G-Protein-Coupled Receptor-Microtubule Interactions Regulate Neurite Development and Protect Against β-Amyloid Neurotoxicity.

G-protein-coupled receptors (GPCRs) regulate multiple cellular functions, including neurite formation and maturation, processes often disrupted in neurodegenerative diseases. Like GPCRs, microtubule-associated proteins (MAPs, including MAP2 and Tuj1) and the synaptic vesicle protein synaptophysin are essential for neurite formation, maturation, and organization, which underpin brain development and cognitive function. Despite their importance, the functional crosstalk between GPCRs and MAPs, particularly in neurogenesis and pathological conditions such as Alzheimer's disease (AD), remains poorly understood. We show that somatostatin and dopamine receptors (SSTR and DR) are the structural anchors in developing neurites, enabling MAP recruitment and synaptic protein localization. Our findings reveal a cAMP-dependent interplay involving PTEN and ERK1/2, modulating neurite formation and MAPs organization. Notably, we show that β-amyloid (Aβ) disrupts the constitutive association of MAP2 and Tuj1, inducing an increase in intracellular cAMP levels, loss of neurite integrity, and impaired neuronal viability. The activation of SSTR and DR signaling restores neurite architecture and synaptic integrity via p-AKT activation and PTEN inhibition, highlighting a neuroprotective mechanism. Together, our results reveal a novel role of GPCRs in orchestrating interactions with MAPs to regulate neuronal maturation, neurite formation, and synaptic integrity. This study provides a new mechanistic rationale for therapeutic strategies aimed at preserving cognitive function in neurological disorders such as AD.