Brain Insulin Resistance and Hippocampal Plasticity: Mechanisms and Biomarkers of Cognitive Decline

Abstract

In the last decade, much attention has been devoted to the effects of nutrient-related signals on brain development and cognitive functions. A turning point was the discovery that brain areas other than the hypothalamus expressed receptors for hormones related to metabolism. In particular, insulin signaling has been demonstrated to impact on molecular cascades underlying hippocampal plasticity, learning and memory. Here, we summarize the molecular evidence linking alteration of hippocampal insulin sensitivity with changes of both adult neurogenesis and synaptic plasticity. We also review the epidemiological studies and experimental models emphasizing the critical role of brain insulin resistance at the crossroad between metabolic and neurodegenerative disease. Finally, we brief novel findings suggesting how biomarkers of brain insulin resistance, involving the study of brain-derived extracellular vesicles and brain glucose metabolism, may predict the onset and/or the progression of cognitive decline.

Keywords: Alzheimer’s disease; adult neurogenesis; brain insulin resistance; hippocampus; synaptic plasticity.

FIGURE 1

Insulin signaling. IR, Insulin receptor; IRS1 and IRS2, IR substrate 1 and 2; PI3K, phosphoinositide-3-kinase–protein kinase B; AKT, protein kinase B; mTOR, target of rapamycin; GSK3β, glycogen synthase kinase 3 beta; GRB2, growth factor receptor-bound protein 2; SOS, Son of Sevenless; RAS, Rat sarcoma GTPase protein; MAPK, mitogen activated protein kinase; FOXO, forkhead box O transcription factor; CREB, cAMP response element-binding protein.