.1007/s12015-023-10542-0
Abstrakt: 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 APP swe and PS1 dE9 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 APP swe/ PS1 dE9 mouse embryo telencephalon. The occurrence of strong innate immune and glial cell responses in APP swe/ PS1 dE9 neurospheres mainly involves microglial activation, inflammatory mediators and chemokines. APP swe/ PS1 dE9 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 APP swe/ PS1 dE9 neurospheres. The secretome of differentiated APP swe/ PS1 dE9 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 APP swe /PS1 dE9 neurospheres was evident in view of increased GFAP expression. Transgenic NPCs differentiated into neural phenotypes presented expression patterns of cytokine, glial cells, and inflammatory mediators characteristic of APP swe/ PS1 dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APP swe/ PS1 dE9 neurospheres spontaneously presents several alterations observed in adult AD brains. Finally, our data strengthen pathophysiological hypotheses that propose an early neurodevelopmental origin for familial AD.
(© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
Databáze: MEDLINE
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