Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer’s disease mouse model

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of β-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment. •Hyperglycemia reduces adult hippocampal neurogenesis in an Alzheimer's disease model.•Hyperglycemia decreases the complexity of 3xTg-AD hippocampal immature neurons.•Hyperglycemia reduces β-catenin levels in 3xTg-AD hippocampal new neurons.•Hyperglycemia affects dentate gyrus long-term synaptic plasticity in 3xTg-AD mice.•Spatial memory impairment is exacerbated in hyperglycemic 3xTg-AD mice.