Mitochondrial Function as a Therapeutic Target for Alzheimer's Disease

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Mitochondrial Function as a Therapeutic Target for Alzheimer's Disease

Thursday, May 13, 2010

New York Academy of Sciences Conference Center

Presented By

Presented by the Alzheimer's Drug Discovery Foundation, the Brain Dysfunction Discussion Group and The New York Academy of Sciences

 

Growing evidence indicates that mitochondrial dysfunction is one of the key intracellular mechanisms associated with the pathogenesis of Alzheimer's disease. The role of mitochondria as regulators of energy metabolism and cell death pathways makes it crucial to neuronal cell survival or death. The goal of this conference is to critically examine potential drug therapeutics for mitochondrial dysfunction in Alzheimer’s disease. Recent findings from basic, clinical, and translational research will be presented in a forum designed to stimulate discussion of mitochondrial function and its relationship to age-related neurodegenerative disease, in particular, Alzheimer’s disease and its treatment.

Networking reception to follow.

Photo credit: Odra Noel

Agenda


Thursday, May 13, 2010

8:00 AM

Registration & Continental Breakfast

8:45 AM

Welcome & Opening Remarks
Sonya Dougal, PhD, The New York Academy of Sciences
Howard M. Fillit, MD, Alzheimer's Drug Discovery Foundation

Session I: Overview of Mitochondria

9:00 AM

Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer Disease and Down Syndrome Dementia
Douglas C. Wallace, PhD, University of California, Irvine

9:30 AM

Mitochondria and Oxidative Stress in Alzheimer Disease
Xiongwei Zhu, PhD, Case Western Reserve University

10:00 AM

Aging, Caloric Restriction and the Mitochondria
Tomas A. Prolla, PhD, University of Wisconsin – Madison

10:30 AM

Break

11:00 AM

Mitochondrial Division and Neurodegeneration
Hiromi Sesaki, PhD, The Johns Hopkins University School of Medicine

11:30 AM

A Mitocentric View of Alzheimer’s Disease suggests that Abnormalities in Mitochondria and Oxidative Stress are Early Changes and Therapeutic Targets in Alzheimer’s Disease
Gary Gibson, PhD, Weill Medical College of Cornell University

12:00 PM

Lunch

Session II: Therapeutics for Mitochondrial Dysfunction in Alzheimer's Disease

1:00 PM

Amyloid beta Toxicity, Mitochondrial Dysfunction and Synaptic Damage in Alzheimer’s disease: Implications for Mitochondria-Targeted Antioxidant Therapeutics
P. Hemachandra Reddy, PhD, Oregon Health & Science University

1:30 PM

Mitochondrial Approaches to the Treatment of Alzheimer's Disease
M. Flint Beal, MD, Weill Medical College at Cornell University

2:00 PM

Implications of TOMM40 Variants and Risk for Alzheimer's Disease for Therapeutic Intervention
William Kirby Gottschalk, PhD, Duke University

2:30 PM

Break

3:00 PM

S-Nitrosylation/Redox Control of Protein Misfolding, Mitochondrial Fragmentation, and Neuronal Synaptic Damage in Neurodegenerative Diseases
Stuart A. Lipton, MD/PhD, Sanford-Burnham Institute for Medical Research

3:30 PM

Mitochondrial Pore and Synaptic Function in Alzheimer disease: Role of Cyclophilin D
Shi Du Yan, PhD, Taub Institute of Columbia University

4:00 PM

PPAR-Sparing, Mitochondrial Targeting Thiazolidinediones (TZDs) for the Treatment of Alzheimer's Disease
Jerry R. Colca, PhD, Metabolic Solutions Development Company

4:30 PM

Closing Remarks
Howard M. Fillit, MD, Alzheimer's Drug Discovery Foundation

5:00 PM

Networking Reception

Speakers

Organizers

Howard M. Fillit

Alzheimer's Drug Discovery Foundation

Sonya Dougal

The New York Academy of Sciences

Speakers

M. Flint Beal

Weill Medical College of Cornell University

Dr. M. Flint Beal is an internationally recognized authority on neurodegenerative disorders. He is the Anne Parrish Titzell Professor in the Department of Neurology and Neuroscience at the Weill Medical College of Cornell University - New York Presbyterian Hospital. Dr. Beal received his medical degree from the University of Virginia in 1976 and did his internship and first year residency in Medicine at New York-Cornell before completing his residency in Neurology at The Massachusetts General Hospital. He joined the neurology faculty at Harvard in 1983. Dr. Beal was Professor of Neurology at the Harvard Medical School and Chief of the Neurochemistry laboratory at Massachusetts General Hospital before moving to Cornell. Dr. Beal’s research has focused on the mechanism of neuronal degeneration in Alzheimer’s Disease, Huntington’s Disease, Parkinson’s Disease and amyotrophic lateral sclerosis (ALS). Dr. Beal is the author or co-author of more than 400 scientific articles and more than 125 books, book chapters and reviews. He serves on the editorial boards of seven journals, including the Journal of Neurochemistry, the Journal of Neurological Sciences, Journal of Molecular Neuroscience, Experimental Neurology and Neurobiology of Disease. He is a co-editor of the “Dana Guide to Brain Health”. Dr. Beal is a member of the Alpha Omega Alpha Medical Honorary Society and received the Derek Denny-Brown Neurological Scholar Award of the American Neurologic Association. He has served on the Council of the American Neurologic Association and on the Science Advisory Committees of the Hereditary Disease Foundation, Huntington’s Disease Society of America, Parkinson’s Disease Study Group, Parkinson’ Disease Foundation, Bachman-Strauss Foundation, The ALS Association, and the American Health Assistance Foundation. Dr. Beal is a member of the Institute of Medicine of the National Academy of Sciences.

