A ketogenic approach in a new mouse model of early Alzheimer's disease: characterisation of diets and the APPNL-G-F/MAPT model in males and females

Glucose brain metabolism impairment is one of the earliest hallmarks of Alzheimer’s disease (AD). It starts to decrease several years before the first clinical symptoms. A new hypothesis states that high consumption of fructose, as part of our modern diet, could contribute to glucose hypometabolism. Fructose intake can activate an evolutionary survival pathway that leads to decreased mitochondrial function and insulin resistance among others in order to prepare the body for times of food shortage. An overactivation of this pathway by our modern diet could therefore induce neuroinflammation and mitochondrial oxidative stress that would ultimately contribute to glucose hypometabolism. On the contrary, ketone body metabolism in the brain remains intact in early AD. A low-carbohydrate ketogenic diet could then be useful to counteract glucose hypometabolism by enhancing brain energetic metabolism through the production of ketone bodies. This study aims to investigate the effect of both a ketogenic diet (85 %Kcal fat, 10 %Kcal protein and 5 %Kcal carbohydrates) and a high fructose diet (10 %Kcal fat, 20 %Kcal protein and 70 %kcal carbohydrates half of which consists of sucrose) against a classic chow diet (10 %Kcal fat, 20 %Kcal protein and 70 %kcal carbohydrates) on the development of AD in vivo in the new APPNL-G-F/MAPT model. Diets were introduced at 3 months of age for 3 months before testing synaptic activity on hippocampal slices. As there are gender differences in the incidence of the disease and in metabolism, the sex of the mice has been considered. The weight of the mice didn’t differ following the 3-month diets in both males and females. In addition, no groups have developed hyperglycaemia as indicated by a measure of glycated albumin concentration in serum by ELISA. Neither diets nor the mouse line had an effect on synaptic plasticity and properties (long-term potentiation, excitability and glutamate release probability). This result could be explained by mice that might be too young to develop an impairment on synaptic plasticity despite literature showing behavioural deficits at this age. 1H-NMR has been used in a non-targeted way to search for metabolite differences in the groups. In the future, Apeptides, cytokines and neurotransmitters will be quantified in the brain. Further metabolism investigation through SeaHorse and mass spectrometry are considered as well as exploration of PPAR-alpha activity.