(434) Amyloid-β (Aβ) proteoforms impair trophoblast survival and function - relevance to defective placentation in preeclampsia

Thursday, January 30, 2025

4:00 PM – 6:00 PM

Submitting Author and Presenting Author(s)

Bani Medegan Fagla, BS

MD/PhD Student
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States

Coauthor(s)

CD

Cielo Dela Rosa, BS, MSc

University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
AV

Ana C. Valencia-Olvera, PhD

University of Illinois at Chicago College of Medicine
Chicago, Illinois, United States
GZ

Guomao Zhao, BS

Laboratory Manager, Perinatal Research
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
AV

Almudena Veiga-Lopez, PhD

University of Illinois at Chicago College of Medicine
Chicago, Illinois, United States
JW

Juan M. Weng, PhD

University of Illinois at Chicago College of Medicine
Chicago, Illinois, United States
IB

Irina A. Buhimschi, MD, MSc

Professor and Director, Perinatal Research
University of Illinois at Chicago, College of Medicine
Chicago, Illinois, United States
ET

Elvis Ticiani, PhD

University of Illinois at Chicago College of Medicine
Chicago, Illinois, United States

Objective: Misfolding of proteins and their subsequent assembly into supramolecular aggregates are key mechanisms involved in neurodegenerative diseases such as Alzheimer’s disease (AD). These aggregates range from small prefibrillar cytotoxic oligomers to large β-sheet rich fibrils that accumulate in tissues and disrupt normal function. In AD, the accumulation of amyloid-β (Aβ) oligomers (O_Aβ) and fibrils (F_Aβ) in the brain is a disease hallmark. Excess Aβ aggregates were recently detected in the serum, urine, and placenta of patients with preeclampsia, which is now considered a protein misfolding disease of pregnancy. Whether Aβ aggregates directly impact placental function thereby contributing to pathogenesis of preeclampsia has yet to be elucidated. We aimed to characterize the effect of different Aβ proteoforms on trophoblast cell survival and function.

Study Design:

We exposed an immortalized human extravillous trophoblast (EVT) cell line (HTR8/SVNeo) to exogenous unaggregated (U_Aβ), O_Aβ, or F_Aβ preparations (0.001-10μM) and assessed their effect on cell survival by measuring cytotoxicity (MTT assay), migration (scratch assay) and invasion (Transwell assay ± epidermal growth factor [EGF], an essential regulator of placental development). Data from n=3-5 independent experiments was analyzed. A dual apoptosis/necrosis assay was used to determine the mechanism of cell death.

Results:

1) Both O_Aβ and F_Aβ decreased EVT survival with O_Aβ having a more profound effect (p< 0.001); at higher concentrations, U_Aβ also decreased cell viability likely due to spontaneous oligomerization (Fig. A). 2) EVT death occurred primarily via apoptosis (not shown). 3) While O_Aβ decreased EVT migration (increased gap size), F_Aβ increased cell migration compared to vehicle control (Fig. B). 4) Both O_Aβ and F_Aβ inhibited EGF-mediated invasion (p= 0.017) without affecting baseline invasion (Fig. C).

Conclusion:

Presence of excess Aβ aggregates during placental development has the potential to contribute to preeclampsia pathogenesis by disrupting key cellular processes such as EVT survival, migration and invasion.