SUMMARY
Presenilin (PS), the catalytic subunit of γ-secretase and its main substrate the amyloid precursor protein (APP) are mutated in a large majority of patients with familial Alzheimer disease. PS and APP interact with proteins of the neurotransmitter release machinery but the functional consequences of these interactions are unknown. Here we report that genetic deletion of presynaptic PS markedly decreases the axonal expression of the Ca2+ sensor synaptotagmin-7 (Syt7), and impairs synaptic facilitation and replenishment of release-competent synaptic vesicles. These properties are fully restored by presynaptic re-expression of Syt7. The regulation of Syt7 expression occurs post-transcriptionally and depends on γ-secretase activity. In the combined absence of both APP and PS1, the loss of Syt7 is prevented, indicating that the action of γ-secretase on presynaptic mechanisms depends on its substrate APP. The molecular mechanism involves the substrate of PS, APP-βCterminal (APP-βCTF), which interacts with Syt7 and accumulates in synaptic terminals under conditions of pharmacological or genetic inhibition of γ-secretase. These results reveal a role of PS in presynaptic mechanisms through regulation of Syt7 by APP-dependent cleavage, and highlight aberrant synaptic vesicle processing as a possible new pathway in AD.
