Intracellular Aβ42 Sequestration by a Serine Protease Mitigates Neurotoxicity

ABSTRACT: The repeated failures in developing disease-modifying therapies for Alzheimer's disease (AD) by targeting extracellular Aβ have urged a complete reassessment of the cellular mechanisms underlying Aβ neurotoxicity. Emerging evidence suggests that intraneuronal Aβ accumulation represents an early pathogenic event in AD, preceding extracellular plaque formation and neuroinflammatory responses. However, whether targeting intracellular Aβ can halt disease progression and how this can be achieved remain unknown. While investigating the brain transcriptional responses to Aβ pathology, we identified a neuroprotective role for the serine protease Yip7 in a Drosophila AD model. Neuronal overexpression of yip7 alleviated multiple Aβ42- induced deficits, including declines in locomotor activity, impaired proteostasis, increased brain ageing and neuronal death, and reduced lifespan. Unlike canonical digestive proteases, Yip7 is not secreted but instead localizes to the endosomal/lysosomal compartments via a putative transmembrane domain initially predicted as a signal peptide. Crucially, Yip7’s neuroprotective function depends on its proper subcellular localization rather than the catalytic triad of serine proteases. Mechanistically, rather than directly eliminating Aβ, Yip7 increased neuronal retention of Aβ, supporting a model in which Yip7 reduces Aβ42 toxicity by limiting its degradation/secretion. Notably, yip7 overexpression also conferred protection in a Huntington's disease model, underscoring its broader relevance. Together, these findings introduce a novel concept that intracellular Aβ sequestration by a serine protease can mitigate neurotoxicity, and propose targeting intracellular amyloid as a promising therapeutic strategy for AD.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE300826 | GEO | 2026/04/01

REPOSITORIES: GEO