Modulation of glial autophagy by periodic dietary restriction as a potential therapeutic strategy in an animal model of Alzheimer?s disease

GREGOSA, AMAL; VINUESA A; POMILIO C; BENTIVEGNA M; PRESA J; SARAVIA, F; BEAUQUIS J

Mar del Plata

Congreso; Reunion de la Sociedad Argentina de Investigación Clínica; 2019

SAIC

Alzheimer?s disease (AD) is the leading cause of dementia for which there are no effective treatments. Dietary restriction (DR) has been proposed as a potential therapeutic strategy for age-associated diseases. Our objectives were to analyze memory and hippocampal alterations in an animal model of familial AD, the PDAPP-J20 transgenic mouse (Tg) and to evaluate 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 (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. Therefore, we evaluated the C6 astrocyte line exposed to fibrillar beta amyloid (fAB, 2, 6 or 24h) and previously nutrient restricted (NR; 2% FBS) or not (10% FBS) for 6h. Exposure to fAB for 2h showed that LC3 was increased after bafilomycin treatment, an inhibitor of autophagosome-lysosome fusion, indicating a functional autophagy (AB NR vs AB NR BAF, p