Alzheimer's disease amyloid-β affects membrane structure and mechanical properties of human neural progenitors

Abstract

Background

In Alzheimer's disease (AD), neurogenesis and neuroplasticity are severely affected but there is not yet a consensus about the underlying mechanisms. The amyloid cascade hypothesis is associated with overproduction of the amyloid-β (Aβ) peptide in the brain and points out the soluble Aβ oligomers to be the primary toxic species.

Objective

As the ability of neuronal cells to deform is involved in neurogenesis and neuroplasticity processes, we investigated how an exposure to Aβ oligomers could affect the mechanical properties of the neural progenitor cells.

Methods

Human neural progenitor cells (h-NPCs) were derived from human embryonic pluripotent stem cells (h-ESCs). The effect of Aβ₄₂ oligomers on the mechanical viscoelastic moduli of h-NPCs was determined using a custom-made microplate rheometer and the frequency analysis method. Fluorescence confocal microscopy of Di-4-ANEPPDHQ-stained cells was performed to assess the lipid order of h-NPC membranes. Aβ₄₂ aggregation in the cell culture medium was thoroughly characterized by combining Thioflavin T fluorescence, dynamic light scattering, and transmission electron microscopy as complementary techniques.

Results

We present here the first measurement of the visco-elastic moduli of a relevant model of h-NPC having the potential to differentiate in neuronal and glial subtypes. h-NPC exhibit a predominant elastic behavior, with low elastic modulus values of ∼200 Pa, in the range of those reported for the Young's modulus of glial cells and neurons in previous studies. Aβ₄₂ oligomers induced 3-fold increase of both elastic and viscous h-NPC moduli, revealing a significant stiffening effect. This Aβ₄₂-induced cell stiffening correlates with an increase in plasma membrane lipid order.

Conclusions

Our findings raise questions about whether and how such Aβ₄₂-induced effects on h-NPC deformability and membrane structure might have an impact on the differentiation of h-NPC which is at the root of neurogenesis, and could thus be involved in AD.