Persistent PirB cleavage drives Golgi-directed trafficking deficits underlying neurodegeneration.

BACKGROUND

Extensive research evidence indicates that neuronal immune receptors play a critical role in Alzheimer's disease (AD). However, it remains unclear how these receptors convert extracellular signals into cellular pathological changes. Proteolytic cleavage of membrane receptors serves as an unconventional pathway for reprogramming cellular functions, and the cleaved fragments often play important roles within the cell. Whether immune receptors mediate their effects in AD through this cleavage-dependent signaling mechanism remains to be clarified.

METHODS

We performed proteomic screening of human cerebrospinal fluid to identify cleaved membrane proteins. Cleavage events were validated in postmortem AD brains, primary neurons, and APP/PS1 mice by immunoprecipitation, liquid chromatography-tandem mass spectrometry (LC-MS/MS), and immunofluorescence. Functional impacts were assessed through cathepsin D maturation assays, Retention Using Selective Hooks (RUSH) systems, live imaging of axonal transport, and behavioral tests (e.g., Barnes maze and fear conditioning). Therapeutic potential was evaluated by inhibiting the paired immunoglobulin-like receptor B (PirB) cleavage and overexpression of the GAT domain of Golgi-associated, gamma adaptin ear-containing, ARF binding protein 3 (GGA3).

RESULTS

This study identified a pathogenic proteolytic pathway in AD patients and mouse models, which cleaves PirB, a mouse ortholog of human leukocyte immunoglobulin-like receptor B2 (LILRB2), upon Aβ exposure, generating a C-terminal fragment (PirB-CTF) that accumulated in the Golgi apparatus via retrograde transport. PirB-CTF bound to the GAT domain of GGA3, disrupting Golgi transport, impairing lysosomal maturation, and compromising anterograde synaptic vesicle transport. Inhibiting PirB cleavage or overexpressing GGA3-GAT restored Golgi function, reduced Aβ plaque burden and tau phosphorylation, and rescued memory deficits.

CONCLUSION

Our study revealed a non-canonical pathway in which proteolytic cleavage repurposes PirB into an intracellular disruptor of Golgi trafficking, directly coupling immune receptor activation to organelle dysfunction in AD. The PirB-CTF/GGA3 interface represents a promising therapeutic target for mitigating trafficking deficits and cognitive decline in neurodegenerative disorders.