Administration of Amyloid Precursor Protein Gene Deleted Mouse ESC-Derived Thymic Epithelial Progenitors Attenuates Alzheimer's Pathology

Abstract

Alzheimer's disease (AD) is a devastating neurodegenerative disorder and the most common cause of dementia in older adults. Although amyloid-beta (Aβ) plaque deposition and chronic neuroinflammation in the central nervous system (CNS) contribute to AD pathology, neither Aβ plaque removal nor anti-inflammatory therapy has shown much clinical success, suggesting that the combinational therapies for the disease-causative factors may be needed for amelioration. Recent data also suggest that systemic immunity in AD should be boosted, rather than suppressed, to drive an immune-dependent cascade needed for Aβ clearance and brain repair. Thymic epithelial cells (TECs) not only play a critical role in supporting T cell development but also mediate the deletion of autoreactive T cells by expressing autoantigens. We have reported that embryonic stem cells (ESCs) can be selectively induced to differentiate into thymic epithelial progenitors (TEPs) <i>in vitro</i> that further develop into TECs <i>in vivo</i> to support T cell development. We show here that transplantation of mouse ESC (mESC)-TEPs into AD mice reduced cerebral Aβ plaque load and improved cognitive performance, in correlation with an increased number of T cells, enhanced choroid plexus (CP) gateway activity, and increased number of macrophages in the brain. Furthermore, transplantation of the amyloid precursor protein (APP) gene deleted mESC-TEPs (APP^-/-) results in more effective reduction of AD pathology as compared to wild-type (APP^+/+) mESC-TEPs. This is associated with the generation of Aβ-specific T cells, which leads to an increase of anti-Aβ antibody (Ab)-producing B cells in the spleen and enhanced levels of anti-Aβ antibodies in the serum, as well as an increase of Aβ phagocytosing macrophages in the CNS. Our results suggest that transplantation of APP^-/- human ESC- or induced pluripotent stem cell (iPSC)-derived TEPs may provide a new tool to mitigate AD in patients.