Exposure to oligomeric and fibrillar species of amyloid-β induces toxicity and impairs extravillous trophoblast cell function in vitro.

BACKGROUND: Misfolding of proteins and their subsequent assembly into supramolecular aggregates are key pathophysiological mechanisms involved in neurodegenerative diseases, such as Alzheimer's disease (AD). These aggregates range from small prefibrillar oligomers to large fibrils of β-sheet-rich assemblies that can accumulate in tissues and disrupt normal physiological function. In AD, accumulation of amyloid-β (Aβ) oligomers (AβO) and fibrils (AβF) in the brain is a hallmark of disease. Critically, Aβ aggregates, among other proteins, are also detectable in the serum, urine, and placenta of women with preeclampsia (PE). However, the effects of misfolded protein buildup on placental function remain unclear. We hypothesized that accumulation of Aβ aggregates in placental tissue may disrupt key cellular processes, notably, extravillous trophoblast (EVT) cell survival, migration, and invasion.

METHODS: HTR-8/SVneo cells, an immortalized EVT cell line, were exposed to exogenous AβO or AβF preparations. Cytotoxicity, cell death mechanism, cell migration, and cell invasion were assessed using MTT, apoptosis/necrosis assays, scratch assays, and Transwell invasion assays, respectively.

RESULTS: While both AβO and AβF induced cytotoxicity via apoptosis in EVT cells, AβO had a more profound effect than AβF (p < 0.001). Furthermore, scratch assays revealed that AβO decreased the rate of cell migration while AβF led to an increased rate compared to vehicle controls. Finally, both AβO and AβF inhibited epidermal growth factor-mediated cellular invasion when tested in a Transwell assay (p = 0.017).

DISCUSSION: Our findings indicate that exposure to aggregated Aβ species alters trophoblast function in vitro in ways that may be relevant to placental mechanisms associated with preeclampsia.