Targeting Metals in Alzheimer's and Other Neurodegenerative Diseases

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Targeting Metals in Alzheimer's and Other Neurodegenerative Diseases

Thursday, November 29, 2012

The New York Academy of Sciences

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Presented by the Brain Dysfunction Discussion Group at the New York Academy of Sciences

 

Alzheimer's disease (AD) is characterized by elevated brain iron levels and accumulation of copper and zinc in cerebral β-amyloid deposits. Both ionic zinc and copper accelerate the aggregation of Aβ, the principle component of β-amyloid deposits. Copper and iron can also promote the neurotoxic redox activity of Aβ and induce oxidative cross-linking into stable oligomers. Recent reports documented the release of Aβ together with ionic zinc and copper in cortical glutaminergic synapses following excitation, leading to the formation of Aβ oligomers. Excessive accumulation of Aβ oligomers in the synaptic cleft is thought to adversely affect synaptic neurotransmission, and transition metals have been implicated in the misfolding and accumulation of a-synuclein and Huntington protein in Parkinson's and Huntington's diseases (PD and HD), respectively, as well as tau hyperphosphorylation in AD, contributing to disease pathogenesis and progression. The "Metal Hypothesis of Neurodegenerative Diseases" is proposed to describe the underlying, possibly causative, events, leading to the neuropathology that drives AD, PD, and HD. This symposium examines how these findings led to the discovery of small molecules designed to restore the physiologic balance of transition metals in the brain, prevent further accumulation of misfolded proteins, and possibly even have a disease-modifying effect. A review of the early clinical experience of one such compound, PBT2, will be presented.

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Agenda

* Presentation times are subject to change.


Thursday, November 29, 2012

12:00 pm

Welcome and Introduction
Jennifer Henry, PhD, The New York Academy of Sciences
George Zavoico, PhD, MLV

12:10 pm

The Metal Hypothesis of Alzheimer's Disease
Rudolph Tanzi, PhD, Massachusetts General Hospital and Harvard Medical School

12:55 pm

Targeting Metal Homeostasis Protects Against the Toxicity Caused by Neurodegenerative Disease Proteins in Yeast
Daniel Tardiff, PhD, Whitehead Institute for Biomedical Research

1:40 pm

Coffee Break

2:15 pm

Transition Metals and the Pathogenesis and Treatment of Huntington's Disease
Steven M. Hersch, MD, PhD, Massachusetts General Hospital and Harvard Medical School

3:00 pm

Transition Metals in Neurodegenerative Disease: Opportunities for Therapeutic Intervention
Robert A. Cherny, PhD, The Florey Institute of Neuroscience and Mental Health, Australia

3:45 pm

Panel Discussion
All speakers, moderated by George Zavoico, PhD, MLV

4:15 pm

Networking Reception

5:00 pm

Close

Speakers

Organizers

Rudolph Tanzi, PhD

Massachusetts General Hospital and Harvard Medical School

Dr. Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since the 1980's when he participated in the first study that to use genetic markers to find a disease gene (Huntington's disease). Dr. Tanzi co-discovered the three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson's disease. As leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer's families leading to the identification of novel AD candidate genes, and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led recently to successful clinical trials at Prana Biotechnology. Dr. Tanzi serves on dozens of editorial and scientific advisory boards, and as Chair of the Cure Alzheimer's Fund Research Consortium. He has received numerous awards, including the two highest awards for Alzheimer's disease research: The Metropolitan Life Award and The Potamkin Prize. Dr. Tanzi was included on the list of the "Harvard 100 Most Influential Alumni" by 02138 magazine, and was chosen by the Geoffrey Beene Foundation as a "Rock Star of Science". Dr. Tanzi has co-authored over 400 research articles, including three of the top ten most cited AD papers. He co-authored the popular trade books "Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease" (with Ann Parson) and the recent New York Times Bestseller, "Super Brain" (with Deepak Chopra). In musical pursuits, Dr. Tanzi professionally plays keyboards, most recently on Aerosmith's new album released in November, 2012.

George Zavoico, PhD

MLV & Co.

George B. Zavoico, PhD, is Managing Director, Research, and a Senior Equity Research Analyst at MLV, a boutique investment bank and institutional broker-dealer based in New York. He has over 6 years of experience as a life sciences analyst writing research on publicly traded equities. Prior to MLV, he was an equity analyst with Westport Capital Markets and Cantor Fitzgerald. Prior to working as an analyst, Dr Zavoico established his own consulting company serving the biotech and pharmaceutical industries by providing competitive intelligence and marketing research, due diligence services, and guidance in regulatory affairs. He also wrote extensively on healthcare and the biotech and pharmaceutical industries for periodicals targeting the general public and industry executives. Dr Zavoico began his career as a Senior Research Scientist at Bristol-Myers Squibb Co., moving on to management positions at Alexion Pharmaceuticals, Inc. and T Cell Sciences, Inc. (now Celldex Therapeutics, Inc.). He has a BS in Biology from St. Lawrence University and PhD in Physiology from the University of Virginia and has held post-doctoral positions at the University of Connecticut Health Sciences Center and Brigham and Women's Hospital and Harvard Medical School.