Jerry R. Colca

Metabolic Solutions Development Company

Jerry Colca, PhD, is a co-founder, part owner, and President/Chief Scientific Officer of Metabolic Solutions Development Company (MSDC; msdrx.com) in Kalamazoo, MI. Jerry has spent his professional career studying the endocrine control of metabolism as relates to diabetes. He has a BS in Biology and MS and PhD in Physiology and Biochemistry from the University of Houston where he studied the regulation of secretion of pancreatic hormones. His post doctoral training at Washington University concentrated on the biochemistry of isolated pancreatic islets and the study of stimulus-secretion coupling in the control of metabolism. Jerry joined the Upjohn Company in 1984 to study to the mechanism of action of the thiazolidinediones and was instrumental in selection and development of pioglitazone hydrochloride (Actos®) as an anti-diabetic agent through Phase 2A clinical studies. The company formally known as Upjohn exited the insulin sensitizing field in 1993. Jerry remained with the Upjohn Company through the mergers with Pharmacia, Monsanto-Searle, and Pfizer until he retired from the merged company in 2005. During this time he was leader of diabetes discovery team in Kalamazoo, helped build a new diabetes discovery effort in Sweden after the merger with Pharmacia, and finally building a new targets discovery effort in St. Louis after the Pfizer merger. Jerry has been interested in the mechanism of action of the insulin sensitizer TZDs from the early days of their discovery and especially in the safety and pharmacology of pioglitazone. In January of 2006, Jerry co-founded MSDC with Dr. Rolf Kletzien to take advantage of their unique insight into these molecules.

Gary E. Gibson

Weill Cornell Medical College at Burke Medical Research Institute

Dr. Gary E. Gibson received his BS degree in zoology and chemistry from the University of Wyoming. He received his PhD in physiology with emphasis in biochemistry and neuroscience at Cornell University. He did his postdoctoral work at UCLA and was on the faculty at UCLA. He then moved to Cornell University Medical College and Burke Medical Research Institute. He is currently Professor of Neuroscience, and is also a member of the graduate program in Neuroscience at Cornell Medical College. He also served as the Associate Director of the Dementia Research Service. Dr. Gibson received the American Society for Neurochemistry award for outstanding young investigator. He has given lectures at many institutions and honorary lectures including the Deans hour at Cornell University Medical College, the NIH Director's Talk and the Visek Lectureship at the University of Illinois. He has served on over 25 NIH grant review panels and regularly reviews grants for the Alzheimer Association. He is a member of numerous scientific societies and was the secretary of the American Society for Neurochemistry. He has served(s) on the editorial board of several journals including Neurochemical Research, Neurochemistry International, the Journal of Neurochemistry, Mitochondria and the Journal of Alzheimer’s Disease. He has been continuously funded by NIH grants for his whole career at Cornell/Burke. Within the last three years he has edited three volumes on the role of mitochondria and energy metabolism in the brain including a NY Academy of Sciences volume (#1147). Many of his 157 research papers and 76 reviews reflect his long research interest in the role of calcium and mitochondria in normal brain function as well as in Alzheimer’s disease and other age-related neurodegenerative diseases.

William Kirby Gottschalk

Duke University

I received my Ph.D. under David Sonneborn at the University of Wisconsin – Madison, working on an aquatic fungus, Blastocladiella emersonii, which possesses only a single, albeit large, mitochondria during an important phase of its life cycle. Although my work didn’t involve Blasto’s mitochondria I was never-the-less “hooked” and the bulk of my career since then has focused on cellular and mitochondrial physiology. I have conducted extensive research on the effects of physiological and pharmacological perturbations on mitochondrial function, in both Academia and private industry. Beginning with my post-doctoral training at the University of Pennsylvania, I investigated the mechanism of insulin regulation of mitochondrial function, including respiration and enzymes of the TCA cycle, oxidative phosphorylation and substrate transport, both in vivo with primary cells and ex vivo, with the goal of understanding how mitochondrial function contributed to insulin resistance. As Senior Investigator at GlaxoSmithKine I headed a research group who designed and implemented mitochondrial functional assays for target validation, mechanism-of-action studies, and drug toxicology studies. As a member of the Alzheimer’s team at GSK, I led the work that first showed that PPARγagonists enhance cerebral glucose metabolism in vivo.

