Current Pharmaceutical Design - Volume 17, Issue 31, 2011

Several sporadic neurodegenerative diseases display phenomena that directly or indirectly relate to mitochondrial function. Data suggesting altered mitochondrial function in these diseases could arise from mitochondrial DNA (mtDNA) are reviewed. Approaches for manipulating mitochondrial function and minimizing the downstream consequences of mitochondrial dysfunction are discussed.

Mitochondrial dynamics play a crucial role in the pathobiology underlying Alzheimer's disease (AD) and Parkinson's disease (PD). Although a complete scientific understanding of these devastating conditions has yet to be realized, alterations in mitochondrial fission and fusion, and in the protein complexes that orchestrate mitochondrial fission and fusion, have been well established in AD- and PD-related neurodegeneration. Whether fission/fusion disruption in the brain is a causal agent in neuronal demise or a product of some other upstream disturbance is still a matter of debate; however, in both AD and PD, the potential for successful therapeutic amelioration of degeneration via mitochondrial protection is high. We here discuss the role of mitochondrial dynamics in AD and PD and assess the need for their therapeutic exploitation.

Mitochondria fulfill a number of essential cellular functions, being recognized that the strict regulation of the structure, function and turnover of these organelles is an immutable control node for the maintenance of neuronal integrity and homeostasis. Many lines of evidence posit that mitochondria constitute a convergence point of preconditioning - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Indeed, it has been described that preconditioning activates an adaptive reprogramming of mitochondrial biology in response to a noxious stress-stimulus, which in turn will contribute to augment both mitochondrial and neuronal tolerance. Mitochondrial reactive species (ROS), mitochondrial ATP-sensitive potassium (mitoKATP) channels and mitochondrial permeability transition pore have been identified as specific mitochondrial mediators and targets of the adaptive program underlying preconditioning. Recent studies further link mitochondrial biogenesis, dynamics and mitophagy to preconditioning, thereby representing novel mechanisms by which preconditioning may mediate brain tolerance. The present review summarizes the current views on how mitochondrial biology is linked to preconditioning-induced neuroprotection. A better understanding of the mitochondrial mechanisms underlying preconditioning will help in the development of novel therapeutic approaches with the primary goal of modulating mitochondria to enhance brain tolerance against neurodegenerative events.

During the past decades, we have witnessed significant advances in our understanding of the molecular etiology of Parkinson's disease (PD). The unearthing of the causative genes for hereditary PD accelerated not only the studies of the molecular mechanisms underlying this pathology, but also set mitochondria at the center of PD pathology. In this review we revisit mitochondrial key role and propose a hypothesis for PD, that allows the unification of both sporadic and familial PD forms. In light of this we also discuss new promising disease-modified therapies.

Epigenetic alterations have been associated with several human diseases including Alzheimer's disease (AD). AD is a complex neurodegenerative disease characterized by a progressive decline in cognitive functions, neuronal cell loss and by the presence of β amyloid (Aβ) plaques and neurofibrillary tangles (NFTs) in the cortex. Mutations in specific genes have been identified but can only explain a small percentage of the AD cases. The origins of the sporadic cases of AD are still not known but there is evidence for a role of epigenetics in the etiology of the disease. In this review we focus on discussing the roles of DNA methylation and hydroxymethylation in the development and potential treatment of AD. We discuss papers showing that there are alterations in methylated cytosine (5mC) levels in AD and also highlight the potential role of hydroxylated methylcytosine (5hmC) in the epigenetic regulation of brain gene expression and perhaps in AD. We discuss the potential influence of environmental factors, working through epigenetic mechanisms, on increasing the risk of developing AD and their potential in treating this major neurodegenerative disorder.

This review focuses on the discovery of activity-dependent neuroprotective protein (ADNP) and the ensuing discovery of NAP (davunetide) toward clinical development with emphasis on microtubule protection. ADNP immunoreactivity was shown to occasionally decorate microtubules and ADNP silencing inhibited neurite outgrowth as measured by microtubule associated protein 2 (MAP2) labeling. ADNP knockout is lethal, while 50% reduction in ADNP (ADNP haploinsufficiency) resulted in the microtubule associated protein tau pathology coupled to cognitive dysfunction and neurodegeneration. NAP (davunetide), an eight amino acid peptide derived from ADNP partly ameliorated deficits associated with ADNP deficiency. NAP (davunetide) interacted with microtubules, protected against microtubule toxicity associated with zinc, nocodazole and oxidative stress in vitro and against tau pathology and MAP6 (stable tubuleonly polypeptide - STOP) pathology in vivo. NAP (davunetide) provided neurotrophic functions promoting neurite outgrowth as measured by increases in MAP2 immunoreactivity and synapse formation by increasing synaptophysin expression. NAP (davunetide) protection against neurodegeneration has recently been shown to extend to katanin-related microtubule disruption under conditions of tau deficiencies. In conclusion, NAP (davunetide) provided potent neuroprotection in a broad range of neurodegenerative models, protecting the neuroglial cytoskeleton in vitro and inhibiting tau pathology (tauopathy) in vivo. Based on these extensive preclinical results, davunetide (NAP) is now being evaluated in a Phase II/III study of the tauopathy, progressive supranuclear palsy (PSP); (Allon Therapeutics Inc.).

