Journal of Alzheimer's Disease - Volume 20, issue s2

Authors: Zhu, Xiongwei | Beal, M. Flint | Wang, Xinglong | Perry, George | Smith, Mark A.

Article Type: Editorial

DOI: 10.3233/JAD-2010-1424

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S253-S253, 2010

Authors: Morais, Vanessa A. | De Strooper, Bart

Article Type: Review Article

Abstract: Mitochondria are crucial regulators of energy metabolism and apoptotic pathways and have been closely linked to the pathogenesis of neurodegenerative disorders. In this review we mainly focus on mitochondrial dysfunction in two of the most prevalent neurological disorders: Alzheimer's disease and Parkinson's disease. We discuss whether the role of mitochondria in those diseases should be considered primordial or secondary to other processes that eventually lead to neurodegeneration. In the case of Parkinson's disease, the role of mitochondria is quite clear and might be involved in the mechanism of this disorder. For Alzheimer's disease, the evidence in favor of such a …link is more indirect, and mitochondrial dysfunction likely occurs at a later stage of the disorder. Show more

Keywords: Alzheimer's disease, apoptosis, mitochondria, oxidative stress, Parkinson's disease

DOI: 10.3233/JAD-2010-100345

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S255-S263, 2010

Authors: Swerdlow, Russell H. | Burns, Jeffrey M. | Khan, Shaharyar M.

Article Type: Review Article

Abstract: We first proposed the mitochondrial cascade hypothesis of sporadic Alzheimer's disease (AD) in 2004. Our core assumptions were a person's genes determine baseline mitochondrial function and durability, this durability determines how mitochondria change with advancing age, and critical changes in mitochondrial function initiate other pathologies characteristic of AD. Since then several lines of investigation report data consistent with or supportive of our hypothesis. In particular, AD endophenotype studies suggest a strong maternal genetic contribution, and links between mitochondrial function, tau phosphorylation, and amyloid-β (Aβ) amyloidosis are increasingly recognized. As predicted, AD therapies designed to reduce Aβ thus far have had …at best very limited clinical benefits; our hypothesis identifies alternative therapeutic targets. While placing mitochondria at the apex of an AD cascade certainly remains controversial, it is increasingly accepted by the AD research community that mitochondria play an important role in the late-onset forms of the disease. Even if the mitochondrial cascade hypothesis proves incorrect, considering its assumptions could potentially advance our understanding of sporadic, late-onset AD. Show more

Keywords: Alzheimer's disease, amyloid-β, cytochrome oxidase, endophenotype, mitochondria, mitochondrial DNA

DOI: 10.3233/JAD-2010-100339

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S265-S279, 2010

Authors: Schon, Eric A. | Area-Gomez, Estela

Article Type: Review Article

Abstract: The subcellular localization of presenilin-1 (PS1) and presenilin-2 (PS2), two proteins that, when mutated, cause familial Alzheimer's disease (AD), is controversial. We have discovered that mitochondria-associated membranes (MAM) – a specialized subcompartment of the endoplasmic reticulum (ER) involved in lipid metabolism and calcium homeostasis that physically connects ER to mitochondria – is the predominant subcellular location for PS1 and PS2, and for γ-secretase activity. We hypothesize that presenilins play a role in maintaining MAM function, and that not only altered amyloid-β levels and hyperphosphorylated tau, but also many other features of AD (e.g., altered phospholipid and cholesterol metabolism, aberrant calcium …homeostasis, and abnormal mitochondrial dynamics) result from compromised MAM function. The localization of presenilins and γ-secretase in MAM may help reconcile disparate ideas regarding the pathogenesis of AD, under a unifying hypothesis that could explain many features of both sporadic and familial AD, thereby taking AD research in a new and fruitful direction. Show more

Keywords: Alzheimer's disease, calcium, cholesterol, endoplasmic reticulum (ER), mitochondria, mitochondria-associated membranes (MAM), phospholipids

DOI: 10.3233/JAD-2010-100495

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S281-S292, 2010

Authors: Coskun, Pinar E. | Wyrembak, Joanne | Derbereva, Olga | Melkonian, Goar | Doran, Eric | Lott, Ira T. | Head, Elizabeth | Cotman, Carl W. | Wallace, Douglas C.