Stuart A. Lipton

Sanford|Burnham Institute for Medical Research

Stuart A. Lipton, MD, PhD, Professor, and Scientific Director, Del E. Webb Center for Neuroscience, Aging, and Stem Cell Research, Sanford | Burnham Institute for Medical Research; Professor, The Salk Institute, The Scripps Research Institute, and the University of California, San Diego. Educated at three Ivy League universities, Dr. Lipton is a research scientist and, clinical neurologist. He completed his clinical and scientific training at Harvard as a postdoctoral fellow with Professor Torsten N. Wiesel when Wiesel won the Nobel Prize. Dr. Lipton then spent 25 years on the faculty at Harvard before moving to La Jolla in the fall of 1999. He is best known for discovering the mechanism of action and contributing to the clinical development of the latest FDA-approved treatment for Alzheimer’s disease (memantine/Namenda). His group also characterized the molecular pathways for protecting nerve cells by Erythropoietin (a drug marketed for the treatment of anemia). Lipton and collaborator Stamler discovered the chemical reaction termed S-nitrosylation as a ubiquitous redox-regulator of protein function. Additionally, Lipton was the first to clone and characterize the transcription factor MEF2C, and showed that it is a redox-regulated master swtich for the generation of new nerve cells (termed neurogenesis) from human ESCs and iPSCs. Lipton’s group has also shown that dysregulation of MEF2C is involved in the etiology of autism-spectrum disorders. In 2004, Dr. Lipton won the Ernst Jung Prize in Medicine, considered one of the top five or six medical prizes worldwide.

Tomas A. Prolla

University of Wisconsin-Madison

Tomas A. Prolla, Ph.D, received his B.S in Biochemistry from the University of California at Berkeley in 1990, and his Ph.D from the Department of Molecular Biophysics and Biochemistry at Yale University in 1994. He is currently Professor of Genetics & Medical Genetics at the University of Wisconsin-Madison. Dr. Prolla is internationally recognized for research in two main areas, gene expression changes associated with aging, and the role of mitochondria in aging. Dr. Prolla’s research group was the first to employ large-scale gene expression profiling using DNA microarrays to the analysis of aging and its retardation by caloric restriction. Dr. Prolla has also generated a widely used mouse model of aging, mice with a defective DNA polymerase gamma that result in the accumulation of mitochondrial DNA mutations. Recently, Dr. Prolla has focused on the role of mitochondria and associated apoptotic signaling in specific aspects of aging, including age-related hearing loss and sarcopenia. Dr. Prolla has also co-founded LifeGen Technologies in 2001, a company focused on the use of transcriptional markers of aging and caloric restriction in the development of aging interventions.

P. Hemachandra Reddy

Oregon Health & Science University

P. Hemachandra Reddy is an Associate Scientist in the Division of Neuroscience at the Oregon National Primate Research Center of Oregon Health and Science University (OHSU). He received his B.Sc. and M.Sc. in biology from Sri Venkateswara University, Tirupati, India. He received an M.Phil in human cytogenetics from Delhi University. He was a commonwealth scholar (1990-1993) before receiving his Ph.D. (1994) in human genetics from London University. He did his postdoctoral training (1995-2000) at the National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland. After his postdoctoral training, he joined the OHSU-Neurological Sciences Institute Faculty in July 2000, and joined the primate center in July 2008. Dr. Reddy has received several awards and honors, including Commonwealth Scholarship from Commonwealth Commission, Great Britain; Fellows Award for Research Excellence from National Institutes of Health; Alzheimer Award from the Journal of Alzheimer’s Disease, and Technology Innovations Award from Oregon Health and Science University. Dr. Reddy is a standing member of the Veteran Affairs Merit Review Study Section, and has served on several NIH study sections, including the section Cell Death in Neurodegeneration. Dr. Reddy is an associate editor of Frontiers in Aging Neuroscience and has been a guest editor for special issues of Frontiers in Aging Neuroscience and Pharmaceuticals: 1) Synaptic Damage in Aging and Neurodegenerative Diseases (Frontiers in Aging Neuroscience), 2) Mitochondrial Drugs for Neurodegenerative Diseases (Pharmaceuticals) and 3) Genes, Mechanism and Drugs for Asthma (Pharmaceuticals). Dr. Reddy is an editorial board member for seven journals. Dr. Reddy is an expert in mitochondrial biology and function, gene expression analysis, and neurodegenerative diseases. The research focus in the Reddy laboratory is on understanding molecular and cellular bases of neurodegenerative diseases such as Alzheimer’s disease (AD). Currently, the Reddy laboratory is focusing on unraveling the connection between amyloid beta and synaptic damage, and amyloid beta and mitochondrial oxidative damage in AD. The Reddy laboratory is funded by National Institutes of Health, Alzheimer’s Association, Vertex Pharmaceuticals, Medivation and KaloBios Pharmaceuticals.

