First International
Neuron to Synapse 2008 Meeting

On

‘Neurobiology to Neurodegenerative Diseases & Therapeutics’
May 27 – 28, 2008
The Joseph B. Martin Conference Center at Harvard Medical School
77 Avenue Louis Pasteur, Boston, MA 02115, USA

“A Unique Theme to Combine Biology of Neurosynapses, Cognition, Memory & Diseases”

Focus of the Theme Meeting:

Brain diseases, in particular neurodegenerative diseases, represent a growing public health concern. Understanding the biology of neuronal cells (neurons) and their communication with neighboring cells at synapses is crucial in order to know the defects and pathophysiology of brain disorders. To discover and develop innovative drug compounds for these central nervous system diseases it is essential to gather intellectual minds from academia, biotech and pharmaceutical industries to have a forum. Such forum will enhance knowledge and dissipate of data and ideas which will ultimately bring more scientific and business collaborations.

The conference will bring together experts and young researchers with diverse backgrounds in molecular and cellular neurobiology, biochemistry, electrophysiology, behavior, cognition, perception, and disease biology, and the first conference discussing new developments in this highly interdisciplinary area of brain research. The conference should be interesting for graduate students, postdoctoral fellows, professors from academia and scientists, directors and executives from industry, as well as for anyone interested in brain functions and their associated diseases. Authorities in the filed will be invited as key speakers. Few speakers will be also selected from the applicants, based on the submitted abstracts. Dedicated time will be allowed for presentation of posters and viewing the exhibits and to know the available cutting-edge reagents, services in the field.

Topics or Highlights of the Meeting:

Biology of Neurons, Synapses and Signaling Mechanisms
Synaptic Plasticity, Development & Behavior
Neural Circuits, Cognition, Learning and Perception
Neurodegenerative diseases & Therapeutic Strategies
Diseases of Channels, Receptors and Synapses
Biomarker Development for CNS Diseases
PharmacoNeurogenomics

AGENDA/SPEAKERS

Click Here For Detailed Agenda

Tuesday, May 27, 2008

8:00AM Registration Open
8:00 – 9:00 A.M: Breakfast
9.00 AM – 6.00 PM Scientific Sessions

Wednsday, May 28, 2008

7:30 – 8:30 A.M: Registration Open
7:30 – 8:45 A.M: Breakfast
8.00 AM – 5.30 PM Scientific Sessions

Scientific Committee:
	Krishnarao Appasani, PhD., MBA Founder & CEO GeneExpression Systems, Inc. Waltham, MA, USA
	Sha Mi (Misha), PhD. Principal Investigator & Director of Neuro- Discovery Biology, Biogen Idec, Cambridge, MA, USA Title: LINGO-1 and its Role in CNS Repair
	Ed Boyden, Ph. D. Benesse Career Development Professor, Neuroengineering & Neuromedia Lab & Biological Engineering MIT, Cambridge, MA, USA Title: Optical Neural Control: Analyzing and Engineering Normal and Pathological Neuronal Circuit Dynamics

Key Speakers:

	Lifetime Achievement Awardee, Talk on May 28 Leon N Cooper, PhD. Nobel Laureate in Physics 1972 Thomas J. Watson, Sr. Professor of Science Director of the Institute for Brain and Neural Systems Brown University Providence, RI, USA Title: Towards a Cellular and Molecular Basis for Learning and Memory
	Keynote speaker on May 27 Bradley T. Hyman, MD., PhD. Director, Alzheimer Disease Research Center John B Penney Jr Professor Harvard Medical School Massachusetts General Hospital Charlestown MA 02129, USA Title: Molecular imaging and the pace of Alzheimer disease
	Keynote speaker on May 28 Joshua Sanes, PhD. Neuron Innovator Awardee, Professor of Molecular and Cellular Biology Paul J. Finnegan Family Director, Center for Brain Science Harvard University, Cambridge, MA, USA. Title: Formation, maturation and maintenance of synapses

Other Speakers:

