APLP1 Interacts with SARM1 and Regulates Axonal Maintenance and Post-Injury Degeneration

Amyloid beta precursor-like protein 1 (APLP1), a member of the APP protein family, has been associated with the pathogenesis of neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases. However, its role in the peripheral nervous system remains unclear. Here, we demonstrate that APLP1 binds to sterile alpha and TIR motif-containing 1 (SARM1), an NAD⁺ hydrolase critical for peripheral axonal degeneration, and plays a role in axonal maintenance and post-injury degeneration. To identify potential regulators of SARM1-dependent axonal degeneration, we performed yeast two-hybrid screening using the SARM1 auto-inhibitory domain as bait and identified APLP1 as a SARM1-binding protein. We observed a significant increase in APLP1 levels after axonal injury in the proximal axon segments of cultured sensory neurons and mouse sciatic nerve. Knockdown of Aplp1 in vitro reduced neuronal NAD⁺ levels and caused spontaneous axon degeneration in a SARM1-dependent manner. Furthermore, Aplp1 knockdown also accelerated injury-induced axonal degeneration. Collectively, these results show that APLP1 interacts with SARM1 and contributes to axonal maintenance in the peripheral nervous system.