Novel aspects of hippocampal neuro-glia-plasticity: focus on diet and Alzheimer’s disease

Neuroplasticity is the brain’s intrinsic ability to adapt and reorganize both its structure and function in response to internal and external stimuli, supporting processes such as learning and memory. Among brain regions, the hippocampus exhibits exceptional plasticity and plays a pivotal role in the formation and consolidation of memories. Within the dentate gyrus, neural stem cells continuously generate new neurons and glial cells throughout adulthood, contributing to adult hippocampal neurogenesis (AHN) and the ongoing remodeling of hippocampal circuits. Dysregulation or impairment of these processes has been increasingly linked to neurological and neurodegenerative disorders. This PhD thesis investigated novel aspects of hippocampal neuro-glial plasticity under both physiological and pathological conditions. The first project examined the effects of short-term exposure to a high-fat diet (HFD) on hippocampal plasticity in adolescent male mice. In particular, the study assessed whether brief HFD exposure affects astrocytes and the maturation stages of doublecortin-positive cells, from neuroblasts to immature neurons, representing key phases of neuronal development. The second project explored alterations in AHN during the early stages of Alzheimer’s disease (AD). Using AD mouse models, we investigated the role of ADAMA10 (A Disintegrin and Metalloproteinase Domain 10) and evaluated the potential therapeutic effects of a cell-permeable peptide designed to inhibit ADAM10 endocytosis through both in vitro and in vivo approaches. Overall, this PhD thesis highlights the dynamic nature of hippocampal neuro-glial-plasticity and its sensitivity to both lifestyle and pathological factors, providing insights that may contribute to the development of innovative therapeutic strategies for neurodegenerative diseases such as AD.