Review Exercise counteracts declining hippocampal function in aging and Alzheimer's disease Karlie A. Intlekofer, Carl W. Cotman ⁎ Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine CA 92697–4260, USA abstract article info Article history: Received 13 February 2012 Revised 25 May 2012 Accepted 22 June 2012 Available online 30 June 2012 Keywords: Alzheimer's disease Exercise Neurodegeneration Hippocampus Transgenic models Physical activity Alzheimer's disease (AD) afflicts more than 5.4 million Americans and ranks as the most common type of dementia (Thies and Bleiler, 2011), yet effective pharmacological treatments have not been identified. Substantial evidence indicates that physical activity enhances learning and memory for people of all ages, including individuals that suffer from cognitive impairment. The mechanisms that underlie these benefits have been explored using animal models, including transgenic models of AD. Accumulating research shows that physical activity reinstates hippocampal function by enhancing the expression of brain-derived neuro- trophic factor (BDNF) and other growth factors that promote neurogenesis, angiogenesis, and synaptic plasticity. In addition, several studies have found that physical activity counteracts age- and AD-associated declines in mitochondrial and immune system function. A growing body of evidence also suggests that exercise interven- tions hold the potential to reduce the pathological features associated with AD. Taken together, animal and human studies indicate that exercise provides a powerful stimulus that can countervail the molecular changes that underlie the progressive loss of hippocampal function in advanced age and AD. © 2012 Published by Elsevier Inc. Contents Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 Exercise promotes brain health in advancing age and AD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Exercise improves learning and memory in AD mouse models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48 Brain tau and Aβ pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Exercise-induced Neurotrophins and Growth Factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49 Oxidative capacity and energy metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50 Immune system modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 APOE ε4 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51 Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 52 Introduction Alzheimer's disease (AD) affects more than one in eight Americans over the age of 65 and nearly half of those over the age of 85 (Thies and Bleiler, 2011). Current estimates of AD prevalence are 33.9 million worldwide, but surging rates of AD are anticipated as the number of elderly rises. By 2050, AD prevalence is anticipated to soar to over 100 million people (Barnes and Yaffe, 2011; Brookmeyer et al., 2007). Although research to address this looming crisis has generated several pharmaceutical candidates, current treatments are plagued by limited efficacy, the risk of substantial side effects, and generally do not significantly alter the course of AD (Mangialasche et al., 2010). While further work is warranted to identify effective pharmacological treatments, the growing AD prevalence and escalating health care costs argue for the accessible and potent strategy of physical activity (Ahlskog et al., 2011). Neurobiology of Disease 57 (2013) 47–55 ⁎ Corresponding author at: Institute for Memory Impairments and Neurological Disorders, University of California Irvine, 1113 Gillespie Building, Irvine CA 92697– 4260, USA. Fax: +1 949 824 2071. E-mail address: cwcotman@uci.edu (C.W. Cotman). Available online on ScienceDirect (www.sciencedirect.com). 0969-9961/$ – see front matter © 2012 Published by Elsevier Inc. doi:10.1016/j.nbd.2012.06.011 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi