Prophylactic effect of physical exercise on Aβ1–40-induced depressive-like behavior: Role of BDNF, mTOR signaling, cell proliferation and survival in the hippocampus

Abstract Alzheimer's disease (AD) is characterized by progressive cognitive impairments as well as non-cognitive symptoms such as depressed mood. Physical exercise has been proposed as a preventive strategy against AD and depression, an effect that may be related, at least partially, to its ability to prevent impairments on cell proliferation and neuronal survival in the hippocampus, a structure implicated in both cognition and affective behavior. Here, we investigated the ability of treadmill exercise (4 weeks) to counteract amyloid β 1–40 peptide-induced depressive-like and anxiety-like behavior in mice. Moreover, we addressed the role of the BDNF/mTOR intracellular signaling pathway as well as hippocampal cell proliferation and survival in the effects of physical exercise and/or Aβ 1–40 . Aβ 1–40 administration (400 pmol/mouse, i.c.v.) increased immobility time and reduced the latency to immobility in the forced swim test, a finding indicative of depressive-like behavior. In addition, Aβ 1–40 administration also decreased time spent in the center of the open field and increased grooming and defecation, alterations indicative of anxiety-like behavior. These behavioral alterations were accompanied by a reduction in the levels of mature BDNF and mTOR (Ser 2448 ) phosphorylation in the hippocampus. In addition, As 1–40 administration reduced cell proliferation and survival in the ventral, dorsal and entire dentate gyrus of the hippocampus. Importantly, most of these behavioral, neurochemical and structural impairments induced by Aβ 1–40 were not observed in mice subjected to 4 weeks of treadmill exercise. These findings indicate that physical exercise has the potential to prevent the occurrence of early emotional disturbances associated with AD and this appears to be mediated, at least in part, by modulation of hippocampal BDNF and mTOR signaling as well as through promotion of cell proliferation and survival in the hippocampal DG.