Hydroxytyrosol stimulates neurogenesis in aged dentate gyrus by enhancing stem and progenitor cell proliferation and neuron survival

Abstract

The dentate gyrus of the hippocampus is one of two brain areas generating throughout life new neurons, which contribute to the formation of episodic/associative memories. During aging, the production of new neurons decreases and a cognitive decline occurs. Dietary factors influence neuronal function and synaptic plasticity; among them the phenolic compound hydroxytyrosol (HTyr), present in olive oil, displays neuroprotective effects. As age impacts primarily on the hippocampus‐dependent cognitive processes, we wondered whether HTyr could stimulate hippocampal neurogenesis in vivo in adult and aged wild‐type mice as well as in the B‐cell translocation 1 gene (Btg1) knockout mouse model of accelerated neural aging. We found that treatment with HTyr activates neurogenesis in the dentate gyrus of adult, aged, and Btg1‐null mice, by increasing survival of new neurons and decreasing apoptosis. Notably, however, in the aged and Btg1‐null dentate gyrus, HTyr treatment also stimulates the proliferation of stem and progenitor cells, whereas in the adult dentate gyrus HTyr lacks any proliferative effect. Moreover, the new neurons generated in aged mice after HTyr treatment are recruited to existing circuits, as shown by the increase of BrdU+/c‐fos+ neurons. Finally, HTyr treatment also reduces the markers of aging lipofuscin and Iba1. Overall, our findings indicate that HTyr treatment counteracts neurogenesis decline during aging.

An Industrial and Sustainable Platform for the Production of Bioactive Micronized Powders and Extracts Enriched in Polyphenols From Olea europaea L. and Vitis vinifera L. Wastes

“…A recent in vivo study evidenced that HT stimulates neurogenesis in aged dentate gyrus by enhancing stem and progenitor cell proliferation and neuron survival (69).…”

Potential Beneficial Effects of Extra Virgin Olive Oils Characterized by High Content in Minor Polar Compounds in Nephropathic Patients: A Pilot Study

“…Olive oil phenols have powerful antioxidant, anticancer, and anti-inflammatory activity [ 3 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. The presence and content of these compounds are the basis of a health claim approved by the European Food Safety Authority (EFSA) in 2012 [ 19 ], which states that “olive oil polyphenols contribute to the protection of blood lipids from oxidative stress”.…”

Interaction Between Neurogenic Stimuli and the Gene Network Controlling the Activation of Stem Cells of the Adult Neurogenic Niches, in Physiological and Pathological Conditions

“…It appears that stem cells can be reactivated in the dentate gyrus or SVZ by appropriate stimuli, under conditions, in apparent paradox, favoring their depletion, such as aging or depression, i.e., when neurogenesis is lower, and/or after deletion of quiescence-maintaining genes. For instance, HTyr or running activate stem cells in aged dentate gyrus or aged SVZ, respectively (Blackmore et al, 2009;D'Andrea et al, 2020). Actually, the preservation of the quiescent state of stem cells appears less effective when the system is aging or carrying mutations, i.e., when a neurogenic stimulus can activate also stem cells.…”

“…Moreover, in a recent study of the effect on dentate gyrus cells of hydroxytyrosol (HTyr), a natural anti-oxidant phenolic compound present in extra virgin olive oil, we observed that HTyr in adult mice increases the number of new neurons by enhancing their survival without effect on the proliferation of stem and progenitor cells (D'Andrea et al, 2020; Table 1). However, in aged mice as well as in the Btg1 knockout neural aging model, HTyr increases not only the survival of new neurons and improves their integration into memory circuits, but also strongly increases the proliferation of stem and progenitor cells and reduces aging markers such as lipofuscin and Iba-1 (D'Andrea et al, 2020 ; Tables 1, 3). Thus, HTyr is able to counteract the effect of aging on neurogenesis.…”