APLP1 (amyloid beta precursor-like protein 1) is a membrane-associated glycoprotein predominantly expressed in the brain 1 that functions as a critical mediator of pathological protein transmission and axonal maintenance. Mechanistically, APLP1 binds to lymphocyte-activation gene 3 (Lag3) through its E1 domain to facilitate cell-to-cell transmission of pathological α-synuclein by preferentially recognizing α-synuclein amyloid fibrils over monomeric forms 23. Additionally, APLP1 interacts with SARM1, an NAD+ hydrolase, to regulate axonal maintenance and post-injury degeneration in the peripheral nervous system 4. APLP1 undergoes unique γ-secretase cleavage without prior ectodomain shedding, distinguishing it from APP and APLP2 5. Clinically, APLP1 is highly relevant to neurodegenerative diseases. Elevated plasma APLP1 levels correlate with faster motor deterioration in Parkinson's disease patients 6. Chr19 manganese exposure upregulates APLP1 expression, triggering cellular stress responses, amyloid-beta plaque accumulation, and neurodegeneration in the frontal cortex 78. Deletion of both APLP1 and Lag3 prevents dopaminergic neurodegeneration induced by α-synuclein preformed fibrils, positioning the APLP1-Lag3 interaction as a potential therapeutic target for Parkinson's disease and α-synucleinopathies 2.