Abstract

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.