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

Autor: Wu YC; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland., Lehtonen Š; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland. sarka.lehtonen@uef.fi.; A.I.Virtanen Institute for Molecular Sciences, University of Eastern Finland, 70211, Kuopio, Finland. sarka.lehtonen@uef.fi., Trontti K; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland., Kauppinen R; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland., Kettunen P; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland., Leinonen V; NeuroCenter, Kuopio University Hospital, Kuopio, Finland.; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Laakso M; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland., Kuusisto J; Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.; Department of Medicine and Clinical Research, Kuopio University Hospital, Kuopio, Finland., Hiltunen M; Institute of Biomedicine, University of Eastern Finland, Kuopio, Finland., Hovatta I; SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland., Freude K; Department of Veterinary and Animal Sciences, University of Copenhagen, 1870, Frederiksberg, Denmark., Dhungana H; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland., Koistinaho J; Helsinki Institute of Life Science, University of Helsinki, 00014, Helsinki, Finland. jari.koistinaho@helsinki.fi.; Drug Research Program, Division of Pharmacology and Pharmacotherapy, University of Helsinki, 00014, Helsinki, Finland. jari.koistinaho@helsinki.fi., Rolova T; Neuroscience Center, University of Helsinki, 00014, Helsinki, Finland. taisia.rolova@helsinki.fi.
Jazyk: angličtina
Zdroj: Fluids and barriers of the CNS [Fluids Barriers CNS] 2024 Sep 27; Vol. 21 (1), pp. 78. Date of Electronic Publication: 2024 Sep 27.
DOI: 10.1186/s12987-024-00576-y
Abstrakt: Background: Patients with Alzheimer's disease (AD) frequently present with cerebral amyloid angiopathy (CAA), characterized by the accumulation of beta-amyloid (Aβ) within the cerebral blood vessels, leading to cerebrovascular dysfunction. Pericytes, which wrap around vascular capillaries, are crucial for regulating cerebral blood flow, angiogenesis, and vessel stability. Despite the known impact of vascular dysfunction on the progression of neurodegenerative diseases, the specific role of pericytes in AD pathology remains to be elucidated.
Methods: To explore this, we generated pericyte-like cells from human induced pluripotent stem cells (iPSCs) harboring the Swedish mutation in the amyloid precursor protein (APPswe) along with cells from healthy controls. We initially verified the expression of classic pericyte markers in these cells. Subsequent functional assessments, including permeability, tube formation, and contraction assays, were conducted to evaluate the functionality of both the APPswe and control cells. Additionally, bulk RNA sequencing was utilized to compare the transcriptional profiles between the two groups.
Results: Our study reveals that iPSC-derived pericyte-like cells (iPLCs) can produce Aβ peptides. Notably, cells with the APPswe mutation secreted Aβ1-42 at levels ten-fold higher than those of control cells. The APPswe iPLCs also demonstrated a reduced ability to support angiogenesis and maintain barrier integrity, exhibited a prolonged contractile response, and produced elevated levels of pro-inflammatory cytokines following inflammatory stimulation. These functional changes in APPswe iPLCs correspond with transcriptional upregulation in genes related to actin cytoskeleton and extracellular matrix organization.
Conclusions: Our findings indicate that the APPswe mutation in iPLCs mimics several aspects of CAA pathology in vitro, suggesting that our iPSC-based vascular cell model could serve as an effective platform for drug discovery aimed to ameliorate vascular dysfunction in AD.
(© 2024. The Author(s).)
Databáze: MEDLINE
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