Abstract
Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and transmissible spongiform encephalopathies (TSEs), share fundamental mechanisms of protein misfolding, synaptic dysfunction, and progressive neuronal loss. The cellular prion protein (PrPC), long viewed through the lens of prion biology, is now recognized as a pleiotropic modulator of neuronal physiology and a central interaction hub for amyloidogenic proteins. PrPC undergoes tightly regulated proteolytic processing (α-, β-, γ-cleavage, and ectodomain shedding), generating soluble fragments and peptides with distinct and sometimes opposing biological activities. These derivatives modulate neurotrophic signaling, oxidative stress responses, and the uptake/toxicity of Alzheimer's disease-relevant soluble amyloid-β (Aβ), α‑synuclein, and tau. Recent work highlights PrPC as a ligand for low-density lipoprotein receptor‑related protein‑1 (LRP1) and the NMDA receptor (NMDAR), with shed PrPC and PrP‑derived peptides capable of initiating cell signaling and attenuating inflammatory responses, including when PrPC is delivered via extracellular vesicles. In parallel, ultrasensitive seed amplification assays (SAA; RT‑QuIC/PMCA) have transformed prion diagnostics and underscore the biomarker potential of both full-length PrPC and of its proteolytic fragments. Here, we synthesize current knowledge on PrPC structure-function relationships, proteolytic processing, and crosstalk with disease‑ associated protein aggregates. We also outline emerging translational opportunities, ranging from PrP‑derived peptide therapeutics to fluid-based biomarkers that track disease onset and progression.