	Peter T. Lansbury, Jr. PhD. Professor of Neurology, Harvard Medical School and Chief Scientific Officer and Chairman Link Medicine Corporation Cambridge, MA, USA Title: New approaches to the treatment of neurodegenerative diseases
	Amar Thyagarajan, PhD. Postdoctoral Associate in the Lab of Dr. Alice Ting Department of Chemistry Massachusetts Institute of Technology Cambridge, MA, USA Title: Novel protein labeling technologies to image protein interactions and trafficking at neuronal synapses
	Robert C. Green, M.D., M.P.H. Professor of Neurology, Genetics and Epidemiology Boston University Schools of Medicine and Public Health Boston, MA, USA Title: Genetic Risk Assessment for Alzheimer's disease
	Holly D. Soares, PhD. Director in Translational Medicine Pfizer Global Research and Development Title: The Use of Biomarkers in Clinical Development of Alzheimer’s Disease
	Janice R. Naegele, PhD. Professor and Chair of Biology Wesleyan University, Middletown, CT, USA Title: Stem Cell Therapies for Treating Temporal Lobe Epilepsy
	Ronald B. DeMattos, PhD. Research Advisor in Neuroscience Division Lilly Research Laboratories, Indianapolis, IN, USA Title: Aβ Immunotherapy: Translation of Preclinical Biomarkers into the Clinic
	Jesus'Tito' Gonzalez , Ph.D. Sr. Director, Biology Vertex Pharmaceuticals San Diego, CA, USA Title: Accessing Voltage-gated Channels Drug Targets for Nervous System Disorders
	Grant A. Krafft, PhD. Chairman and Chief Science Officer Acumen Pharmaceuticals, Inc. Title: ADDL-Mediated synaptic signaling causes AD memory deficits: New Therapeutic strategies to restore cognitive function
	Kenton H. Zavitz, Ph.D. Senior Director, Clinical Affairs Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA Title: Tarenflurbil (Flurizan™), 42-Lowering Agent, as a Potential Treatment for Alzheimer’sba Selective A Disease
	Chris Mathes, Ph.D. Vice-president & General Manager, NA Sophion Bioscience, Inc., North Brunswick, NJ, USA Title: Diseases of Channels
	Alistair Stewart, Ph.D. Allon Therapeutics Inc., Vancouver, Canada Title: Translation from research to clinical proof-of-concept: AL-108 for neurodegenerative diseases
	Andreas Jeromin, PhD. Manager, Methods Development Allen Institute for Brain Science Seattle, WA 91803, USA Title: Single-molecule tracking and total-internal reflectance microscopy to monitor the membrane dynamics and organization of Kv4.2 and high-throughput profiling of ion channel expression in human brain
	Ru-Rong Ji, PhD. Associate Professor of Anesthesiology Pain Research Center, Brigham & Women's Hospital, Boston Title: Unraveling neuropathic pain mechanisms
	Alberto Ascherio, MD., Dr.Ph. Associate Professor of Nutrition and Epidemiology Harvard School of Public Health, Boston, MA, USA Title: Role of epidemiology in neurodegeneration research: Lessons from Parkinson's
	John Lisman, PhD. Professor of Biology Volen Center for Complex Systems Brandeis University, Waltham, MA, USA  Title: The Molecular and Synaptic Basis of Memory
	Israel Schechter, M.D., Ph.D. Professor of Immunology The Weizmann Institute of Science, Rehovot, Israel Title: Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional b-secretase candidate(s)
	Dione Kobayashi, PhD. Principal scientist Rinat Labs, Pfizer, Inc., South San Francisco, CA, USA Title: Inert C-terminal Ab antibody efficacy in an Alzheimer’s model
	Trine Veje Axelsen, M.S. Industry PhD-student Loke Diagnostics ApS, Risskov, Denmark Title: Development of monoclonal antibodies against beta-amyloid
	Ian L. Scott, PhD. Senior Director of Chemistry Acucela, Inc., Seattle, WA 98103, USA Title:Visual Cycle Modulation - An Approach to the Treatment of Age-Related Macular Degeneration
	J. Thomas Megerian, MD, PhD. Executive Director for Clinical Development EPIX Pharmaceuticals, Inc., Lexington, MA, USA Title: From In Silico to Patient; A case study in expedited drug development for Alzheimers Disease
	Stephan Schilling, PhD. Director of Enzymology Probiodrug AG Halle (Saale), Germany Title: Pyroglutamated Ab peptides-N-terminally blocked Ab variants generated by glutam(in)yl cyclase
	Zhigang He, Ph.D. Associate Professor of Neurology Children's Hospital, Boston, MA, USA Title: Mechanisms of Axon regeneration

Exhibitors are welcome to reserve their booth space early!

