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

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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 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 APPswe/PS1dE9 adult animals. Consequently, the neurogenic niche obtained from differentiation of embryonic APPswe/PS1dE9 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.

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Data Availability

The manuscript has associated data in a data repository (GEO database, https://www.ncbi.nlm.nih.gov/geo under accession No. GSE227002) and as electronic supplementary material.

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Code Availability

Raw and normalized expression data are deposited in GEO database (https://www.ncbi.nlm.nih.gov/geo) under accession GSE227002.

Funding

This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq Project No. 406396/2021 and 308012/2021–6, awarded to HU), Brazil. HU acknowledges grant support by Fundação de Amparo à Pesquisa do Estado de São Paulo [São Paulo Research Foundation (FAPESP) Project No. 2018/08426–0 and 2018/07366–4] and the National Institute of Science and Technology in Regenerative Medicine (INCT-REGENERA), Brazil. MMP acknowledges Grant support by Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul [Rio Grande do Sul Research Foundation (FAPERGS) Project No. 21/2551–0001982-4 and 23/2551–0000150-0] and Marylou Ingram Scholarship from International Society for Advancement of Cytometry (ISAC).

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Authors and Affiliations

  1. Department of Microbiology and Parasitology, Health Sciences Center, Federal University of Santa Maria, Santa Maria, RS, Brazil

    Micheli Mainardi Pillat, Carine Meinerz & Carlos Fernando Mello

  2. Department of Biochemistry, Institute of Chemistry, University of São Paulo, São Paulo, SP, Brazil

    Ana Carolina Ayupe, Guilherme Juvenal, Talita Glaser, Eduardo Moraes Reis & Henning Ulrich

  3. Interunit Graduate Program in Bioinformatics, University of São Paulo, Sao Paulo, SP, Brazil

    Diogo Vieira da Silva Pellegrina

  4. Department of Physiology, Federal University of São Paulo, São Paulo, SP, Brazil

    Daisylea Souza Paiva & Beatriz Monteiro Longo

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  1. Micheli Mainardi Pillat
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Contributions

MMP, HU, ACA and EMR designed the research; MMP, ACA, DSP and TG performed the experiments; MMP, ACA, EMR, GJ, CM, and HU wrote the manuscript; MMP, CM, ACA, GJ and DVSP analyzed the data; and HU, CFM and BML revised the manuscript. All authors read and approved the final manuscript.

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Correspondence to Micheli Mainardi Pillat or Henning Ulrich.

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H.U. is s scientific advisor of TissueGnostics, Vienna, Austria receiving consulting fees. All other authors declare that there are no conflicts of interest regarding the publication of this paper.

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All animal experiments were performed according to protocols approved by the ethics committee of Universidade Federal de São Paulo (UNIFESP), São Paulo, Brazil, under the authorization number CEUA 1435020517.

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Pillat, M.M., Ayupe, A.C., Juvenal, G. et al. Differentiated Embryonic Neurospheres from Familial Alzheimer’s Disease Model Show Innate Immune and Glial Cell Responses. Stem Cell Rev and Rep 19, 1800–1811 (2023). https://doi.org/10.1007/s12015-023-10542-0

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