Aging is the major known risk factor for the onset of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Mitochondria play a central role in aging as mitochondrial dysfunction increases with age and produces harmful levels of reactive oxygen species which leads to cellular oxidative stress (free-radical theory of aging). Oxidative stress is highly damaging to cellular macromolecules and is also a major cause of the loss and impairment of neurons in neurodegenerative disorders. A growing body of evidence suggests that modulation of sirtuin activity and restricting calorie intake has a strong neuroprotective effect. SIRT1 induction by the use of pharmacological activators or by calorie restriction (CR) diet regimen has been shown to protect against neuronal loss and impairment in the cellular and animal models of AD and PD. Here, we review the current knowledge and recent data related to the role of sirtuins and CR in neurodegeneration and discuss the potential underlying signaling pathways of neuroprotection that might serve as attractive targets for the future therapeutic intervention of these age-related neurodegenerative diseases.

Alzheimer's and Parkinson's diseases represent the most prevalent neurodegenerative disorders worldwide. Current pharmacological or surgical treatments provide symptomatic benefits, particularly in the early stages, but none can delay or stop the progression of these diseases. There is an urgent need for new therapies able to modify disease progression. Gene therapy, mainly based on viral vectors, is presently being assumed as an important alternative to conventional treatments. After decades of preclinical developments, we are now facing an important period, in which several viral vector-mediated gene therapies are being tested in Phase 1 and Phase 2 clinical trials, with some of them showing promising results. This review intends to present an overview of the current efforts in the field for the treatment of Alzheimer's and Parkinson's diseases.

Cellular homeostasis relies on quality control systems so that damaged biologic structures are either repaired or degraded and entirely replaced by newly formed proteins or even organelles. The clearance of dysfunctional cellular structures in long-lived postmitotic cells, like neurons, is essential to eliminate, per example, defective mitochondria, lipofuscin-loaded lysosomes and oxidized proteins. Short-lived proteins are degraded mainly by proteases and proteasomes whether most long-lived proteins and all organelles are digested by autophagy in the lysosomes. Recently, it an interplay was established between the ubiquitin-proteasome system and macroautophagy, so that both degradative mechanisms compensate for each other. In this article we describe each of these clearance systems and their contribution to neuronal quality control. We will highlight some of the findings that provide evidence for the dysfunction of these systems in Alzheimer's and Parkinson's diseases. Ultimately, we provide an outline on potential therapeutic interventions based on the modulation of cellular degradative systems.

Iron is a redox active metal involved in the oxidation-reduction reactions and regulation of cell growth and differentiation. Iron is an integral part of many proteins and enzymes that maintains various physiological functions. Most of the human body's iron is contained in red blood cells. Despite iron being an abundant trace metal in food, millions of people worldwide suffer from anemia. Iron deficiency results in impaired production of iron-containing proteins and inhibition of cell growth. In contrast, abnormal iron uptake has been related to the most common hereditary disease hemochromatosis, leading to tissue damage derived from free radical toxicity. In addition, disruption of iron regulation plays a key role in the etiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, Friedreich's ataxia and other neurological disorders, cancer (lung cancer, breast cancer, colon cancer), Fanconi anemia, stroke and ageing. Thus the control of this necessary but potentially toxic substance is an important part of many aspects of human health and disease. The most frequent is the toxic role of iron linked with the catalytic decomposition of hydrogen peroxide (Fenton reaction) leading to the formation of reactive oxygen species (ROS) causing damage to biomolecules, including lipids, proteins and DNA. The binding of irondesigned chelators via nitrogen, oxygen or sulphur donor atoms blocks iron’s ability to catalyze the formation of free radicals. Thus the design of various metal chelators to prevent free radical reactions is an important approach in the treatment of many iron-related diseases. The development of effective dual functioning antioxidants, possessing both metal-chelating and free radical-scavenging properties is awaited. The aim of this review is to discuss the role of iron and importance of iron-chelation in human disease and ageing.

Alzheimer's is a neurodegenerative disease with a complex and progressive pathological phenotype characterized first by hypometabolism and impaired mitochondrial bioenergetics followed by pathological burden. The progressive and multifaceted degenerative phenotype of Alzheimer's suggests that successful treatment strategies necessarily will be equally multi-faceted and disease stage specific. Traditional therapeutic strategies based on the pathological aspect of the disease have achieved success in preclinical models which has not translated into clinical therapeutic efficacy. Meanwhile, increasing evidence indicates an antecedent and potentially causal role of mitochondrial bioenergetic deficits and brain hypometabolism coupled with increased mitochondrial oxidative stress in AD pathogenesis. The essential role of mitochondrial bioenergetics and the unique trajectory of alterations in brain metabolic capacity enable a bioenergetic- centric strategy that targets disease-stage specific pattern of brain metabolism for disease prevention and treatment. A combination of nutraceutical and pharmaceutical intervention that enhances glucose-driven metabolic activity and potentiates mitochondrial bioenergetic function could prevent the antecedent decline in brain glucose metabolism, promote healthy aging and prevent AD. Alternatively, during the prodromal incipient phase of AD, sustained activation of ketogenic metabolic pathways coupled with supplement of the alternative fuel source, ketone bodies, could sustain mitochondrial bioenergetic function to prevent or delay further progression of the disease.