Small GTPases control macropinocytosis of amyloid precursor protein and cleavage to amyloid-β.

The overproduction of the toxic peptide amyloid-beta (Aβ) generated from the cleavage of amyloid precursor protein (APP) is proposed to be a critical event in the development of Alzheimer's disease. Evidence suggests that the cleavage of APP occurs after its internalization from the cell surface. Previously, we identified a novel pathway for APP internalization, which trafficks cell surface APP directly to lysosomes by macropinocytosis, leading to its processing into Aβ. We also demonstrated that ADP-ribosylation factor 6 (Arf6) is required for the macropinocytosis of APP. Here, we characterized the roles of Arf6's downstream effectors Rac1, Cdc42 and RhoA. Both pharmacological inhibition and siRNA knockdown of these proteins reduced the amount of APP colocalized with LAMP1-labeled lysosomes without affecting APP transport to early endosomes. Decreases in the production of both Aβ40 and Aβ42 were also observed by ELISA in response to inhibitor treatment. These findings together demonstrate that Rac1, Cdc42 and RhoA are components of the mechanism regulating the macropinocytosis of APP and targeting these components can reduce the production of Aβ.
Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Stephen Pasternak reports financial support was provided by The Canadian Institute for Health Research (10.13039/501100000024CIHR) Canada. Stephen Pasternak reports financial support was provided by Beaconbright Foundation. London, Canada. Stephen Pasternak reports a relationship with Zywie Bio LLC, Princeton NJ, USA that includes: shareholding, consulting or advisory and grant funding.
(© 2024 The Authors. Published by Elsevier Ltd.)