Dottorato in NEUROSCIENZE DEL COMPORTAMENTO

Titolo della tesi: NUTRITIONAL MODULATION IN DIFFERENT AGING MODELS

Although an increase in life expectancy is one of humanity's greatest achievements, the growing older population with its age-related problems represents a significant social and economic challenge. Brain alterations that occur during aging are due to a progressive impairment of different cell processes, such as: neural membrane fluidity reduction, neuroinflammation, oxidative stress, reduced synaptic plasticity and neurogenesis. To date, pharmacological interventions to treat dementia and particularly Alzheimer Disease (AD) remain controversial and elusive. For these reasons the focus is on strategies to promote healthy aging. Emerging evidence proposes that healthy lifestyles may reduce the risk, or delay the occurrence, of cognitive decline in old age. In particular, the role of nutrition in preventing or delaying chronic age-related disability is receiving much attention. In fact, diet is one of the principal environmental factors impacting brain plasticity. In this context, omega-3 fatty acids (n-3 PUFA) are major components of neuronal membranes and key modulators of many neural functions. They influence brain plasticity throughout the entire lifespan. Different studies show their beneficial effects, such as decreased inflammation, reduced risk of depression and anxiety, and improved cognitive functions. Also, a derivative of palmitic fatty acid, the palmitoylethanolamide (PEA) appears to come to the forefront as nutritional substance owing to its analgesic, anti-inflammatory and neuroprotective role. It can be found in high concentrations in brain tissues and is synthesized starting by lipid components of the cellular membranes. N-3 PUFA and PEA are present in certain foods we use every day and might be good options because of high efficacy/risk ratio and lack of interference with other conventional therapies used for counteracting mental decline. In order to better understand the behavioral, morphological, and biochemical effects of nutraceutical modulation on AD we performed three experiments. In the first study (Experiment 1) we analyzed the neuroprotective influence of 8 weeks of n-3 PUFA supplementation on behavioral deficits, hippocampal neurogenesis, volume loss, and astrogliosis in aged mice that, after supplementation, were subjected to basal forebrain cholinergic depletion with mu-p75-saporin immunotoxin. Such a lesion represents a valid model to mimic key components of the cognitive deficits associated with dementia. Mice were tested for anxiety, motivational, social, mnesic, and depressive behaviors. Subsequently, morphological, and biochemical analyses were performed. In lesioned aged mice the n-3 PUFA pre-treatment preserved explorative skills and associative retention memory, enhanced neurogenesis in the dentate gyrus, and reduced volume and VAChT levels loss as well as astrogliosis in hippocampus. In the second study (Experiment 2) we investigated the action of 8-week n-3 PUFA supplementation on behavioral performance and hippocampal neurogenesis, volume and astrogliosis after mu-p75-saporin injury. Four weeks after initiation of dietary supplementation, levels of anxiety and mnesic, social, and depressive behaviors were assessed. Subsequently, hippocampal morphological and biochemical analyses and n-3 PUFA brain quantification were performed. The n-3 PUFA treatment regulated the anxiety alterations and reversed the impairment of novelty recognition memory induced by cholinergic depletion in aged mice. Furthermore, n-3 PUFA preserved hippocampal volume, enhanced neurogenesis in the dentate gyrus, and reduced astrogliosis in the hippocampus. Brain levels of n-3 PUFA positively correlated with mnesic abilities. The demonstration of these two studies that n-3 PUFA are able to counteract behavioral deficits and hippocampal neurodegeneration in cholinergically depleted aged mice promotes their use as a low-cost, safe nutraceutical tool to improve life quality at old age, even in the presence of first stages of AD. In the third study (Experiment 3) we investigated the effects of 6 months intake of PEA on cognitive, motor, and emotional performances as well as biochemical correlates and neurobiological processes induced by a build-up of Aβ protein in Tg2576 mice, experimental model of AD. The initial behavioral analyses demonstrate that chronic PEA supplementation exerts beneficial effects on memory in Tg mice during the fully symptomatic phase and produces a significant reduction in markers of astrogliosis and oxidative stress (i.e., 3-nitrotyrosine) in Tg mice hippocampus, indicating that the drug exerts an anti-inflammatory action coupled with anti-oxidative effects on the preclinical model of amyloidosis.