Intracellular Aβ42 Sequestration by a Serine Protease Mitigates 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.