Hiromi Sesaki

Johns Hopkins University School of Medicine

Dr. Hiromi Sesaki received his PhD from the Department of Physiology at Osaka University in Japan. He is currently Assistant Professor of Cell Biology at the Johns Hopkins University School of Medicine. The laboratory of Dr. Sesaki is studying mitochondrial dynamics and membrane biogenesis using yeast and mice. The website for his laboratory is www.hopkinsmedicine.org/cellbio/dept/SesakiProfile.html

Douglas C. Wallace

University of California Irvine

Douglas C. Wallace, Ph.D., Donald Bren Professor of Molecular Medicine, Director, ORU for Molecular and Mitochondrial Medicine and Genetics (MAMMAG), Professor of Biological Chemistry, Ecology and Evolutionary Biology, and Pediatrics. Douglas C. Wallace has been a pioneer in the study of human mitochondrial genetics and the role of mitochondrial DNA variation in human evolution, disease, cancer, and aging. In the 1970s Dr. Wallace defined the basic principles of human mitochondrial DNA genetics, demonstrating that the human mitochondrial DNA encodes heritable traits, is maternally transmitted, has a high mutation rate, that intracellular mixtures on mutant and normal mitochondrial DNA are common and can segregate randomly during both mitotic and meiotic cell division, and that the clinical phenotype of a mutation depends on the severity of the mitochondrial defect and the reliance of each individual tissue on mitochondrial energy production. Once Dr. Wallace had defined the basic principles of mitochondrial DNA genetics, he applied these principles to the investigation of human origins and disease. Dr. Wallace also identified the first maternally inherited mitochondrial DNA diseases and has subsequently shown that deleterious mitochondrial DNA mutations are common and result in a plethora of complex multi-system diseases which encompasses all of the clinical phenotypes associated with aging, including neurological problems such as deafness, blindness, movement disorders, and dementias; cardiovascular disease; muscle degeneration and pain; renal dysfunction; endocrine disorders including diabetes, cancer, etc.

Shi Du Yan

Taub Institute of Columbia University

Shi Du Yan (Shirley ShiDu Yan), MD, is a Professor, Department of Pathology and Surgery, Taub Institute for Research on Alzheimer’s disease and the Aging Brain, Columbia University, New York. Dr. Yan’s research focuses on investigating cellular and molecular mechanisms of cell stress and survival in neurodegenerative disorders relevant to Alzheimer’s disease. She was the first to identify the specific cellular (RAGE) and mitochondrial (ABAD and cyclophilin D) targets of amyloid-beta peptide (Aβ) and found the evidence of Aβ-mediated mitochondrial, synaptic, and neuronal dysfunction. Her recent studies highlight the significant impact of mitochondrial Aβ on neuronal stress and cognitive decline relevant to the pathogenesis of Alzheimer disease. Dr. Yan and her research team‘s findings have been published in worldwide leading Journals including Nature, Science, Nature Medicine, Proceeding of National Academy Sciences, and first class of the professional Journals. Dr. Yan has authored 140 publications. Her research project is supported by NIH. She is the member of the scientific review committee for the Institute for the Aging and Alzheimer’s Association.

Xiongwei Zhu

Case Western Reserve University

Dr. Xiongwei Zhu received his B.S. in 1995 and M.S. in 1998 from the Department of Biochemistry at Wuhan University in China. He received his Ph.D. in 2002 from the Department of Pathology at Case Western Reserve University. He became Assistant Professor in 2004 and rose to Associate Professor in 2009. Dr. Zhu’s research focuses on the mitochondrial dysfunction in Alzheimer disease and other neurodegenerative diseases and his research program is supported by National Institute of Health, Alzheimer’s Association and American Parkinson Disease Association. Dr. Zhu is the recipient of several awards including the Junior Faculty Award from 9th International Conference on Alzheimer Disease and Parkinson Disease (2009), and the Young Investigator Lectureship Award from the International Society for Neurochemistry (2009).

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Abstracts

Systemic Mitochondrial Dysfunction and the Etiology of Alzheimer Disease and Down Syndrome Dementia

Douglas C. Wallace, University of California Irvine

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 beta-peptide (Aβ40 & Aβ42) in the brain. An AD-like dementia is also common in older Down Syndrome (DS) patients, though with a much earlier onset. We have shown that somatic mitochondrial DNA (mtDNA) 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 control region (CR) mutations in AD brains are associated with a reduction in the mtDNA copy number and in the mtDNA L-strand transcript levels. Furthermore, mtDNA CR mutations are markedly elevated in the brains of DS and dementia (DSAD) patients, relative to age matched controls and younger DS patients, and the increased DSAD mtDNA CR mutation rate is also associated with reduced mtDNA copy number and L-strand transcripts. The increased mtDNA CR mutation rate in both AD and DSAD patients is also seen in peripheral blood DNA and in lymphoblastoid cell DNAs of AD demonstrating that the elevated somatic mtDNA mutation rate is a systemic feature associated with the dementia and not simply a by product of Aβ deposition. Distinctive somatic mtDNA mutations are seen in aging, AD and DSAD brains and blood cell DNAs, and many of these mutations preferentially alter known functional mtDNA transcription and replication regulatory elements. Finally, in brains of increasing ages, the mtDNA mutation level of control, DS, and DSAD samples is positively correlated with β-secretase activity and mtDNA copy number is inversely correlated with insoluble Aβ40 & Aβ42 levels. Therefore, mtDNA alterations may be responsible for both age-related dementia and the associated neuropathological changes observed in AD and DSAD.

