Metabolic Dysfunction in Alzheimers Disease and Related Neurodegenerative Disorders

Metabolism Unit, National Institute on Aging, Baltimore, MD 21224, USA.
Current Alzheimer research (Impact Factor: 3.89). 01/2012; 9(1):5-17. DOI: 10.2174/156720512799015064
Source: PubMed

ABSTRACT Alzheimer's disease and other related neurodegenerative diseases are highly debilitating disorders that affect millions of people worldwide. Efforts towards developing effective treatments for these disorders have shown limited efficacy at best, with no true cure to this day being present. Recent work, both clinical and experimental, indicates that many neurodegenerative disorders often display a coexisting metabolic dysfunction which may exacerbate neurological symptoms. It stands to reason therefore that metabolic pathways may themselves contain promising therapeutic targets for major neurodegenerative diseases. In this review, we provide an overview of some of the most recent evidence for metabolic dysregulation in Alzheimer's disease, Huntington's disease, and Parkinson's disease, and discuss several potential mechanisms that may underlie the potential relationships between metabolic dysfunction and etiology of nervous system degeneration. We also highlight some prominent signaling pathways involved in the link between peripheral metabolism and the central nervous system that are potential targets for future therapies, and we will review some of the clinical progress in this field. It is likely that in the near future, therapeutics with combinatorial neuroprotective and 'eumetabolic' activities may possess superior efficacies compared to less pluripotent remedies.

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Available from: Stuart Maudsley, Sep 28, 2015
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    • "Importantly, beyond its effects on the circadian system and hippocampal dependent memory, ghrelin may also have potential for preventing or treating neurodegenerative disease. Neurodegenerative disorders often display coexisting metabolic dysfunction, and there are several converging lines of evidence linking metabolic syndromes with an increased risk of developing AD (Naderali et al., 2009; Kapogiannis and Mattson, 2011; Cai et al., 2012). For example, there is a growing literature suggesting that insulin deficiency and insulin resistance act as mediators of AD-type neurodegeneration. "
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    ABSTRACT: Alzheimer's disease (AD) is a global epidemic. Unfortunately, we are still without effective treatments or a cure for this disease, which is having devastating consequences for patients, their families, and societies around the world. Until effective treatments are developed, promoting overall health may hold potential for delaying the onset or preventing neurodegenerative diseases such as AD. In particular, chronobiological concepts may provide a useful framework for identifying the earliest signs of age-related disease as well as inexpensive and noninvasive methods for promoting health. It is well reported that AD is associated with disrupted circadian functioning to a greater extent than normal aging. However, it is unclear if the central circadian clock (i.e., the suprachiasmatic nucleus) is dysfunctioning, or whether the synchrony between the central and peripheral clocks that control behavior and metabolic processes are becoming uncoupled. Desynchrony of rhythms can negatively affect health, increasing morbidity and mortality in both animal models and humans. If the uncoupling of rhythms is contributing to AD progression or exacerbating symptoms, then it may be possible to draw from the food-entrainment literature to identify mechanisms for re-synchronizing rhythms to improve overall health and reduce the severity of symptoms. The following review will briefly summarize the circadian system, its potential role in AD, and propose using a feeding-related neuropeptide, such as ghrelin, to synchronize uncoupled rhythms. Synchronizing rhythms may be an inexpensive way to promote healthy aging and delay the onset of neurodegenerative disease such as AD.
    Frontiers in Aging Neuroscience 09/2014; 6. DOI:10.3389/fnagi.2014.00234 · 4.00 Impact Factor
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    • "With increasing life-span and lack of interventions to slow or stop the progression of AD, epidemiological studies indicate that this number is expected to reach 115.4 million in 2050 (21–25). Two different forms of AD have been described: the inherited form called “early-onset familial AD” (FAD) is caused by rare genetic variations in genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1), and 2 (PSEN2) involved in β-amyloid (Aβ) processing and which affect the intracellular trafficking of Aβ or APP (26, 27). Since <1% of AD cases are caused by genetic variations (27), the vast majority of AD cases are affected by the “sporadic late-onset” form of AD (SAD) (26, 27), which remains poorly understood. "
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    ABSTRACT: With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington' disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand-receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum.
    Frontiers in Endocrinology 09/2014; 5:142. DOI:10.3389/fendo.2014.00142
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    • "Accumulating evidence supports the hypothesis that AD is a degenerative metabolic disease, in which glucose uptake and utilization are impaired. Decreased cerebral glucose metabolism and energy deficiency occur at the early stage of the disease and deteriorate further with its progression [3] [4] [5] [6] [7] . The impairment in cerebral glucose metabolism is associated with brain insulin defi ciency and dysregulated signal transduction that have been identifi ed in the AD brain. "
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    ABSTRACT: Contrary to the previous belief that insulin does not act in the brain, studies in the last three decades have demonstrated important roles of insulin and insulin signal transduction in various functions of the central nervous system. Deregulated brain insulin signaling and its role in molecular pathogenesis have recently been reported in Alzheimer's disease (AD). In this article, we review the roles of brain insulin signaling in memory and cognition, the metabolism of amyloid β precursor protein, and tau phosphorylation. We further discuss deficiencies of brain insulin signaling and glucose metabolism, their roles in the development of AD, and recent studies that target the brain insulin signaling pathway for the treatment of AD. It is clear now that deregulation of brain insulin signaling plays an important role in the development of sporadic AD. The brain insulin signaling pathway also offers a promising therapeutic target for treating AD and probably other neurodegenerative disorders.
    Neuroscience Bulletin 03/2014; 30(2). DOI:10.1007/s12264-013-1408-x · 2.51 Impact Factor
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