Effects of Dietary Supplementation of Carnosine on Mitochondrial Dysfunction, Amyloid Pathology, and Cognitive Deficits in 3xTg-AD Mice

Molecular Neurology Unit, Center of Excellence on Aging (Ce.S.I.), University G. d'Annunzio, Chieti-Pescara, Italy.
PLoS ONE (Impact Factor: 3.23). 03/2011; 6(3):e17971. DOI: 10.1371/journal.pone.0017971
Source: PubMed


The pathogenic road map leading to Alzheimer's disease (AD) is still not completely understood; however, a large body of studies in the last few years supports the idea that beside the classic hallmarks of the disease, namely the accumulation of amyloid-β (Aβ) and neurofibrillary tangles, other factors significantly contribute to the initiation and the progression of the disease. Among them, mitochondria failure, an unbalanced neuronal redox state, and the dyshomeostasis of endogenous metals like copper, iron, and zinc have all been reported to play an important role in exacerbating AD pathology. Given these factors, the endogenous peptide carnosine may be potentially beneficial in the treatment of AD because of its free-radical scavenger and metal chelating properties.
In this study, we explored the effect of L-carnosine supplementation in the 3xTg-AD mouse, an animal model of AD that shows both Aβ- and tau-dependent pathology.
We found that carnosine supplementation in 3xTg-AD mice promotes a strong reduction in the hippocampal intraneuronal accumulation of Aβ and completely rescues AD and aging-related mitochondrial dysfunctions. No effects were found on tau pathology and we only observed a trend toward the amelioration of cognitive deficits.
Our data indicate that carnosine can be part of a combined therapeutic approach for the treatment of AD.

