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

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Pillat, Micheli Mainardi ; Ayupe, Ana Carolina ; Juvenal, Guilherme ; Meinerz, Carine ; Glaser, Talita ; da Silva Pellegrina, Diogo Vieira ; Paiva, Daisylea Souza ; Mello, Carlos Fernando ; Longo, Beatriz Monteiro ; Reis, Eduardo Moraes ; Ulrich, Henning

• Document type: Journal article
• Source: STEM CELL REVIEWS AND REPORTS; v. 19, n. 6, p. 12-pg., 2023-05-02.

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 -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. (AU)

• FAPESP's process: 18/07366-4 - Purine and kinin receptors as targets of study and therapeutic interventions in neurological diseases
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 18/08426-0 - Indole alkaloid sub products of Maqui (Aristotelia chilensis) processing as food additives to Alzheimer's Disease treatment
• Grantee: Alexander Henning Ulrich
• Support Opportunities: Regular Research Grants