Mitochondria and Oxidative Stress in Alzheimer Disease

Xiongwei Zhu, Case Western Reserve University

Alzheimer disease (AD) is characterized by the degeneration of select neuronal populations in the hippocampus and other cortical brain regions. Oxidative stress is the result in an imbalance between the generation and detoxification of reactive oxygen species (ROS). Multiple lines of evidence support an early pathogenic role for oxidative stress in AD such that oxidative stress temporally precedes and contributes to the formation of pathological lesions of the disease and oxidative damage involves all categories of biological macromolecules. ROS generation is the unavoidable byproduct of aerobic respiration. As the predominant site of oxidative/energy metabolism within the cell, mitochondria make a significant contribution to oxidative damage and related events. Extensive evidence indicates that cerebral metabolism is reduced, placing mitochondrial dysfunction at the source of increased oxidative stress in AD. In this regard, abnormal mitochondria are a predominant feature in AD and damage to both the components and the structure of mitochondria occur. Also, enhanced mitochondrial fission likely contributes to mitochondrial damage and oxidative stress. Interactions between abnormal mitochondria and disturbed metal homeostasis are likely responsible, at least in part, for cytoplasmic oxidative damage. Evidence for oxidative stress and its likely sources and consequences in relationship to other pathological changes in AD will be discussed.

Aging, Caloric Restriction and the Mitochondria

Tomas A. Prolla, University of Wisconsin-Madison

We have previously used large-scale gene expression profiling to obtain a global view of key molecular events associated with the aging process and its retardation by caloric restriction. Our studies have uncovered evidence for the activation of a mitochondrial apoptotic program in several tissues with aging. Gene expression profiling of caloric restriction suggests reduced endogenous damage, and inhibition of apoptotic pathways. Based on these observations, we are testing the role of the two key mitochondrial apoptotic factors Bak and Bax in aging phenotypes. Age-related hearing loss (AHL) is the most common sensory disorder in humans, and it has been reported in several mammalian species. In mice, AHL is often associated with loss of hair cells and spiral ganglion neurons, and caloric restriction can profoundly inhibit the process. We have shown that AHL requires the pro-apototic protein Bak, and can be inhibited by a mitochondrially targeted catalase transgene or mitochondrial dietary antioxidants. These observations support the role of reduced oxidative stress and apoptotic signaling as key mechanisms of aging retardation by CR. We propose that these mechanisms may underlie the beneficial effects of CR as a preventive approach to AD.

Mitochondrial Division and Neurodegeneration

Hiromi Sesaki, Johns Hopkins University School of Medicine

Mitochondria are highly dynamic organelles that continuously fuse and divide within cells. A balance between mitochondrial fusion and division is critical for the maintenance of normal mitochondrial structures and cellular physiology. For example, defects in mitochondrial fusion typically result in mitochondrial fragmentation due to excessive division. On the other hand, defects in mitochondrial division produce highly connected mitochondrial tubules due to excessive mitochondrial fusion. Normal mitochondrial dynamics is critical for human health and disease. Mitochondrial fusion defects cause human neuropathies, including autosomal dominant optic atrophy and Charcot-Marie-Tooth disease type 2A. Abnormalities in division are also implicated in Charcot-Marie-Tooth type 4A, Parkinson's disease and Alzheimer's disease. The neurodegeneration associated with these diseases suggests that neuronal function and survival depend on mitochondrial dynamics. We are studying mitochondrial fusion and division using complete and tissue-specific mouse knockouts. In this meeting, we will discuss physiological functions of Drp1, a dynamin-related GTPase that mediates mitochondrial division.

A Mitocentric View of Alzheimer’s Disease suggests that Abnormalities in Mitochondria and Oxidative Stress are Early Changes and Therapeutic Targets in Alzheimer’s Disease

Gary Gibson, Weill Cornell Medical College at Burke Medical Research Institute

Alzheimer’s disease (AD) is defined by plaques made of amyloid-β peptide (Aβ), tangles made of hyper-phosphorylated tau proteins and memory deficits. Thus, the events initiating the cascade leading to these end points may be more effective therapeutic targets than treating each facet individually. In the small percentage of cases of AD that are genetic (or animal models that reflect this form of AD), the factor initiating AD is clear (e.g. genetic mutations that lead to high Aβ1-42 ). In the vast majority of AD cases, the cause is unknown. Substantial evidence now suggests that abnormalities in Glucose metabolism/Mitochondrial function/Oxidative stress (GMO) are an invariant feature of AD and occur at early stage of the disease process in both genetic and non-genetic forms of AD. Indeed, decreases in brain glucose utilization are diagnostic for AD. Changes in calcium homeostasis also precede clinical manifestations of AD. Experiments in animal and tissue culture models demonstrate that abnormal GMO can lead to the plaques, tangles and the calcium abnormalities that accompany AD. Abnormalities in GMO diminish the ability of the brain to adapt. Therapies targeting GMO may ameliorate the abnormalities in plaques, tangles, calcium homeostasis and cognition that comprise AD. (Supported by NIH and “Institute for the Study of Aging & Alzheimer's Drug Discovery Foundation”)