Please contact if you are interested in speaking in the scientific or Technology workshops of this meeting.

GeneExpression Systems, Inc.
P.O. Box 540170
Waltham, MA 02454 USA
Tel: (781) 891-8181
Fax: (781) 891-8234
E-mail: Genexpsys@expressgenes.com
www.expressgenes.com

Poster Abstract Submission by May 10, 2008

ALL ABSTRACTS

Towards a Cellular and Molecular Basis for Learning and Memory
Leon N Cooper, PhD. Thomas J. Watson, Sr. Professor of Science & Director of the Institute for Brain and Neural Systems, Brown University, Providence, RI, USA

I retrace the journey that has taken me from abstract mathematical representations of memory to biochemical pathways that provide the likely cellular and molecular basis for learning and memory storage. It is a journey marked by an interaction between theory and experiment, the norm in physics since Galileo, but still novel and not universally accepted in neuroscience. I will show how this interaction has proved to be extraordinarily fruitful. Theory has suggested experiments that have uncovered new phenomena such as: Long Term Depression (LTD), bi-directional synaptic modification dependent on the depolarization of the post-synaptic cell and the sliding modification the threshold in agreement with BCM synaptic modification function. This has provided experimental verification of the postulates of the BCM theory of synaptic plasticity. Theory has also clarified connections between seemingly unrelated observations in different brain regions such as LTD/LTP in hippocampus to reverse suture results in visual cortex.

Optical Neural Control: Analyzing and Engineering Normal and Pathological Neuronal Circuit Dynamics
Ed Boyden, Ph. D., Benesse Career Development Professor, Assistant Professor, MIT Media Lab & Biological Engineering, MIT, Cambridge, MA, USA

The ability to control specific cell types and neural circuits will open up the ability to test the role of specific patterns of activity in neural computations and behaviors. It will also enable us to develop a new generation of neurological and psychiatric therapies, based upon precise reprogramming of neural circuits. Our lab both invents novel methods for controlling neural circuits, and discovers principles for how to use them to systematically sculpt neural dynamics. We will talk about our recent development of methods for controlling very precise neural functions using light, and their application to studying and engineering normal and pathological neural circuit dynamics.

Unraveling neuropathic pain mechanisms
Ru-Rong Ji, PhD., Associate Professor of Anesthesiology, Pain Research Center, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA

Treatment of neuropathic pain, triggered by multiple insults to the nervous system, such as diabetic neuropathy, spinal cord injury, viral infection, and chemotherapy, is a clinical challenge because the underlying mechanisms of neuropathic pain development remain poorly understood. Most treatments simply focus on blocking neurotransmission, producing transient pain relief. We have thought to understand how activation of glial cells such as microglia and astrocytes in the spinal cord after nerve injury contributes to the development and maintenance of neuropathic pain via neural-glial interaction. Our studies have demonstrated that MAP kinase (e.g., p38) and matrix metalloproteinases (e.g., MMP-9 & 2) play important role in glial activation and neuropathic pain sensitization and may serve as therapeutic targets for the management of debilitating neuropathic pain.

The Molecular and Synaptic Basis of Memory
John Lisman, PhD., Professor of Biology, Volen Center for Complex Systems, Brandeis University, Waltham, MA, USA 

It now appears likely that memory is encoded by activity-dependent processes that increase the strength of synapses, a process termed long-term potentiation (LTP). We have sought to understand the molecular basis of the storage process that underlies the persistence of LTP, which lasts for years. The focus of our work has been on a protein kinase (CaMKII) that is highly concentrated at synapses. CaMKII is activated during LTP and this activation is required for LTP and learning. We have recently shown that after LTP is induced, it can be turned off by an inhibitor of CaMKII. These results strongly suggest that the memory process at synapses is encoded by changes in CaMKII.

LINGO-1 and its Role in CNS Repair
Sha Mi (Misha), PhD. Principal Investigator & Director, Department of Discovery Neurobiology, Biogen Idec, Cambridge, MA, USA

LINGO-1 is a CNS-specific and membrane associated glycoprotein that is expressed only in oligodendrocyte and neurons. In neurons, LINGO-1, NgR1/p75 and NgR1/TAJ (TROY) together form a signaling complex that binds myelin inhibitors (MAG, Omgp, and Nogo-66) to mediate axonal outgrowth via RhoA activation. Soluble LINGO-1 (LINGO-1-Fc), which antagonizes LINGO-1 binding to NgR1, decreases RhoA activation, promotes axonal sprouting, and significantly improves functional recovery in both rubrospinal or corticospinal tract injury models. In oligodendrocyte, LINGO-1 functions as a negative regulator of oligodendrocyte differentiation and myelination. Blocking LINGO-1 function by a LINGO-1 antagonist promotes spinal cord remyelination and axon integrity in lysolecithin- or cuprizone-induced chemical demyelination and MOG-induced EAE demyelination models.

