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bioRxiv · 10.1101/2024.07.11.603028

APP beta-CTF triggers cell-autonomous synaptic toxicity independent of Abeta

Luo, M.·Zhou, J.·Sun, C.·Chen, W.·Fu, C.·Si, C.·Zhang, Y.·Geng, Y.·Chen, Y.
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Abstract

A{beta} is believed to play a significant role in synaptic degeneration observed in Alzheimers disease (AD) and is primarily investigated as a secreted peptide. However, the contribution of intracellular A{beta} or other cleavage products of its precursor protein (APP) to synaptic loss remains uncertain. In this study, we conducted a systematic examination of their cell-autonomous impact using a sparse expression system. Here, these proteins/peptides were overexpressed in a single neuron, surrounded by thousands of untransfected neurons. Surprisingly, we found that APP induced dendritic spine loss only when co-expressed with BACE1. This effect was mediated by {beta}-CTF, a {beta}-cleavage product of APP, through an endosome-related pathway independent of A{beta}. Neuronal expression of {beta}-CTF in mouse brains resulted in defective synaptic transmission and cognitive impairments, even in the absence of amyloid plaques. These findings unveil a {beta}-CTF-initiated mechanism driving synaptic toxicity irrespective of amyloid plaque formation and suggest a potential intervention by inhibiting the endosomal GTPase Rab5.

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Luo, M., Zhou, J., Sun, C., Chen, W., Fu, C., Si, C., Zhang, Y., Geng, Y., Chen, Y.. 2024-07-16. APP beta-CTF triggers cell-autonomous synaptic toxicity independent of Abeta. https://doi.org/10.1101/2024.07.11.603028

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