Amyloid beta Toxicity, Mitochondrial Dysfunction and Synaptic Damage in Alzheimer’s disease: Implications for Mitochondria-Targeted Antioxidant Therapeutics

P. Hemachandra Reddy, Oregon Health & Science University

Alzheimer’s disease (AD) is a late-onset mental illness that is characterized by the loss of memory and an impairment of multiple cognitive functions. Synaptic pathology and mitochondrial oxidative damage have been identified as early events in AD progression. We have conducted a time-course global gene expression analysis using cortical tissues from AD transgenic mice (Tg2576 line), and our gene array analysis revealed an up-regulation of mitochondrial genes in AD transgenic mice, suggesting that mitochondrial metabolism is impaired by mutant APP/Aß and that the up-regulation of mitochondrial genes may be a compensatory response to mutant APP/Aß. We also found abnormal mitochondrial gene expressions in AD postmortem brains. Recently, we and others found that Aß is associated with mitochondria and is responsible for generating free radicals and initiating mitochondrial dysfunction. Further, using mouse neuroblastoma (N2a) cells incubated with Aß peptide and primary neurons from AD transgenic mice, we investigated the connection between Aß and mitochondrial structure/function and neurite outgrowth. We also investigated the effects of mitochondria-targeted antioxidants, MitoQ and SS31 using AD transgenic mice primary neurons and N2a cells incubated with Aß. In N2a cells only incubated with the Aβ, we found increased expressions of mitochondrial fission genes (Drp1, Fis1) and decreased expression of fusion genes (Mfn1, Mfn2 and Opa1) and also decreased expression of endogenous antioxidant enzymes, peroxiredoxins 1-6. Electron microscopy of the N2a cells incubated with Aβ revealed a significantly increased number of mitochondria, indicating that Aβ fragments mitochondria. Biochemical analysis revealed that function is defective in mitochondria. Neurite outgrowth was significantly decreased in Aβ-incubated N2a cells, indicating that Aβ affects neurite outgrowth. However, mitochondrial structural and functional changes were rescued/prevented in primary neurons from AD transgenic mice and Aβ-incubated N2a cells that were treated with mitochondria-targeted antioxidants, MitoQ and SS31. Neurite outgrowth was significantly increased and cyclophilin D expression was significantly decreased in primary neurons treated with MitoQ and SS31. These findings suggest that MitoQ and SS31 prevent Aβ toxicity and increase synaptic connectivity, which would warrant the study of MitoQ and SS31 as potential drugs to treat patients with AD.

Mitochondrial Approaches to the Treatment of Alzheimer's Disease

M. Flint Beal, Weill Medical College of Cornell University

We carried out studies, which established that both mitochondrial dysfunction and oxidative damage occur in Alzheimer's Disease (AD) post mortem brain tissue. There was a marked age-dependent increase in levels of 8-hydroxy-2-deoxyguanosine, a marker of oxidative damage to DNA, in mitochondrial DNA from AD subjects. Crossing presenilin/APP AD mice with mice deficient in inducible nitric oxide synthase attenuated the amyloid deposition and improved overall survival. We also used the Tg19559 mouse model of AD, which has two mutations in the amyloid precursor protein. In these mice thioflavin positive A—deposits occur at three months of age, and dense core plaques and neuritic pathology from 5 months of age. We crossed these mice with mice having a partial deficiency of manganese superoxide dismutase (MnSOD). This markedly exacerbated A—deposition, providing direct evidence of a link between A—deposition and oxidative damage. Furthermore, we crossed mice, which overexpress MnSOD, with the Tg19959 mice. This markedly attenuated the deposition of A—and improved memory in the Morris Water Maze test. Coenzyme Q10 (CoQ10) significantly reduced levels of A—1-42, and numbers of A—plaques, and amyloid burden, in both cerebral cortex and hippocampus. It significantly improved performance in the Morris Water Maze test of memory. We recently studied triterpenoids, a group of compounds, which activate the Nrf2/ARE pathway. This is a transcriptional pathway, which leads to upregulation of a large number of antioxidant enzymes, including enzymes which synthesize glutathione. TP224 to our AD mice significantly increased hemoxygenase 1, a target of Nrf2/ARE. Administration of TP224 reduced protein carbonyl levels, as well as numbers of plaques and the amyloid burden in our AD mice. Furthermore, TP224 significantly improved memory as assessed using the Morris Water Maze test. These studies show that there is a direct link between oxidative damage produced by mitochondria, amyloid deposition and memory dysfunction in a transgenic mouse model of AD. Pharmacologic interventions such as Coenzyme Q10, or triterpenoids, significantly attenuate the A—deposition, A—levels and memory dysfunction.

