Partial rescue of memory deficits induced by calorie restriction in a mouse model of tau deposition

Abstract

Calorie restriction (CR) was shown previously to improve cognition and decrease pathology in transgenic mouse models with Alzheimer-like amyloid deposition. In the present study, we investigated the effects of CR on the Tg4510 model of tau deposition. Mice in the calorie restriction group had food intake gradually decreased until they reached an average of 35% body weight reduction. Body weight and food intake were monitored throughout the study. After being on their respective diets for 3 months, all animals were submitted to behavioral testing. Tg4510 mice fed ad libitum showed lower body weight than nontransgenic littermates despite their increased food intake. Additionally, Tg4510 showed increased locomotor activity in the open field regardless of diet. Calorie restricted Tg4510 mice performed significantly better than ad libitum fed mice in the novel object recognition test, suggesting improved short-term memory. CR Tg4510 mice also performed significantly better in contextual fear conditioning than mice fed ad libitum. However, in a modified version of the novelty test that allows for interaction with other mice instead of inanimate objects, CR was not able to rescue the deficit found in Tg4510 mice in this ethologically more salient version of the task. No treatment differences in motor performance or spatial memory were observed in the rotarod or radial arm water maze tests, respectively. Histopathological and biochemical assessments showed no diet-induced changes in total or phospho-tau levels. Moreover, increased activation of both astrocytes and microglia in Tg4510 mice was not rescued by calorie restriction. Taken together, our data suggests that, despite an apparent rescue of associative memory, CR had no consistent effects on pathological outcomes of a mouse model of tau deposition.