Neuronal PRRT3 coordinates amyloidogenic processing and Tau phosphorylation via distinct Ras-ERK-AP-1 and CaMKII/PP2A pathways

Alzheimer's disease (AD) is characterized by extracellular β-amyloid (Aβ) deposition and intracellular Tau hyperphosphorylation, yet upstream factors that coordinately regulate both pathologies remain poorly understood. Here, we identify proline-rich transmembrane protein 3 (PRRT3) as a previously unrecognized, neuron-enriched upstream regulator of AD dual pathology. PRRT3 expression is elevated in brain tissues from AD patients and exhibits abnormal persistence in APP/ PS1 mice. PRRT3 knockdown markedly reduces APP, PS1, and BACE1 mRNA expressions, thereby decreasing Aβ generation in neuronal cells. Mechanistically, PRRT3 promotes the expressions of these amyloidogenic genes via activation of the activator protein-1 (AP-1) complex, as evidenced by reduced phosphorylation of c-Fos and c-Jun after PRRT3 knockdown. Transcriptomic profiling further reveals broad downregulation of calcium signaling-related receptors and intracellular calcium-handling proteins, accompanied by attenuated calcium signaling and ERK activity. Artificially elevating intracellular calcium with thapsigargin completely reverses the neuroprotective effects of PRRT3 knockdown, restoring both the Ras-ERK-AP-1-dependent amyloidogenic machinery and CaMKII/PP2A-mediated Tau hyperphosphorylation. In parallel, PRRT3 knockdown shifts the balance between the CA ²⁺-dependent Tau kinase CaMKII and the Phosphatase PP2A, leading to reduced Tau hyperphosphorylation at multiple AD-relevant sites. Collectively, these findings establish PRRT3 as a neuron-enriched upstream regulator linking calcium dysregulation to both amyloidogenic processing and Tau phosphorylation. Targeting PRRT3 may therefore represent a promising strategy to simultaneously modulate the two core pathological processes in AD.