Implications of TOMM40 Variants and Risk for AD for Therapeutic Intervention

William Kirby Gottschalk, Duke University

PET scanning recognition that cerebral energy metabolism is compromised in AD patients and, moreover, in individuals at risk for developing AD years before clinical manifestation of disease has focused efforts on identifying the possible causes of this hypometabolism. Because mitochondria play a central role in energy metabolism they have been the focus of much of this work. One hoped for outcome of these efforts is identification of tractable therapeutic targets for treating or delaying the onset of AD. Genetic factors contribute significantly to the predisposition to late-onset AD (LOAD) and we have used genetic analysis to understand the etiology of LOAD and identify potential therapeutic targets. The APOE e4 allele had been the strongest, and is most highly replicated, genetic factor for LOAD. However a newly discovered, highly polymorphic poly-T variant of TOMM40 (rs10524523), which is the immediately adjacent gene to APOE, is predictive of age of disease onset. TOMM40 encodes the mitochondrial protein import translocase (Translocase of the Outer Mitochondrial Membrane, 40kD) and is essential for the life and death of mitochondria. There are three size classes of polyT variants. APOEe4 is, almost without exception, linked to a long poly-T repeat (>20 dT), accounting for its replicated effects. The association of APOE e3 with the poly-T variant is biphasic: association with the very long poly-T variant (>30 dT) leads to earlier onset of LOAD, but association of APOE e3 with a short poly-T variant (<20) leads to delayed onset. These evolutionarily conserved poly-T variants may affect disease risk by causing exon skipping, by affecting the expression of APOE, by facilitating interactions between mitochondria and APP or mitotoxic fragments of ApoE e4, or by disrupting the activity of the TOM complex, and we are currently exploring these hypotheses.

S-Nitrosylation/Redox Control of Protein Misfolding, Mitochondrial Fragmentation, and Neuronal Synaptic Damage in Neurodegenerative Diseases

Stuart A. Lipton, Sanford|Burnham Institute for Medical Research

The relationship between misfolded proteins, observed in Alzheimer’s, Parkinson’s, and Huntington’s disease (AD/PD/HD), and excitotoxicity has remained obscure, although excitotoxicity has been implicated in a final common pathway contributing to synaptic injury and neuronal death in these disorders. Hyperactivation of extrasynaptic NMDA-type glutamate receptors (NMDARs) leads to excessive Ca2+ influx and generation of free radicals, including nitric oxide (NO) and reactive oxygen species (ROS). These free radicals trigger a variety of injurious pathways; emerging evidence suggests a major role for protein S-nitrosylation (transfer of NO to a critical thiol group to regulate protein function via SNO-Protein formation). We recently reported this reaction mimics the effect of rare genetic mutations causing disease. For example, -SNO modification can herald protein misfolding, and thus contribute to neurodegeneration. One such molecule affected is protein-disulfide isomerase (PDI), an enzyme responsible for normal protein folding. We found that redox stress precipitates S-nitrosylation of PDI (forming SNO-PDI), thus compromising enzyme function, and leading to misfolded proteins, neuronal cell injury and death. SNO-PDI occurs at pathologically-relevant levels in neurodegenerative disorders, including AD, PD and ALS. This discovery links protein misfolding to excitotoxicity and free radical formation. We showed that blockade of NMDAR activity can, in large measure, protect neurons from this type of injury if Uncompetitive/Fast Off-rate (UFO)-type antagonists like Memantine are employed because they block excessive, predominantly extrasynaptic NMDAR activity without disrupting normal synaptic activity. Another protein that is S-nitrosylated in AD and in HD is the mitochondrial fission protein dynamin-related protein 1 (Drp1). Mitochondria continuously undergo two opposing processes, fission and fusion. The disruption of this dynamic equilibrium can injure neurons and contribute to developmental and neurodegenerative disorders. NO mediates neuronal injury, in part via excessive mitochondrial fission or fragmentation. However, the underlying mechanism for NO–induced pathological fission has remained unclear. We found that NO, produced in response to oligomeric β-amyloid peptide and NMDAR hyperactivation, triggers excessive mitochondrial fission, synaptic loss, and neuronal damage via S-nitrosylation of Drp1 (forming SNO-Drp1). Preventing nitrosylation of Drp1 by specific cysteine mutation abrogated these neurotoxic events. SNO-Drp1 is increased in brains of human AD and HD patients and may thus contribute to the pathogenesis of neurodegeneration. Taken together, our recent findings suggest that aberrant nitrosylation events contribute to both protein misfolding and excessive mitochondrial fragmentation in neurodegenerative conditions, thus contributing to synaptic damage and neuronal cell death. References Uehara T, Nakamura T, Yao D, Shi Z-Q, Gu Z, Masliah E, Nomura Y, Lipton SA. S-Nitrosylation of protein-disulphide isomerase links protein misfolding to neurodegeneration. Nature 2006;441:513-517. Cho D-H, Nakamura T, Fang J, Cieplak P, Godzik A, Gu Z, Lipton SA. S-Nitrosylation of Drp1 mediates β-amyloid-related mitochondrial fission and neuronal injury. Science 2009;324:102-105. Okamoto S-i , Pouladi M, Talantova M, Yao D, Xia P, Ehrnhoefer DE, Zaidi R, Clemente A, Kaul M, Graham RK, Zhang D, Chen H-SV, Tong G, Hayden MR, Lipton SA. Balance between synaptic versus extrasynaptic NMDA receptor activity influences inclusions and neurotoxicity of mutant huntingtin. Nat Med 2009;15:1407-1413.