Article Type: Research Article

Abstract: Increasing evidence is implicating mitochondrial dysfunction as a central factor in the etiology of Alzheimer's disease (AD). The most significant risk factor in AD is advanced age and an important neuropathological correlate of AD is the deposition of amyloid-β peptide (Aβ40 and Aβ42 ) in the brain. An AD-like dementia is also common in older individuals with Down syndrome (DS), though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) control region (CR) mutations accumulate with age in post-mitotic tissues including the brain and that the level of mtDNA mutations is markedly elevated in the …brains of AD patients. The elevated mtDNA CR mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. We now show that mtDNA CR mutations increase with age in control brains; that they are markedly elevated in the brains of AD and DS and dementia (DSAD) patients; and that the increased mtDNA CR mutation rate in DSAD brains is associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD and DSAD patients, and distinctive somatic mtDNA mutations, often at high heteroplasmy levels, are seen in AD and DSAD brain and blood cells DNA. In aging, DS, and DSAD, the mtDNA mutation level is positively correlated with β-secretase activity and mtDNA copy number is inversely correlated with insoluble Aβ40 and Aβ42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD. Show more

Keywords: Alzheimer's disease, amyloid-β, AβPP, control region, dementia, Down syndrome, mitochondria, mitochondrial dysfunction, mtDNA

DOI: 10.3233/JAD-2010-100351

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S293-S310, 2010

Authors: Shi, Ping | Wei, Yanming | Zhang, Jiayu | Gal, Jozsef | Zhu, Haining

Article Type: Review Article

Abstract: A better understanding of the etiology of amyotrophic lateral sclerosis (ALS) is needed to develop effective therapies for the treatment of this fatal neurodegenerative disease. Extensive studies have produced a general agreement that ALS is likely to be a multifactorial and multisystem disease. Many mechanisms have been postulated to be involved in the pathology of ALS, such as oxidative stress, glutamate excitotoxicity, mitochondrial damage, defective axonal transport, glia cell pathology, and aberrant RNA metabolism. Mitochondria have shown to be an early target in ALS pathogenesis and contribute to the disease progression. Morphological and functional defects in mitochondria were found in …both human patients and ALS mice overexpressing mutant SOD1. Mutant SOD1 was found to be preferentially associated with mitochondria and subsequently impair mitochondrial function. Recent studies suggest that axonal transport of mitochondria along microtubules is disrupted in ALS. Furthermore, new evidence suggests that mitochondrial fission and fusion as well as mitophagy clearance may also be affected by mutant SOD1. These results also illustrate the critical importance of maintaining proper mitochondrial function in axons and neuromuscular junctions, supporting the emerging "dying-back" axonopathy model of ALS. In this review, we will discuss findings supporting that mitochondrial dysfunction is likely to be a converging point of multiple pathways underlying the ALS pathogenesis and progression. Show more

Keywords: Amyotrophic lateral sclerosis, autophagy, axonal transport, mitochondrial dynamics, mitochondrial function, mutant SOD1

DOI: 10.3233/JAD-2010-100366

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S311-S324, 2010

Authors: Zhu, Jianhui | Chu, Charleen T.

Article Type: Review Article

Abstract: It is clear from a striking convergence of human tissue studies, neurotoxin models, and genetic models that mitochondrial dysregulation plays a central pathogenic role in Parkinson's disease (PD) and related neurodegenerative conditions. Impaired mitochondrial quality could result from both increased damage and decreased ability to repair or clear damaged mitochondria. In particular, common deficits in mitochondrial respiratory chain function, oxidative stress, morphology/dynamics, and calcium handling capacities have been described in multiple PD model systems employing complex I inhibitors, 6-hydroxydopamine and molecular manipulation of Parkinsonian genes including α-synuclein, PTEN-induced kinase 1, Parkin, DJ-1, and, to a lesser extent, leucine rich repeat …kinase 2. The most recent and exciting work implicates alterations in the regulation of macroautophagy and likely of selective mitophagic clearance of damaged mitochondria, although additional studies are needed to resolve some issues in this area. Future studies emphasizing the normal mitoprotective function(s) of proteins associated with recessive loss-of-function causes of familial PD, as well as compensatory mechanisms operating in their absence, may offer particularly valuable insights into strategies to enhance mitochondrial health. Show more

Keywords: Autophagy, calcium dysregulation, electron transport chain, 1-methyl-4-phenylpyridinium (MPP+), mitochondria, mitophagy, neurodegeneration, oxidative stress, Parkinson's disease, PTEN-induced kinase 1

DOI: 10.3233/JAD-2010-100363

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S325-S334, 2010

Authors: Martin, Lee J.

