IGF2 in memory, neurodevelopmental disorders, and neurodegenerative diseases

Insulin-like growth factor 2 (IGF2) plays a critical role in memory and cognition in adult rodents, whereas its alterations contribute to CNS diseases. Yet, the mechanisms by which IGF2 is involved in these processes are unclear.In rodents, IGF2 administration promotes memory enhancement and persistence. IGF2 administration restores impaired memory functions in aged rats and reverses cognitive impairments and several other deficits in rodent models of neurodevelopmental and neurodegenerative disorders.The beneficial effects of IGF2 occur via its high-affinity receptor, the IGF2 receptor (IGF2R), which may represent a target for potential therapeutic development.Current knowledge of IGF2R-mediated mechanisms in both heathy brains and diseases remains limited. Here, I propose a conceptual model for these mechanisms in which IGF2 or other IGF2R ligands promote vesicle network communications and protein metabolism quality control. This framework may explain how treatments based on IGF2R ligands could counteract diseases characterized by protein accumulation in the brain. Insulin-like growth factor 2 (IGF2) emerged as a critical mechanism of synaptic plasticity and learning and memory. Deficits in IGF2 in the brain, serum, or cerebrospinal fluid (CSF) are associated with brain diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and amyotrophic lateral sclerosis (ALS). Increasing IGF2 levels enhances memory in healthy animals and reverses numerous symptoms in laboratory models of aging, neurodevelopmental disorders, and neurodegenerative diseases. These effects occur via the IGF2 receptor (IGF2R) – a receptor that is highly expressed in neurons and regulates protein trafficking, synthesis, and degradation. Here, I summarize the current knowledge regarding IGF2 expression and functions in the brain, particularly in memory, and propose a novel conceptual model for IGF2/IGF2R mechanisms of action in brain health and diseases.