Mitochondrial Pore and Synaptic Function in Alzheimer disease: Role of Cyclophilin D

Shi Du Yan, Taub Institute of Columbia University

Amyloid beta (Aβ) deposition and the resultant synaptic dysfunction have been widely observed in Alzheimer’s disease (AD). The mechanisms underlying Aβ-induced synaptic toxicity remain to be elucidated. The mitochondrial permeability transition causes mitochondrial swelling, outer membrane rupture, release of cell death mediators, dysregulation of calcium, and production of reactive oxygen species (ROS). Cyclophilin D (cypD) is an integral component of MPTP formation and triggers opening of MPTP, leading to mitochondrial dysfunction. The level of cypD is correlated to the vulnerability of mitochondrial in response to calcium insult. To determine if there is mitochondrial built-in mechanism by which Aβ induces synaptic dysfunction, we analyzed expression of CypD and synaptic mitochondrial properties/function of transgenic mice overexpressing Aβ (Tg mAPP mice) and nontransgenic (nonTg) littermates. Synaptic mitochondria enriched for Aβ from Tg mAPP mice demonstrate a higher level of cypD and a lower calcium retention capacity as well as decreased a key enzyme activity (cytochrome C oxidase) associated with respiratory chain, compared to those from nonTg littermates. The mAPP synaptic mitochondria containing high levels of Aβ promoted production of ROS and cytochrome c release in contrast with nonTg synaptic mitochondria in response to calcium. To determine the effect of cypD on Aβ-mediated synaptic function, hippocampal slices were treated with oligomeric Aβ. We found that cypD-deficient slices were resistant to Aβ-induced reduction of long term potentiation (LTP) compared to the slices from nonTg mice. Further, transgenic mAPP mice lacking cypD greatly improved the learning and memory. Taken together, our results demonstrate that Aβ-containing synaptic mitochondria are more susceptible to toxic insults such as calcium and oxidative stress. Increased levels of cypD and the resultant decreased threshold of MPTP in synaptic mitochondria may be one of mechanisms for augmenting mitochondrial vulnerability to calcium insults. The absence of cypD rescues Aβ-mediated synaptic stress, and improves cognitive function Thus, we conclude that cypD-dependent membrane transition pore in synaptic mitochondria contributes importantly to Aβ-mediated synaptic perturbation relevant to the pathogenesis of AD. Blockade of cypD may have a therapeutic benefit for halting synaptic failure of AD. (supported by NIA)

PPAR-sparing, Mitochondrial Targeting Thiazolidinediones (TZDs) for the Treatment of AD

Jerry R. Colca, Metabolic Solutions Development Company

Mitochondrial dysregulation of metabolism plays a key role in the pathology of both diabetes and neurodegenerative diseases such as AD. Insulin sensitizing TZDS have been used for more than 10 years clinically to treat Type 2 diabetes. Although these compounds, particularly pioglitazone.HCL, have important effects on the symptoms of diabetes and its sequelae, the use of these compounds is limited by their side effects. Dose-limiting side effects such as fluid retention and weight gain are known to be driven by direct activation of the nuclear receptor PPARγ. In spite of considerable effort, no new improved insulin sensitizers have been approved since pioglitazone in 1999. We have found that direct activation of PPARg is in fact not a pre-requisite for anti-diabetic activity. We are currently developing a PPAR-sparing analog, which is an isomer of one of the pioglitazone metabolites and which spares activation of PPARγ. Proof of concept Phase II clinical trials have shown that the compound, also called Mitoglitazone, has similar pharmacology to pioglitazone but does not increase plasma volume or cause weight gain. Because this compound has similar affinity for the mitochondrial target of thiazolidinediones (mTOT) and similar effects in cellular systems as pioglitazone, we suggest that that is the effect on mitochondrial metabolism that is driving the anti-diabetic pharmacology. We also suggest that this and similar compounds may also be useful in neurodegenerative diseases. In cell culture studies, Mitoglitazone and other PPAR-sparing molecules inhibit production of nitric oxide from glial cells and suppress inflammatory activation of NFkB transcription. Oral dosing of Mitoglitazone resulted in brain levels that were from 35-41% /mg brain tissue as compared to plasma concentration/ml. Treatment of 2 month old female TgAPP mice ("5xFAD" which express APP having 3 mutations, and PS1 having 2 mutations) with Mitoglitazone reduced soluble Ab1-42 levels measured by ELISA and decreased total GFAP staining. Studies are underway with both earlier and longer treatments with compound that include the evaluation of biochemical, structural, and cognitive effects of treatment. We will discuss possible mechanisms by which mitochondrial effects of PPAR-sparing TZDs might impact both diabetes and neurodegenerative processes.

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