APP beta-CTF triggers cell-autonomous synaptic toxicity independent of Abeta
Abeta is believed to play a significant role in synaptic degeneration observed in Alzheimer's disease (AD) and is primarily investigated as a secreted peptide. However, the contribution of intracellular Abeta 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 Abeta. 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.