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Available from: Enrico Rizzarelli, Oct 05, 2015
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    • "Although the highest levels of carnosine lie within skeletal muscle, there are sizeable concentrations within brain and cardiac tissues (O'Dowd et al., 1988; Sale et al., 2010). Recent data have suggested that carnosine may act as a neuroprotective mediator (Bae & Majid, 2013) leading to significant positive neurological control mechanisms under clinical conditions (Dobrota et al., 2005; Corona et al., 2011). Carnosine may also be an effective cardioprotective agent, regulating calcium flux and cardiac contractility (Roberts & Zaloga, 2000; Zieba & Wagrowska-Danilewicz, 2003). "
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    ABSTRACT: Beta-alanine (BA) supplementation has been shown to delay neuromuscular fatigue as a result of increased muscle carnosine concentrations. Carnosine has also been found in brain and cardiac tissue. The physical working capacity test at heart rate threshold (PWCHRT ) is a global estimate of the onset of fatigue during exercise, influenced by central and peripheral factors. The purpose of this study was to determine the effects of 28 days of BA supplementation on the PWCHRT . Thirty subjects (mean ± SD; age: 21·0 ± 2·1 years; body mass: 72·7 ± 14·5 kg; height: 170·1 ± 7·9 cm) were randomly assigned to BA (n = 15) or placebo (PL, n = 15) groups. Testing included eight to nine total visits: an enrolment day, physical screening, peak oxygen consumption (V(·) O2peak ) and two PWCHRT assessments over 4 days. Significant differences existed between BA and PL for PWCHRT (P = 0·001; mean∆: BA∆ = +24·2 watts, PL∆ = +11·2 watts), but not for V(·) O2peak (P = 0·222), time to exhaustion (TTE; P = 0·562) or ventilatory threshold (VT; P = 0·134). Results suggest that BA may increase heart rate training threshold. These results, in combination with one previous study reporting a potential effect of BA on HR, suggest that future studies should evaluate both central and peripheral aspects of fatigue with BA intake.
    Clinical Physiology and Functional Imaging 12/2013; 34(5). DOI:10.1111/cpf.12111 · 1.44 Impact Factor
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    • "The other possible therapeutic compound for AD, suggested recently is carnosine—a peptide with cooper/zinc chelating properties (Trombley et al., 1998). Corona et al. (2011) found that dietary supplementation of carnosine reduces hippocampal intraneuronal accumulation of Aβ and rescues mitochondrial dysfunctions in triple-transgenic AD mice (3 × Tg-AD) but does not affect the development of the tau pathology and only slightly reduces cognitive deficits (Corona et al., 2011). Furthermore, the paper of Donnelly et al. (2008) demonstrated the beneficial effect of the selective intracellular delivery of zinc using bis(thiosemicarbazonato) complexes in the reduction of the extracellular levels of Aβ and suggested the role of these metal-loaded compounds as potential therapeutic agents for AD (Donnelly et al., 2008). "
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    ABSTRACT: Zinc is an essential trace element, whose importance to the function of the central nervous system (CNS) is increasingly being appreciated. Alterations in zinc dyshomeostasis has been suggested as a key factor in the development of several neuropsychiatric disorders. In the CNS, zinc occurs in two forms: the first being tightly bound to proteins and, secondly, the free, cytoplasmic, or extracellular form found in presynaptic vesicles. Under normal conditions, zinc released from the synaptic vesicles modulates both ionotropic and metabotropic post-synaptic receptors. While under clinical conditions such as traumatic brain injury, stroke or epilepsy, the excess influx of zinc into neurons has been found to result in neurotoxicity and damage to postsynaptic neurons. On the other hand, a growing body of evidence suggests that a deficiency, rather than an excess, of zinc leads to an increased risk for the development of neurological disorders. Indeed, zinc deficiency has been shown to affect neurogenesis and increase neuronal apoptosis, which can lead to learning and memory deficits. Altered zinc homeostasis is also suggested as a risk factor for depression, Alzheimer's disease (AD), aging, and other neurodegenerative disorders. Under normal CNS physiology, homeostatic controls are put in place to avoid the accumulation of excess zinc or its deficiency. This cellular zinc homeostasis results from the actions of a coordinated regulation effected by different proteins involved in the uptake, excretion and intracellular storage/trafficking of zinc. These proteins include membranous transporters (ZnT and Zip) and metallothioneins (MT) which control intracellular zinc levels. Interestingly, alterations in ZnT and MT have been recently reported in both aging and AD. This paper provides an overview of both clinical and experimental evidence that implicates a dysfunction in zinc homeostasis in the pathophysiology of depression, AD, and aging.
    Frontiers in Aging Neuroscience 07/2013; 5:33. DOI:10.3389/fnagi.2013.00033 · 4.00 Impact Factor
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    • "Carnosine has been analyzed as a specific metabolic tool against neuronal toxic effects, such as those arising from age-related proteotoxicity or from pathophysiological pathways leading to altered protein accumulation [1], [18], [21]–[29], and its protective effects against aberrant amyloid peptides have been tested in various mammalian tissues and cells [28], [30], [31]. Interestingly, carnosine has also been investigated in tissues and fluids from patients with well-known neurodegenerative conditions/pathologies, such as Parkinson’s Disease, Freiderich’s ataxia and Alzheimer’s Disease (AD) [1], [11], [26], [32]–[37]. In the context of AD, the genes involved in carnosine metabolism have also been investigated. "
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    ABSTRACT: Carnosine is an endogenous dipeptide abundant in the central nervous system, where by acting as intracellular pH buffering molecule, Zn/Cu ion chelator, antioxidant and anti-crosslinking agent, it exerts a well-recognized multi-protective homeostatic function for neuronal and non-neuronal cells. Carnosine seems to counteract proteotoxicity and protein accumulation in neurodegenerative conditions, such as Alzheimer’s Disease (AD). However, its direct impact on the dynamics of AD-related fibril formation remains uninvestigated. We considered the effects of carnosine on the formation of fibrils/aggregates of the amyloidogenic peptide fragment Ab1-42, a major hallmark of AD injury. Atomic force microscopy and thioflavin T assays showed inhibition of Ab1-42 fibrillogenesis in vitro and differences in the aggregation state of Ab1- 42 small pre-fibrillar structures (monomers and small oligomers) in the presence of carnosine. in silico molecular docking supported the experimental data, calculating possible conformational carnosine/Ab1-42 interactions. Overall, our results suggest an effective role of carnosine against Ab1-42 aggregation.
    PLoS ONE 07/2013; 8(7):E68159. DOI:10.1371/journal.pone.0068159 · 3.23 Impact Factor
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