Despite of recent progress in understanding the neurobiology and pathophysiology of Alzheimer¿s disease (AD), no resolutive pharmacological treatments but only a few symptomatic drugs are currently available to patients. Based on this consideration, much effort is aimed at the development of effective prevention lines: accumulation of epidemiological evidence suggests that there is a positive correlation between diet and AD, suggesting the possibility of take action on these important modifiable risk factors to counteract the progression of the disease.
Ketogenic diet (KD) has high fat content, adequate protein intake, but insufficient amounts of carbohydrates, so that the body is forced to use mainly fats as an energy source. The effect of KD supplementation in AD is quite interesting since this disease is preceded by decades of glucose hypometabolism, and earlier dietary intervention might have greater therapeutic effect.
Aims of the present project are:
1) to confirm in in vitro models the anti-inflammatory activity of blueberry polyphenols extracts, studying the activity in relation to the cellular and molecular pathogenic mechanisms underlying the low-grade chronic inflammatory status associated with AD
2) to ascertain the anti-inflammatory activity exerted by ketone bodies or blueberry polyphenolic extracts on microglia stimulated by LPS or Abeta peptide. We will analyze the polarization of the cells towards a pro- or anti-inflammatory phenotype, the synthesis and the release of several cytokines, the cytoskeleton rearrangement influencing migration of the cells
3) in a translational perspective, the in vivo expression of the blueberry polyphenol extract anti-inflammatory activity will be evaluated, through a pilot study, conducted in a sample of subjects suffering from obesity associated with metabolic syndrome, analyzing the effect of fresh blueberry intake in relation to the pro-inflammatory stimulus produced by taking a meal with a known composition
Despite of recent progress in understanding the neurobiology and pathophysiology of Alzheimer¿s disease (AD), no resolutive pharmacological treatments but only a few symptomatic drugs are currently available to patients. Based on this consideration, much effort is aimed at the development of effective prevention lines: accumulation of epidemiological evidence suggests that there is a positive correlation between diet and AD, suggesting the possibility of take action on these important modifiable risk factors to counteract the progression of the disease.
Ketogenic diet (KD) is a nutritional approach consisting of a diet with high fat content, adequate protein intake, but insufficient amounts of carbohydrates, so that the body is forced to use mainly fats as an energy source
The effect of KD in AD is quite interesting since this disease is preceded by decades of cerebral glucose hypometabolism, and earlier dietary intervention might have greater therapeutic effect. This delay in clinical manifestations suggested the possibility of define early intervention strategies in the pre-symptomatic stage of the disease, such as the change of lifestyle to prevent the onset and / or slow the progression of the disease.
Glucose is the primary source of energy for brain activity. Due to the inability of neurons to synthesize or store it, these cells are dependent on glucose transport across the BBB mediated by specific transporters GLUTs. When there is a decreased expression of these transporters in AD, Ketone Bodies (KBs) represent an alternative energy source to glucose for the brain, thanks to their ability to cross the blood-brain barrier (BBB): in this way the KBs should supply the neurons with fuel necessary for their trophism. Furthermore, recent studies have emphasized the antioxidant and anti-inflammatory activity of KD.
Moreover a great attention is focused on anti-inflammatory properties of several food compounds (such as blueberry polyphenols) assumed with the diet. As a matter of fact it has been established that AD is an inflammatory disease and it has been hypothesized that in the AD brain affected areas the neuronal damage may be related to the release of several mediators in the microenvironment by inflammatory cells.
Another new important aspect examined by this project deals with the cytoskeleton modifications characterizing the shift of microglia cells from the resting form to the amoeboid form. Such a phenotypic change is accompanied by migration process that will bring cells at the site of inflammation. The study of the organization of the actin cytoskeleton in treated microglia cells represents an innovative aspect of this project, enabling to associate the maintenance of the physiological cell morphology to the proper cell function.
Our study will analyze the polarization of the cells towards a pro- or anti-inflammatory phenotype, the synthesis and the release of several cytokines, the cytoskeleton rearrangement influencing migration of the cells in cultures stimulated by LPS or Abeta in the presence or in the absence of ketone bodies or blueberry polyphenols extracts.
If we will observe an anti-inflammatory activity of ketone bodies or of blueberry extracts the results will be very promising for the treatment of Alzheimer¿s disease. The set up of a nutritional protocol that may affect the progression of the disease should improve the quality of life of the AD patients, and their care givers, and impact the socio-economic costs associated with the disease.
Moreover, for a translational perspective, a pilot study will be performed in a single-blind manner with crossover in 25 subjects with obesity (BMI> 30 kg / m2) complicated by metabolic syndrome,