SUMMARY Neuronal functions and brain connectivity require a highly coordinated neurovascular unit (NVU). Neurons and vascular cells are not just adjacently located; they communicate with each other vigorously via different signaling modules. Pericytes are vascular mural cells of the endothelium and vital integrators of NVU functions, including maintaining the blood-brain barrier (BBB) and vascular integrity, regulating blood flow and tissue oxygenation, modulating neuroinflammation and supporting neuronal health. Pericyte injury and loss occur commonly in CNS diseases including Alzheimer’s disease and dementia. Our current knowledge implicates a critical role of pericytes for neuronal functions, which calls for a thorough investigation of pericyte–neuronal communication for different neuronal functions in health and particularly in Alzheimer’s disease. Using new 3D co-culture systems and novel transgenic models, we found that pericytes can directly regulate neurogenesis and neuronal functions, which can be attributed to pericyte-derived insulin-like growth factor 2. IGF2 is a peptide hormone with multiple roles in regulating metabolic functions and developmental processes. Human with IGF2 mutation and mice lacking IGF2 exhibited strong growth defects with abnormal neural development. IGF2 is produced locally in the brain; however, the roles of brain IGF2 in neurogenesis and neuronal dysfunction in CNS diseases are poorly understood. Our preliminary studies additionally indicated that IGF2 mediates pericyte-neuronal communication by activating a noncanonical IGF2R-Gαi-PLC pathway to enhance neuronal functions, as well as stimulating a canonical PI3K/Akt pathway to promote neurogenesis or suppressing Tau-phosphorylation. Here, we propose to study the functional crosstalk between pericytes and neurons, and examine the influence of IGF2-mediated paracrine signaling on neurogenesis during development (AIM1), on neuronal maturation and functions in adult (AIM2), and on AD-like pathogenesis (AIM3). Follow the Rigor and Reproducibility guidelines, we plan to: i) explore pericyte–neuronal crosstalk using 3D co-culture systems; ii) pinpoint the receptor mediated signaling by manipulating gene expressions and key kinase activities; iii) to determine the role of pericyte-specific IGF2 on neurogenesis and neuronal functions in new pericyte ablation and Igf2 conditional knockout mouse models; iv) examine the role of IGF2- mediated pericyte–neuronal crosstalk during AD-like pathogenies in mice using complex behavioral tests and histological analysis. We hope to generate first evidence of functional pericyte-neuron crosstalk for brain function in health and diseases, and pinpoint the mechanism of this signaling at molecular level for IGF2-mediated pericyte-neuron crosstalk. The outcomes may provide new insights to the IGF system and neurovascular interaction in brain, and close an important gap between metabolic diseases and CNS neurodegenerative diseases such a...