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bioRxiv · 10.1101/2021.07.30.454423

Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer's disease

KANESHIRO, N.·MASATO, K.·IMAOKA, R.·IKEDA, A.·KAMIKUBO, Y.·HASHIMOTO, T.·IWATSUBO, T.·SAKURAI, T.·UEHARA, T.·TAKASUGI, N.
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Abstract

{beta}-amyloid precursor protein (APP) and their metabolites are deeply involved in the development of Alzheimers disease (AD). Upon the upregulation of {beta}-site APP cleaving enzyme 1 (BACE1), its product, the {beta}-carboxyl-terminal fragment of APP ({beta}CTF), is accumulated in the early stage of sporadic AD brains. {beta}CTF accumulation is currently considered the trigger for endosomal anomalies to form enlarged endosomes, one of the earliest pathologies in AD. However, the details of the underlying mechanism remain largely unclear. In this study, using BACE1 stably-overexpressing cells, we describe that lipid flippase subcomponent TMEM30A interacts with accumulated {beta}CTF. Among the lipid flippases in endosomes, those composed of TMEM30A and active subcomponent ATP8A1 transports phospholipid, phosphatidylserine (PS), to the cytosolic side of the endosomes. The lipid flippase activity and cytosolic PS distribution are critical for membrane fission and vesicle transport. Intriguingly, accumulated {beta}CTF in model cells impaired lipid flippase physiological formation and activity, along with endosome enlargement. Moreover, in the brains of AD model mice before the amyloid-{beta} (A{beta}) deposition, the TMEM30A/{beta}CTF complex formation occurred, followed by lipid flippase dysfunction. Importantly, our novel A{beta}/{beta}CTF interacting TMEM30A-derived peptide "T-RAP" improved endosome enlargement and reduced {beta}CTF levels. These T-RAP effects could result from the recovery of lipid flippase activity. Therefore, we propose lipid flippase dysfunction as a key pathogenic event and a novel therapeutic target for AD.

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KANESHIRO, N., MASATO, K., IMAOKA, R., IKEDA, A., KAMIKUBO, Y., HASHIMOTO, T., IWATSUBO, T., SAKURAI, T., UEHARA, T., TAKASUGI, N.. 2021-07-30. Lipid flippase dysfunction as a novel therapeutic target for endosomal anomalies in Alzheimer's disease. https://doi.org/10.1101/2021.07.30.454423

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