Mathilde Chataigner PhD

Abstract

Brain aging is characterized by a decline in cognitive functions, involving memory impairment, which can significantly impact the quality of life of the elderly. Age-related cognitive deficits are associated with morphological, structural and functional changes in the hippocampus, one of the main brain structures involved in learning and memory, with increased and chronic neuroinflammation, and are accentuated by alterations of the stress response. Several studies have demonstrated the beneficial role of nutrition on memory functions, in particular long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) and low molecular weight peptides derived from marine-source proteins thanks to their immunomodulatory, anxiolytic and neuroprotective properties. Therefore, these nutrients are good candidates for the prevention of age-related cognitive decline.

The objective of this thesis was to demonstrate the beneficial effects of a marine hydrolysate containing n-3 PUFAs and low molecular weight peptides on cognitive functions during aging in mice, and to understand the neurobiological mechanisms involved. It was carried out as part of a collaborative project "BrainBooster", involving various industrial and academic partners, the objective of which was to develop a marine hydrolysate, containing these nutrients of interest, and to assess its beneficial effect on age-related cognitive decline first in a study model, the mouse, then in humans and pets. This hydrolysate and its applications have been the subject of a pending patent.

Our main results show that supplementation in aged mice with the marine hydrolysate, containing n-3 PUFAs and low molecular weight peptides, prevents age-related short-term spatial memory deficits and modulates strategies of navigation adopted during spatial learning. Marine hydrolysate also restores the stress response. These effects are associated with the inhibition of microgliosis, a term defining the activation of microglial cells responsible for brain immunity, induced by aging. In addition, the marine hydrolysate limits neuroinflammation in the hippocampus of adult mice in an acute inflammation model and in vitro on microglial cells. It also promotes the in vitro production of neurotrophic factors involved in neurogenesis and the regulation of inflammation. These effects on inflammation could be due to the effect of the marine hydrolysate on the synthesis of oxylipins, bioactive lipid derivatives, synthesized from PUFAs, which have anti-inflammatory and pro-resolutive properties. Indeed, this synthesis is in favour of anti-inflammatory oxylipines.

All of the results demonstrate the effectiveness of the marine hydrolysate in preventing age-related cognitive decline in mice via the action of n-3 PUFAs and peptides on neuroinflammation, the stress response and the neuroprotection. They served as the basis for setting up a clinical study from 2021 evaluating the effects of marine hydrolysate on the cognitive performance of seniors.

Key words: marine hydrolysate, bioactive peptides, n-3 polyunsaturated fatty acids, oxylipins, aging, memory, age-related cognitive decline, hippocampus, neuroinflammation, microglial cells, stress, neuroprotection.

Jury

Pr. Rozenn RAVALLEC-PLÉ, Professeur, Institut Charles Violette, Lille, Rapporteur

Dr. Niyazi ACAR, Directeur de recherche, INRAE, Dijon, Rapporteur

Pr. Frédéric CALON, Professeur, Université de Laval, Québec, Examinateur

Dr. Corinne JOFFRE, Chargé de recherche, INRAE, Bordeaux, Directrice de thèse

Dr. Anne-Laure DINEL, Docteur, INRAE, Bordeaux, Invitée

Mme Elodie BOUVRET, Responsable R&D, Abyss Ingredients, Invitée