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

BEAUQUIS JUAN; POMILIO C; A VINUESA; GREGOSA, AMAL; GONZALEZ PEREZ N; FLAVIA EUGENIA SARAVIA

Toulouse

Conferencia; 2nd Euro Geroscience Conference,; 2022

Overnutrition and modern diets containing high proportions of saturated fat are among the major factorscontributing 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 understandinghow changes in metabolic function lead to an increased risk for premature brain aging and thedevelopment of neurodegenerative disorders such as Alzheimer’s disease (AD). Cognitive impairmentand decreased neurogenic capacity could be a consequence of metabolic disturbances.In these scenarios, the interplay between inflammation and insulin resistance could represent apotential therapeutic target to prevent or ameliorate neurodegeneration and cognitive ability. Dietaryrestriction (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, thePDAPP-J20 transgenic mouse (Tg) and evaluated the effects of a periodic DR protocol (3 cycles of40% DR for 5 days and ad libitum (AL) diet for 9 days). We observed cognitive impairment, impairedadult neurogenesis and progressive amyloid beta (AB) deposition in the hippocampus of AL-fed Tgmice. Periodic DR was associated to cognitive improvement, increased hippocampal neurogenesis,and reduced hippocampal amyloid load. Through immunofluorescence for LC3 specific marker forautophagosomes and GFAP (astrocytes), we found that autophagy is modulated in Tg mice with a highproportion of LC3 localized in astrocytes. We also found that astrocytes contained AB co-localizing withLC3. From these results we hypothesized that the reduction in amyloid plaques associated to DR wouldbe partly mediated by astroglial autophagy. This data was in line with in vitro results from culturedastrocytes exposed to a nutrient restriction (NR; 2% FBS) or not (10% FBS), where we found evidenceof glial autophagy implication promoted by NR, strongly suggesting a link between metabolic pathwaysand 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 patientsenrolled 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 weperformed a principal component analysis focusing on biomarkers associated to AD measured incerebrospinal fluid. We concluded that MCI metformin-treated patients were globally characterized assubjects with a better CSF biomarkers profile than the mean population of MCI patients (p