Jennifer Henry, PhD

The New York Academy of Sciences

Speakers

Robert A. Cherny, PhD

The Florey Institute of Neuroscience and Mental Health, Australia

Associate Professor Robert Cherny is a Principal Research Fellow in the Oxidation Biology Laboratory at the Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Australia. He has published extensively on the neurobiology of metals and its relevance to neuodegenerative disease with a particular interest in translational medicine. He is also Head of Research for Prana Biotechnology Ltd, a pharmaceutical company based in Melbourne specialising in the development of novel drugs for neurodegenerative diseases.

Steven M. Hersch, MD, PhD

Massachusetts General Hospital and Harvard Medical School

Dr. Hersch directs the New England Center of Excellence for Huntington's Disease and the, Laboratory of Neurodegeneration and Neurotherapeutics at Massachusetts General Hospital. His research areas have included the synaptic organization and molecular pharmacology of the cerebral cortex and basal ganglia and basic, translational, and clinical research related to Huntington Disease. His laboratory studies the pathogenesis of HD, with a focus on identifying and validating potential neuroprotective treatments and biomarkers using genetic HD mouse models and human clinical and postmortem samples. Dr. Hersch has been a principal investigator, steering committee member, or site investigator for many observational and therapeutic studies in HD patients. He is the principal investigator of the first prevention trial in presymptomatic HD and of a global phase III study examining high dose creatine in early symptomatic HD. He is leading a collaborative NIH supported program to develop neuroimaging, protein, small molecule, and genomic biomarkers of HD. He is the co-chair of the Huntington Study Group, an international consortium of academic investigators at almost 100 leading institutions devoted to HD clinical research.

Rudolph Tanzi, PhD

Massachusetts General Hospital and Harvard Medical School

Dr. Rudolph Tanzi is the Joseph P. and Rose F. Kennedy Professor of Neurology at Harvard University, and Director of the Genetics and Aging Research Unit at Massachusetts General Hospital (MGH). Dr. Tanzi has been investigating the genetics of neurological disease since the 1980's when he participated in the first study that to use genetic markers to find a disease gene (Huntington's disease). Dr. Tanzi co-discovered the three familial early-onset Alzheimer's disease (FAD) genes and several other neurological disease genes including that responsible for Wilson's disease. As leader of the Cure Alzheimer's Fund Alzheimer's Genome Project, Dr. Tanzi has carried out multiple genome wide association studies of thousands of Alzheimer's families leading to the identification of novel AD candidate genes, and the first two rare mutations causing late-onset AD in the ADAM10 gene. His research on the role of zinc and copper in AD has led recently to successful clinical trials at Prana Biotechnology. Dr. Tanzi serves on dozens of editorial and scientific advisory boards, and as Chair of the Cure Alzheimer's Fund Research Consortium. He has received numerous awards, including the two highest awards for Alzheimer's disease research: The Metropolitan Life Award and The Potamkin Prize. Dr. Tanzi was included on the list of the "Harvard 100 Most Influential Alumni" by 02138 magazine, and was chosen by the Geoffrey Beene Foundation as a "Rock Star of Science". Dr. Tanzi has co-authored over 400 research articles, including three of the top ten most cited AD papers. He co-authored the popular trade books "Decoding Darkness: The Search for the Genetic Causes of Alzheimer's Disease" (with Ann Parson) and the recent New York Times Bestseller, "Super Brain" (with Deepak Chopra). In musical pursuits, Dr. Tanzi professionally plays keyboards, most recently on Aerosmith's new album released in November, 2012.

Dan Tardiff, PhD

Whitehead Institute for Biomedical Research

After growing up in southern Maine, I attended Stonehill College — a small liberal arts college in Massachusetts. There, I earned my BS in Biochemistry and began my research career in C. elegans. I next attended Brandeis University in the Molecular and Cell Biology PhD program in the lab of Dr. Michael Rosbash, a pioneer in the study of both basic gene expression work in yeast and Circadian rhythms in fruit flies. My work involved new applications of chromatin immunoprecipitation to study cotranscriptional pre-mRNA splicing in budding yeast. In addition, I developed an in vivo crosslinking approach to affinity purify large, labile complexes that typically do not survive affinity purification (e.g., nascent RNA Pol/RNA/DNA complexes). I continued my work with yeast in my post-doc with Dr. Susan Lindquist at the Whitehead Institute in Cambridge, MA. I have worked on several yeast models that recapitulate the basic protein misfolding problems associated with Parkinson's disease, ALS, FTLD, and Alzheimer's Disease. Most of my efforts have focused on high throughput screens for small molecules that rescue the cell death associated with toxic expression of disease proteins. Upon 'hit' identification, I have interrogated several compounds to elucidate their mechanism of action, a difficult task that we are currently making some exciting headway using both yeast genetic screens and other conventional target identification approaches.