Article Type: Review Article

Abstract: Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS) are the second and third most common human adult-onset neurodegenerative diseases, respectively, after Alzheimer's disease. They are characterized by prominent age-related neurodegeneration in selectively vulnerable neural systems. Some forms of PD and ALS are inherited, and genes causing these diseases have been identified. Morphological, biochemical, and genetic, as well as cell and animal model, studies reveal that mitochondria could have a role in this neurodegeneration. The functions and properties of mitochondria might render subsets of selectively vulnerable neurons intrinsically susceptible to cellular aging and stress and overlying genetic variations. In PD, mutations …in putative mitochondrial proteins have been identified and mitochondrial DNA mutations have been found in neurons in the substantia nigra. In ALS, changes occur in mitochondrial respiratory chain enzymes and mitochondrial cell death proteins. Transgenic mouse models of human neurodegenerative disease are beginning to reveal possible principles governing the biology of selective neuronal vulnerability that implicate mitochondria and the mitochondrial permeability transition pore. This review will present how mitochondrial pathobiology might contribute to neurodegeneration in PD and ALS and could serve as a target for drug therapy. Show more

Keywords: Adenine nucleotide translocator, apoptosis, cell death, cyclophilin D, excitotoxicity, mitochondrial permeability transition pore, motor neuron, ppif voltage-dependent anion channel

DOI: 10.3233/JAD-2010-100348

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S335-S356, 2010

Authors: Patten, David A. | Germain, Marc | Kelly, Melissa A. | Slack, Ruth S.

Article Type: Review Article

Abstract: Neuronal cell loss associated with neurodegeneration has recently been linked to mitochondrial dysfunction. Electron transport chain defects and reactive oxygen species (ROS) production are emerging as important players in the etiology of neurodegenerative diseases. Proper management of ROS and disposal of damaged cellular components are vital to the survival and function of neurons. Proteins involved in these pathways are often mutated in neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. In this review, we will discuss the roles of ROS in normal physiology, how changes in ROS production affect neuronal survival in neurodegenerative diseases, …and the recent advances in mitochondrial antioxidants as potential therapeutics. Show more

Keywords: Apoptosis, autophagy, mitochondria, neurodegeneration, reactive oxygen species

DOI: 10.3233/JAD-2010-100498

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S357-S367, 2010

Authors: Di Filippo, Massimiliano | Chiasserini, Davide | Tozzi, Alessandro | Picconi, Barbara | Calabresi, Paolo

Article Type: Review Article

Abstract: The innate immune response is thought to exert a dichotomous role in the brain. Indeed, although molecules of the innate immune response can promote repair mechanisms, during neuroinflammatory processes many harmful mediators are also released. Signs of neuroinflammation and neurodegeneration represent a ubiquitous pathological finding during the course of several different neurological diseases. Interestingly, it has been proposed that mitochondria may exert a crucial role in the pathogenesis of both inflammatory and neurodegenerative central nervous system disorders. In this review, we describe the mechanisms by which neuroinflammation and mitochondrial impairment may synergistically trigger a vicious cycle ultimately leading to neuronal …death. In particular, we describe the close relationship existing among neuroinflammation, neurodegeneration, and mitochondrial impairment in three different widely-diffused neurological diseases in which these pathogenetic events coexist, namely multiple sclerosis, Parkinson's disease, and Alzheimer's disease. Show more

Keywords: Inflammation, mitochondria, multiple sclerosis, neurodegeneration, Parkinson's disease

DOI: 10.3233/JAD-2010-100543

Citation: Journal of Alzheimer's Disease, vol. 20, no. s2, pp. S369-S379, 2010