Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus)

Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Journal of Alzheimer's disease: JAD (Impact Factor: 4.15). 01/2007; 10(4):417-22.
Source: PubMed

ABSTRACT Recent studies from our laboratories and others suggest that calorie restriction (CR) may benefit Alzheimer's disease (AD) by preventing amyloid-beta (Abeta) neuropathology in the mouse models of AD. Moreover, we found that promotion of the NAD+-dependent SIRT1 mediated deacetylase activity, a key regulator in CR extension of life span, may be a mechanism by which CR influences AD-type neuropathology. In this study we continued to explore the role of CR in AD-type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). Monkeys were maintained on the normal and CR diets throughout the entire lifespan until they died of natural causes. We found that 30% CR resulted in reduced contents of Abeta1-40 and Abeta1-42 peptides in the temporal cortex of Squirrel monkeys, relative to control (CON) fed monkeys. The decreased contents of cortical Abeta peptide inversely correlated with SIRT1 protein concentrations in the same brain region; no detectable change in total full-length amyloid-beta protein precursor (AbetaPP) level was found. Most interestingly, we found that 30% CR resulted in a select elevation of alpha- but not beta- or gamma- secretase activity which coincided with decreased ROCK1 protein content in the same brain region, relative to CON group. Collectively, the study suggests that investigation of the role of CR in non-human primates may provide a valuable approach for further clarifying the role of CR in AD.

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    • "In support of this, CR studies in AD-type brain amyloidosis in Squirrel monkeys were similarly found to result in reduced Aβ. Importantly, CR and reduced Aβ are correlated with increased SIRT1 levels in both in monkeys and mice [93, 134]. CR mediated SIRT1 expression appears to reduce Aβ peptide generation through mechanisms that favor a α-secretase non-amyloidogenic processing of APP. "
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    ABSTRACT: Sirtuins are a conserved family of deacetylases whose activities are dependent on nicotinamide adenine dinucleotide (NAD+). Sirtuins act in different cellular compartments, such as the nucleus where they deacetylate histones and transcriptional factors, in the cytoplasm where they modulate cytoskeletal and signaling molecules, and in the mitochondria where they engage components of the metabolic machinery. Collectively, they tune metabolic processes to energy availability, and modulate stress responses, protein aggregation, inflammatory processes, and genome stability. As such, they have garnered much interest and have been widely studied in aging and age-related neurodegeneration. In this chapter, we review the identification of sirtuins and their biological targets. We focus on their biological mechanisms of action and how they might be regulated, including via NAD metabolism, transcriptional and posttranscriptional control, and as targets of pharmacological agents. Lastly, we highlight the numerous studies suggesting that sirtuins are efficacious therapeutic targets in neurodegenerative disease and injury. Electronic supplementary material The online version of this article (doi:10.1007/s13311-013-0214-5) contains supplementary material, which is available to authorized users.
    Journal of the American Society for Experimental NeuroTherapeutics 09/2013; 10(4). DOI:10.1007/s13311-013-0214-5 · 5.05 Impact Factor
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    • "Moderate reduction in calorie intake in the absence of malnutrition has been recently demonstrated to help prevent or delay AD [34] [35]. In addition, it has been demonstrated that CR ameliorates A␤ and tau pathology and improves cognitive performance in AD mouse models [36] [37] [38] [39] [40] [41]. Although the exact mechanism by which CR influences AD remains unclear, there are at least a few identified pathways that involve neurogenesis. "
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    ABSTRACT: Alterations in hippocampal neurogenesis have been recognized as an integral part of Alzheimer's disease. Adult hippocampal neurogenesis is regulated by intrinsic and extrinsic factors; one of them is diet. This review provides an assessment of the current state of the field in hippocampal neurogenesis studies in Alzheimer's disease and focuses on the role of diet. The review highlights some of the key dietary compounds and interventions such as calorie restriction, fat, polyphenols, zinc, folate, alcohol and thiamine, and emphasizes the pathways that they modify.
    Journal of Alzheimer's disease: JAD 08/2013; 38(1). DOI:10.3233/JAD-131004 · 4.15 Impact Factor
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    • "The protective effect of SIRT1 against AD was initially observed in CR studies, where CR reduced Aβ and plaque generation in the brains of transgenic AD mice (Patel et al., 2005; Wang et al., 2005a). Similarly, the reduction of Aβ was also noticed in the cortex of fasted squirrel monkeys and is inversely correlated with SIRT1 levels (Qin et al., 2006a). These studies imply that SIRT1 is involved in neuroprotection against AD. "
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    ABSTRACT: Brain aging is characterized by progressive loss of neurophysiological functions that is often accompanied by age-associated neurodegeneration. Calorie restriction has been linked to extension of lifespan and reduction of the risk of neurodegenerative diseases in experimental model systems. Several signaling pathways have been indicated to underlie the beneficial effects of calorie restriction, among which the sirtuin family has been suggested to play a central role. In mammals, it has been established that sirtuins regulate physiological responses to metabolism and stress, two key factors that affect the process of aging. Sirtuins represent a promising new class of conserved deacetylases that play an important role in regulating metabolism and aging. This review focuses on current understanding of the relation between metabolic pathways involving sirtuins and the brain aging process, with focus on SIRT1 and SIRT3. Identification of therapeutic agents capable of modulating the expression and/or activity of sirtuins is expected to provide promising strategies for ameliorating neurodegeneration. Future investigations regarding the concerted interplay of the different sirtuins will help us understand more about the aging process, and potentially lead to the development of therapeutic approaches for the treatment of age-related neurodegenerative diseases and promotion of successful aging.
    Frontiers in Aging Neuroscience 07/2013; 5:36. DOI:10.3389/fnagi.2013.00036 · 4.00 Impact Factor
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