The Neuroprotective Effects of Moderate Treadmill Exercise in a Rat Model of Alzheimer’s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss, spatial disorientation, and aberrant behaviors. The most important risk factor of AD is aging. Accumulating evidence suggests a neuroprotective role of regular exercise in aging associated memory impairment. In this study, we investigated the ability of regular moderate treadmill exercise to prevent impairment of cognitive and non-cognitive functions, long-term potentiation (LTP), and related signaling pathways in a rat model of AD, which was achieved by i.c.v. infusion of Aβ1-42 peptides (250 pmol/day for 2 weeks). We utilized behavioral assessment, in vivo electrophysiological recording, and immunoblotting in 4 groups of adult Wistar rats: control, treadmill exercise (Ex), β-amyloid-infused (Aβ), and amyloid-infused/treadmill exercised (Ex/Aβ). Our findings indicated that Aβ rats exhibited impaired spatial learning and memory as tested in the radial arm water maze (RAWM). Compared to all other groups, these rats also displayed increased anxiety-like behaviors as indicated by less time spent in the center area of the open field apparatus and the elevated plus maze (EPM), more time in the dark area of the light-dark box, and longer time in the closed arms of the EPM paradigm. Extracellular recordings in urethane-anesthetized rats revealed that these amyloid-infused animals showed suppressed early phase (E-) and late phase (L-) LTP in both CA1 and DG areas, which correlated with deficient signaling pathways in these two brain regions. For example, Western blot analysis indicated that Aβ rats exhibited deleterious alterations in the levels of AD- and LTP-related molecules including amyloid precursor protein (APP), β-secretase enzyme (BACE-1), calcineurin (PP2B), brain derived-neurotrophic factor (BDNF), Ca2+/calmodulin dependent protein kinases II and IV (CaMKII and CaMKIV), cAMP response element binding protein (CREB), and extracellular signal-regulated kinase 1/2 (ERK1/2). Compared to controls, Ex and Ex/Aβ rats showed a similar behavioral performance with normal hippocampal LTP and no detrimental changes in the levels of those LTP- and memory-related molecules in both areas. Thus, regular moderate treadmill exercise may be beneficial in preserving cognitive and non-cognitive functions in the AD brains by preventing the detrimental effects of amyloid toxicity on the synapses and key signaling pathways.