Human iPSC-derived pericyte-like cells carrying APP Swedish mutation overproduce beta-amyloid and induce cerebral amyloid angiopathy-like changes

Abstract

Alzheimer’s disease (AD) patients often exhibit cerebral amyloid angiopathy (CAA), i.e beta-amyloid (Aβ) accumulation within cerebral blood vessels causing cerebrovascular dysfunction. Pericytes wrap around vascular capillaries, thus regulating cerebral blood flow, angiogenesis, and vessel stability. Vascular dysfunction can promote the development and progression of neurodegenerative diseases, yet the specific contribution of pericytes to AD pathology remains unclear. Here we show that human induced pluripotent stem cell (iPSC)-derived pericyte-like cells (iPLCs) can generate Aβ peptides, and that the cells carrying Swedish mutation in amyloid precursor protein (APPswe) secrete 10 times more Aβ1-42 than the control cells. Additionally, APPswe iPLCs have an impaired capacity to support angiogenesis and barrier integrity, exhibit a prolonged contractile response, and produce increased levels of pro-inflammatory cytokines upon inflammatory stimulation. These functional alterations in APPswe iPLCs are accompanied by transcriptional upregulation of actin cytoskeleton and extracellular matrix organization-related genes. Therefore, the APPswe mutation in iPLCs recapitulates several features of CAA pathologyin vitro. Our iPSC-based vascular cell model may thus serve as a platform for drug discovery targeting vascular dysfunction in AD.