APP-CTFβ/C99 oligomers drive synaptic vesicle tethering through C-terminal interactions

Authors

Kapadia, A. B., Cijffers, E., Van, S., Hafner, A.-S.

Abstract

Proteolytic processing of the amyloid precursor protein (APP) generates a 99-amino acid precursor, {beta}-carboxyl-terminal fragments (APP-CTF{beta} or C99). Upon {gamma}-secretase inhibition, APP-CTF{beta} accumulates and induces synaptic defects, resulting in neuronal hyperactivity. However, mechanistic insights in the critical role of APP-CTF{beta} has not been completely elucidated. Here, we show that in primary neurons expressing human APP-CTF{beta} (C99) variants, acute {gamma}-secretase inhibition selectively increases evoked synaptic vesicle release in cells, whereas deletion of the C-terminus abolishes this effect. Using single-molecule approaches and reconstituted membrane systems, we demonstrate that accumulation of APP-CTF{beta} promotes its oligomerisation. In particular, APP-CTF{beta} oligomers augment synaptic vesicle tethering via their C-terminal domain. This effect is driven by the interaction with synaptic vesicle proteins, independent of the YENPTY binding motif. Additionally, APP-CTF{beta} oligomers were associated with alterations in membrane lipid organization. Together, our findings identify APP-CTF{beta} oligomerization as a constitutional gain-of-function mechanism that enhances presynaptic vesicle tethering and release, providing mechanistic insight into how altered APP processing regulates synaptic activity.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 01 Jul 2026.

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