Intermittent fasting and caloric restriction ameliorate age-related behavioral deficits in the triple-transgenic mouse model of Alzheimer's disease
Introduction
Alzheimer's disease (AD) is characterized by progressive impairment of memory accompanied by psychiatric disturbances (Lyketsos et al., 2002, Mattson, 2004, Steffens et al., 2006). The behavioral abnormalities in AD result from dysfunction and death of neurons in brain regions involved in cognition and mood such as the hippocampus, entorhinal cortex, basal forebrain, and frontal and parietal lobes. These brain regions suffer degeneration of synapses and neurons associated with abnormal accumulation of extracellular deposits of amyloid β-peptide (Aβ), a 40–42 amino acid proteolytic cleavage product of the amyloid precursor protein (APP). Aβ may cause synaptic dysfunction and degeneration of neurons by inducing membrane-associated oxidative stress, resulting in disruption of cellular ion homeostasis (Mattson, 2004). Transgenic mouse models that express a familial AD (FAD) APP mutation alone or in combination with an FAD presenilin-1 mutation exhibit progressive Aβ deposition and variable levels of synaptic dysfunction and cognitive impairment depending upon the particular model (Morgan et al., 2000, Ashe, 2001, Jankowsky et al., 2005, Kobayashi and Chen, 2005, Jacobsen et al., 2006). We recently generated a novel triple mutant mouse model of AD (3xTgAD mice) in which the mice express FAD APP and presenilin-1 mutations together with a tau mutation (Oddo et al., 2003a). The 3xTgAD mice exhibit age-dependent Aβ deposition and tau pathology in the hippocampus and cerebral cortex which are associated with impaired synaptic plasticity (Oddo et al., 2003a, Oddo et al., 2003b) and deficits in spatial learning tasks (Billings et al., 2005).
Previous studies have shown that caloric restriction (CR) and intermittent fasting (IF) diets are neuroprotective and improve functional outcome in animal models of stroke, Parkinson's and Huntington's diseases (reviewed in Mattson, 2005). The animal studies suggest that CR and IF may benefit the brain by reducing levels of oxidative stress and by enhancing cellular stress resistance mechanisms. Data from studies of human populations and animal models suggest that reduced food intake may also protect against AD. For example, a prospective epidemiological study of a large cohort in New York City provided evidence that individuals with a low calorie intake have a reduced risk of developing AD (Luchsinger et al., 2002). Another study showed that obesity at midlife increases the risk of AD (Kivipelto et al., 2005). Moreover, diseases caused by excessive calorie intake (diabetes and cardiovascular disease) are associated with increased risk of AD (Launer, 2005). CR was recently reported to reduce the development of amyloid pathology in the hippocampus and cerebral cortex of transgenic mice overexpressing FAD APP mutations (Patel et al., 2005, Wang et al., 2005), suggesting that CR can suppress a key pathogenic process in AD. However, the effects of CR and IF diets on the development of cognitive dysfunction in AD are unknown. In the present study we determined if long-term CR and/or IF could ameliorate age-related behavioral impairments in 3xTgAD mice.
Section snippets
Animals and experimental design
Male and female non-transgenic C57BL/6 mice and 3xTgAD mice (Oddo et al., 2003a) were housed in cages (4–5 five per cage) and maintained under a 12 h light and dark cycle. These mice were in a colony that had been exposed to mouse hepatitis virus, but the mice were not shedding virus at the time of analysis. At 3 months of age mice were divided into 4 groups of 20 males and 20 females per group assigned to the following dietary regimens: non-transgenic ad libitum (nonTg,AL), 3xTgAD ad libitum
An age-related decrease in open-field activity in 3xTgAD mice is attenuated by CR and IF
3xTgAD mice that had been maintained on the AL diet for 7 or 14 months exhibited significantly less ambulatory activity compared to nonTg,AL control mice (Fig. 1a). There was no effect of diet on ambulatory counts in 3xTgAD mice maintained for 7 months on the diets. However, 3xTgAD mice maintained on CR or IF diets for 14 months exhibited significantly greater ambulation compared to 3xTgAD mice maintained on the AL diet for 14 months. Consistent with the ambulatory count data, 3xTgAD mice that
Discussion
Our findings provide evidence that dietary energy restriction regimens can ameliorate learning and memory deficits in an animal model of AD. 3xTgAD mice fed ad libitum exhibited age-dependent impairment in performance in both acquisition (goal latency) and retention (probe trial) tasks in the Morris water maze compared to non-transgenic control mice. In contrast, 3xTgAD mice maintained on CR or IF diets for 14 months exhibited no deficits in water maze tasks, performing as well as
Acknowledgments
This research was supported by the National Institute on Aging Intramural Research Program; and by NIA grant AG022455 (YM). The authors thank Ms Chiho Hirata-Fukae (Department of Neurology, Georgetown University Medical Center) for technical assistance. Antibodies used for Abeta ELISAs were generously provided by Dr Noriaki Kinoshita (Immuno-Biological Laboratories Co., Ltd., Takasaki, Gunma, Japan).
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