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Abstracts

The Metal Hypothesis of Alzheimer's Disease
Rudolph Tanzi, PhD, Massachusetts General Hospital and Harvard Medical School

Alzheimer's disease is the most common form of dementia in the elderly, and is characterized by abundant deposits of beta amyloid, e.g. in senile plaques along with elevated cerebral levels of copper, zinc and iron. In the early-1990's, we first showed that ionic zinc and copper are able to accelerate the aggregation of Abeta, the principle component of beta-amyloid deposits. Copper (and iron) also promote the neurotoxic redox activity of Abeta while inducing oxidative cross-linking of Abeta into stable oligomers that accumulate in the brain. During cortical glutamatergic excitation Abeta is released together with ionic zinc and copper, which, in turn, leads to the formation of Abeta oligomers. These oligomers then suppress long-term potentiation and induce long-term depression by mediating the internalization of the NMDA and AMPA receptors. Excess Abeta oligomers impair synaptic activity and induce tauopathy and neurodegeneration. The combination of excess Abeta deposition and neuronal cell death induces inflammation and further neurodegeneration. Given these findings, we first postulated the "Metal Hypothesis of Alzheimer's Disease," which stipulates that the neuropathogenic effects of Abeta in Alzheimer's disease are dependent on Abeta-metal interactions. Pharmaceutical strategies are currently being implemented to attenuate abnormal Abeta-metal interactions. An example of one of these therapies is PBT2 (Prana Biotechnology), which has been shown to reduce Abeta aggregation, enhance dissolution of Abeta oligomers and plaques, and decrease tauopathy, while also releasing metals that have been sequestered by Abeta, making them bio-available. PBT2 is currently advancing through clinical trials and showing increasing promise as a potential disease-modifying agent for Alzheimer's disease.
 

Targeting Metal Homeostasis Protects Against the Toxicity Caused by Neurodegenerative Disease Proteins in Yeast
Dan Tardiff, PhD, Whitehead Institute for Biomedical Research

Neurodegenerative diseases (ND) affect millions of patients in the US, yet no effective disease modifying drugs have reached the market. Because of their poorly defined and highly complex disease etiologies, it is essential to embrace unbiased and innovative approaches for identifying new chemical entities that target the underlying toxicities associated with NDs. While traditional target-based drug discovery paradigms can suffer from a bias towards a small number of potential targets, phenotypic screening of simple model organisms offers an alternative approach to discover compounds that target the initiating causes and effectors of cellular toxicity. To this end, we have screened multiple validated yeast models of proteotoxicity, including α-synuclein (PD), TDP-43 (ALS, FTLD), and Aβ peptide (AD), and identified numerous compounds that restore protein homeostasis and rescue cells from death. A major class of compounds identified in multiple screens has been metal chelators, including the 8-hydroxyquinolines (8-OHQ). Interestingly, these 8-OHQs display different activities in different toxicity models dependent on the non-chelating regions of the molecule. We have also identified non-8-OHQ compounds, including a class of non-chelating compounds that targets metal homeostasis in our Aβ model. Thus, without any preconceived biases, we have identified several compounds that rescue cell death through altering metal homeostasis. Though it is not clear the precise mechanism in some cases, it is becoming more apparent that, along with molecules like PBT2, targeting metals may ultimately be a productive therapeutic strategy in several neurodegenerative diseases.
 

Transition Metals and the Pathogenesis and Treatment of Huntington's Disease
Steven M. Hersch, MD, PhD, Massachusetts General Hospital and Harvard Medical School

Huntington's disease is an autosomal dominant neurodegenerative disorder that causes progressive cognitive, motor, and psychiatric disturbances. The molecular basis of HD is a CAG repeat expansion mutation in the HD gene leading to the cellular expression of an abnormal huntingtin protein with an extended polyglutamine sequence in its n-teminal. The causative mutant protein undergoes cleavage, misfolding, various post-translational modifications, toxic protein-protein interactions, oligomerization, accumulation and aggregation into insoluble intracellular inclusions. Transition metals, especially iron and copper, have been implicated in the pathogenesis of HD. Iron accumulates progressively in the brain in HD where it may contribute to oxidative damage and dysregulation of metal homeostasis. Huntingtin coordinates copper, which catalyzes its oligomerization through specific cysteine residues and promotes its accumulation and toxicity. Copper could thus directly modulate the toxicity of huntingtin while iron accumulation in response to neurodegeneration likely potentiates the damage to the CNS making both metals potential therapeutic targets.
 

Transition Metals in Neurodegenerative Disease: Opportunities for Therapeutic Intervention
Robert A. Cherny, PhD, The Florey Institute of Neuroscience and Mental Health, Australia

Across the spectrum of neurodegenerative diseases there is evidence of failure of homeostatic mechanisms regulating the trafficking and localisation of vital biological metals, (primarily copper zinc and iron). Under this milieu the increasingly labile metal pool can interact promiscuously with cellular components, promoting oxidative damage and exacerbating the pathological aggregation and toxicity of susceptible proteins including beta amyloid in Alzheimer's disease (AD) and mutant Huntingtin protein in HD. We have been investigating the therapeutic potential of drugs which act to inhibit pathological metal-protein interactions and promote neuronal function by restoring metal homeostasis.
 

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