In Alzheimer’s disease (AD), neurogenesis and neuroplasticity are severely affected. We hypothesize that, during the early steps of AD, the overproduced amyloid-beta (Aβ) peptide binds to and internalizes into the neuronal progenitor cells (NPCs), affecting mechanical properties, such as the ability to deform globally or locally, thereby disturbing neurogenesis/neuroplasticity. We present here a first set of results on the effect of the Aβ peptide on the mechanical properties of NPCs.

Two types of experiments are described:
1) Our early bottom-up experiments on Aβ interactions with model membranes that initially led us to the "mechanical toxicity" hypothesis.
2) Experiments on living cells:
* A protocol to efficiently produce NPCs from human induced pluripotent stem cells (hiPSCs).
* Measurements of visco-elastic mechanical properties of NPCs using an original, custom-made, microplates-based rheometer, Fig.1A). The setup is able to measure the static modulus as well as dynamical storage and loss moduli.
* Elaborating protocols with living NPCs for membrane order evaluation, Fig.1B), as well as membrane dipolar potential measurements.
Our results indicate a rigidification effect of Aβ on the mechanical properties of NPCs, correlating well with the increase of membrane molecular order, and dipolar potential changes. Interestingly, the latter are known to be coupled with protein structures and physiology. This suggests a possible Aβ mebrane-related mechanical toxicity in AD.

Fig. 1 A) A single NPC compressed between the rigid and flexible plate<br /> of the microplate rheometer. B) Di-4-ANEPPDHQ confocal microscopy<br /> imaging of live NPCs without and with Aβ. GP image is in false color<br /> and runs over the range indicated by the color bar.

Fig. 1 A) A single NPC compressed between the rigid and flexible plate
of the microplate rheometer. B) Di-4-ANEPPDHQ confocal microscopy
imaging of live NPCs without and with Aβ. GP image is in false color
and runs over the range indicated by the color bar.

Sophie Asnacios

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