Role of insulin-like growth factor-2 in Alzheimer's disease induced memory impairment and underlying mechanisms

Abstract

Alzheimer's disease (AD) is the most prevalent type of dementia. Treatments for AD do not reverse the loss of brain function; rather, they decrease the rate of cognitive deterioration. Current treatments are ineffective in part because they do not address neurotrophic mechanisms, which are believed to be critical for functional recovery. Given that structural losses are assumed to be the root cause of cognitive impairment in AD, strengthening neurotrophic pathways may be a useful preventative therapeutic approach. Insulin-like growth factor-2 (IGF2), which is widely expressed in the central nervous system (CNS), has emerged as a crucial mechanism of synaptic plasticity and learning and memory, and many studies have indicated that this neurotrophic peptide is a viable candidate for treating and preventing AD-induced cognitive decline. An increase in IGF2 levels improves memory in healthy animals and alleviates several symptoms associated with neurodegenerative disorders. These effects are primarily caused by the IGF2 receptor, which is widely expressed in neurons and controls protein trafficking, synthesis, and degradation. However, the use of IGF2 as a potential target for the development of novel pharmaceuticals to treat AD-induced memory impairment needs further investigation. We compiled recent studies on the role of IGF2 in AD-associated memory issues and summarized the current knowledge regarding IGF2 expression and function in the brain, specifically in AD-induced memory impairment.

Keywords: AD; IGF2; hippocampus; memory; treatment.

Figure 1

Structures of the insulin/insulin-like growth factor (IGF) system. Insulin, IGF1, and IGF2 and their relatively high-affinity receptors, insulin receptor, IGF1 receptor, and IGF2 receptor, are shown. The relative affinity of each ligand for the receptors is represented by the arrow thickness. Insulin, IGF1, and IGF2 can cross-bind to their respective high-affinity receptors; however, due to its lower affinity, insulin does not seem to bind to the IGF2 receptor. Upon receptor binding, a structural change leads to activation of the intracellular tyrosine kinase domain and autophosphorylation. Two main signaling pathways are activated: the Akt/PKB and the Ras/MAPK pathways. Thus, IGF2 activates CREB and induces IGF2 transcription, increases synaptic density and spine maturation, activates the AKT-GSK3β signaling pathway, promotes neural precursor cell differentiation and proliferation, and induces IGF2 production in the hippocampus to improve memory ability. p, phosphorylation; Shc, adaptor protein p66; Grb2, growth factor receptor-bound protein 2; SOS, son of sevenless; CREB, cAMP-response element binding; GSK3β, glycogen synthase kinase-3β; TSC2, Tuberous sclerosis complex 2; BAD, Bcl-2-associated death; mTORC1, mammalian target of rapamycin complex 1.