Deciphering the Janus-Faced Nature of the Apolipoprotein Superfamily in Parkinsonian Neurodegeneration: Molecular Crosstalk Between the Astroglial Secretome and Neuronal Homeostasis.

Astrocytes communicate bidirectionally with neurons. The concerted activity of the neuron-astrocyte system is responsible for the progressive destruction of dopaminergic neurons in Parkinson's disease (PD). There is an urgent need to explore new prevention and treatment strategies for PD because of the lack of effective pharmaceutical therapies. Studies have shown that high levels of the apolipoprotein superfamily proteins apolipoprotein A1, apolipoprotein E, apolipoprotein D, and apolipoprotein J significantly affect susceptibility to PD. Astrocytes are the principal cells of the central nervous system and are responsible for producing these apolipoproteins. An overview of the progress in research on the effects of these astrocytic apolipoproteins on PD, especially their role in pathological processes such as lipid metabolism, α-synuclein aggregation, transcellular propagation, ferroptosis, antioxidant effects, and antiapoptotic effects, is presented. Furthermore, abnormally activated astrocytes may affect the endocytosis and secretion of apolipoprotein superfamily proteins in PD. We highlight the importance of developing novel treatments for PD from a precision medicine perspective based on the roles of apolipoprotein superfamily members within the astrocyte-neuron system. © 2025 International Parkinson and Movement Disorder Society.