Type-2 diabetes, besides being a major causes of morbidity and mortality, appear to be intimately connected with Alzheimer disease. Several pathophysiological mechanisms, including brain hypoglycaemia, have been theorized to be involved in the diet-dependent cognitive impairment. Nevertheless, how nutrient-related signals impact on neuronal network and affect brain functions is still poorly understood. The idea behind this project is that the homeostasis of glucose metabolism in the brain is necessary for the maintenance of learning and memory. An emerging attention has being devoted to the role of nutrient-related post translational modifications as key modulators of brain homeostasis and cognitive functions. Our experimental hypothesis is that diet-driven brain hypoglycaemia impinge on the hexosamine biosynthetic pathway interfering with protein O-GlcNAcylation, which may lead to accelerated brain ageing.
In this scenario our project is based on three interrelated Aims in order to:
1. investigate the effect of early HFD-driven glucose hypometabolism on 3xTg-AD mice, identifying the detrimental role of aberrant protein O-GlcNAcylation.
2. investigate, through the analysis of protein O-GlcNacylation in neuronal primary cell subjected to different metabolic and/or pharmacological stimuli, the molecular mechanism that link reduced glucose uptake with neurodegeneration.
3. test the ability of an OGA inhibitor to rescue the early HFD-driven cognitive decline in 3xTg-AD.
To address these aims we will employ 3xTg-AD mice fed for 6 weeks with HFD and hippocampal primary neurones stimulated with a cocktail of insulin and palmitic acid (IPA).
Considering the exponential increase of metabolic syndromes and life expectancy, this study will contribute to understand the molecular mechanisms and the sequelae of events that link western diet and cognitive decline, identifying the role of protein O-GlcNation and develop novel druggable targets and therapeutic strategies.
During the last decade the scientific community has devoted great attention to age-related cognitive decline and the number of these studies will most likely increase in the near future. Worldwide, around 50 million people present with cognitive decline, and there are nearly 10 million new cases every year. Recently, evidence of a tight correlation between neurodegenerative and metabolic diseases has emerged. Indeed, among the known causes of AD, T2D and metabolic syndrome are definitely the main risk factors. AD-like dementia, such as the other T2D- and metabolic syndrome-related comorbidity, has a strong impact on both cost of healthcare and the quality of life. In fact, the worldwide costs of AD were estimated at US $818 billion in 2015 (an increase of 35% since 2010) and the threshold of US $1 trillion has now been overcome.
Despite the epidemiological evidence of a tight correlation between neurodegenerative and metabolic diseases, the molecular mechanisms linking metabolic dyshomeostasis and cognitive impairment are still poorly understood. Moreover, although notable strides have been made with regard to discerning the pathophysiological processes associated with T2D and cognitive decline, pharmacological treatment trials have generally produced minimal or disappointing results, to date.
This project will identify a novel mechanism which links diet-mediated brain glucose hypometabolism and with AD-like cognitive decline. Indeed, the novel idea underlying this project is that reduced glucose uptake in the brain could lead, through altered protein O-GlcNAcylation to age-related cognitive decline. Brain dysmetabolism can be considered a strong risk factor for the cognitive deterioration and, in particular, it may represent a novel target to slow or delay the age- and diet- related cognitive decline. Moreover, the experimental strategy of investigating the impact of systemic disorders (e.g. metabolic diseases) on nutrient-related intracellular signals (protein O-GlcNAcylation) may reveal novel signal transduction cascades potentially underlying the impact of nutrients on all organs and tissues. Deepening the knowledge of such pathogenic mechanisms could allow to identify novel druggable targets.
The impact of the proposed work is therefore substantial, especially in the light of both the impact of diet on incidence of diseases and quality of life, and the increasing number of people expected to be affected by dementia worldwide in the near future.
The characterization of the exact pathogenic pathways involved in the development of these conditions might help to understand how specific nutrients and dietary patterns impact on functional decline of specific organs, and it could pave the way to developing relatively simple nutritional strategies (or drug therapies) to counteract or delay the onset of metabolic and functional alterations characteristic of ageing.
The use of intranasal route, for drug administration of the compound to be used, represent a further innovation of this project. Indeed, targeting the brain with drugs in a selective manner, as by intranasal delivery, is not easy but very efficacious considering that the compound is rapidly transported along the olfactory nerves into the central nervous system bypassing the blood brain barrier. Behavioural and functional analyses will provide invaluable information about the effectiveness of "metabolic" drugs for age-related brain disease.
Furthermore, deepening the knowledge of such pathogenic mechanisms could allow to identify novel "biomarkers of lifestyle" that might be routinely used in clinical practice to predict the risk of diet- and age-related organ damage, and to guide clinicians in implementing individualized, patient-centred preventive or therapeutic strategies. Indeed, from a public health perspective, targeting and treating metabolic-driven brain damage prior to the presence of clinical symptoms may lead to a drastic reduction in the socioeconomic costs associated with cognitive aging.
In conclusion early preliminary findings strongly encourage to perform the present project, since the results generated by the investigators, each focusing on targets different but all equally crucial and strictly converging, may offer significant advances in the understanding pathophysiological mechanisms involved in age/diet-associate cognitive decline. Interestingly the results may suggest novel and promising therapies that hopefully could have the potential not just to alleviate the symptoms but also to modify the course of cognition decline.