PBX1 Improves Cognition and Reduces Amyloid‐β Pathology in APP / PS1 Mice by Transcriptionally Activating the CRTC2

ABSTRACT Alzheimer's disease (AD) is characterized by progressive cognitive decline, amyloid β (Aβ) deposition, and synaptic dysfunction. However, the mechanisms underlying neurodegeneration remain poorly understood. In this study, we investigated the therapeutic potential of PBX1, a transcriptional regulator implicated in neurodevelopment and neuroprotection, against AD. PBX1 expression was significantly downregulated in postmortem hippocampal tissues from patients with AD and in the APP/PS1 mouse model. In vitro, PBX1a knockdown reduced neurite complexity and increased apoptosis. PBX1a overexpression reversed these effects and reduced soluble Aβ 1–40 and Aβ 1–42 levels. In vivo, hippocampal overexpression of PBX1a restored spatial learning and memory, reduced Aβ burden by 41%, and increased neurite length by 1.5‐fold. These behavioral and structural improvements were accompanied by reduced levels of hyperphosphorylated Tau and toxic Aβ oligomers. Mechanistically, PBX1 directly activated the transcription of CRTC2—a coactivator of CREB, thereby increasing CRTC2 expression and its nuclear colocalization with phosphorylated CREB. Restoration of the PBX1–CRTC2–CREB axis enhanced neuronal survival and synaptic integrity. Notably, CRTC2 knockdown blocked PBX1‐mediated reductions in Aβ deposition, apoptosis, and hyperphosphorylated Tau expression, confirming the role of the PBX1–CRTC2–CREB axis in conferring neuroprotection. Together, our findings indicate that PBX1 is a key modulator of neuronal resilience in AD and that it functions through transcriptional activation of the CRTC2/CREB pathway. By unraveling a mechanism that links transcriptional regulation to amyloid clearance and cognitive function, this study highlights PBX1 as a promising therapeutic target for AD.