Metabolic implications on neuroinflammation in the pathological aging context. Dietary restriction, glial autophagy and metformin in Alzheimer's disease

BEAUQUIS J; POMILIO C; VINUESA A; GREGOSA A; GONZALEZ PEREZ N; SARAVIA F

Toulouse

Conferencia; 2nd Euro Geroscience Conference; 2022

Overnutrition and modern diets containing high proportions of saturated fat are among the major factors contributing to a low-grade state of inflammation, hyperglycemia and dyslipidemia. In the last decades, the global rise of type 2 diabetes and obesity prevalence has elicited a great interest in understanding how changes in metabolic function lead to an increased risk for premature brain aging and the development of neurodegenerative disorders such as Alzheimer?s disease (AD). Cognitive impairment and decreased neurogenic capacity could be a consequence of metabolic disturbances.In these scenarios, the interplay between inflammation and insulin resistance could represent a potential therapeutic target to prevent or ameliorate neurodegeneration and cognitive ability. Dietary restriction (DR) has been proposed as a potential therapeutic strategy for age-associated diseases. We analyzed memory performance and hippocampal alterations in an animal model of familial AD, the PDAPP-J20 transgenic mouse (Tg) and evaluated the effects of a periodic DR protocol (3 cycles of 40% DR for 5 days and ad libitum (AL) diet for 9 days). We observed cognitive impairment, impaired adult neurogenesis and progressive amyloid beta (AB) deposition in the hippocampus of AL-fed Tg mice. Periodic DR was associated to cognitive improvement, increased hippocampal neurogenesis, and reduced hippocampal amyloid load. Through immunofluorescence for LC3 specific marker for autophagosomes and GFAP (astrocytes), we found that autophagy is modulated in Tg mice with a high proportion of LC3 localized in astrocytes. We also found that astrocytes contained AB co-localizing with LC3. From these results we hypothesized that the reduction in amyloid plaques associated to DR would be partly mediated by astroglial autophagy. This data was in line with in vitro results from cultured astrocytes exposed to a nutrient restriction (NR; 2% FBS) or not (10% FBS), where we found evidence of glial autophagy implication promoted by NR, strongly suggesting a link between metabolic pathways and neuroinflammation in AD. In this line, some therapeutic strategies employed on T2D subjects could be beneficial on AD patients. We evaluated the effect of the antidiabetic drug metformin -considered a DR mimetic- on patients enrolled in ADNI, an observational and longitudinal study including patients from all around the world. We employed data from patients diagnosed with mild cognitive impairment (MCI) due to AD and we performed a principal component analysis focusing on biomarkers associated to AD measured in cerebrospinal fluid. We concluded that MCI metformin-treated patients were globally characterized as subjects with a better CSF biomarkers profile than the mean population of MCI patients (p