Translation from research to clinical proof-of-concept: AL-108 for neurodegenerative diseases
Alistair Stewart, PhD., Director, Corporate Development, Allon Therapeutics Inc., Vancouver, Canada

Extensive studies have shown that loss of microtubule integrity and aggregation of hyper-phosphorylated tubulin are critical events in a number of neurodegenerative conditions including Alzheimer’s disease. Maintenance of microtubule function is therefore an important goal in therapeutic strategies toward disease-modification. AL-108 (NAPVSIPQ, intranasal) was originally identified as a potent neuroprotectant and subsequently shown to reduce tau hyperphosphorylation in vivo. By capitalizing on the links between known mechanisms of neurodegeneration in experimental models and the underlying mechanisms of cognitive decline associated with clinical disease, Allon Therapeutics has rapidly advanced AL-108 into proof-of-concept studies in AD. The presentation will discuss the translation of preclinical studies to the choice of a clinical population for Phase II efficacy studies.

Single-molecule tracking and total-internal reflectance microscopy to monitor the membrane dynamics and organization of Kv4.2 and high-throughput profiling of ion channel expression in human brain Andreas Jeromin, PhD., Allen Institute for Brain Science, Seattle, WA 91803, USA

The Kv4.2 pore-forming subunit is the major constituent of the A-type current in dendrites of CA1 pyramidal neurons and one of the key determinants of excitability. Alterations in the expression and phosphorylation status of Kv4.2 have subsequently been identified in models of epilepsy and in pain. The membrane organization and dynamics of Kv4.2 in living neurons and its dependence on phosphorylation have remained largely elusive, however. We have developed single-molecule imaging approach using quantum dots to specifically the localization and mobility of surface-expressed Kv4.2 in neurons and to measure changes in response to activity and activation of kinases.
In addition, we have used total-internal reflectance microscopy to image the membrane insertion and lateral mobility of Kv4.2 fused to a fluorescent tag. These are the first samples of high-resolution imaging of voltage-gated ion channels in neurons. These imaging platforms now allow systematic screening of the role of accessory Kv4.2 interacting molecules in determining the synaptic localization and mobility of Kv4.2 and might reveal novel therapeutic targets in neurological disease. Finally, we will report our results of developing a high-throughput expression profiling platform of ion channels and GPCRs in human brain. This has wide-spread application to characterizing the expression of these gene families in human disease.

Accessing Voltage-gated Channels Drug Targets for Nervous System Disorders
Jesus "Tito" Gonzalez, Ph.D., Sr. Director, Biology, Vertex Pharmaceuticals, San Diego, CA, USA

Voltage-gated ion channels are critical to neuronal excitability and are the drug targets of many anticonvulsants and analgesic agents. An increasing variety of biological and pharmacological evidence, including human genetic data, link these targets to many nervous system indications and disorders, including epilepsy, pain, and neurodegeneration. Examples of therapeutic and technological approaches for accessing these attractive targets will be presented. In addition, key discovery and development challenges will be discussed.

Mechanisms of Axon regeneration
Zhigang He, Ph.D., Associate Professor of Neurology, Children's Hospital Boston, Harvard Medical School, Boston, MA, USA

Regeneration failure of Injured CNS is a major reason for permanent functional deficits associated with neuronal injury and diseases. It has been postulated that both the inhibitory influences and decreased intrinsic growth ability account for such regeneration failure. I will present our results on the mechanisms and in vivo assessment of these proposed mechanisms. We expect that these studies will provide new insights into designing therapeutics to promote neural repair and functional restoration.

Tarenflurbil (Flurizan™), 42-Lowering Agent, as a Potential Treatment for Alzheimer’sba Selective A Disease
Kenton H. Zavitz, Ph.D., Senior Director of Clinical Affairs, Myriad Pharmaceuticals, Inc., Salt Lake City, UT, USA

An extensive body of evidence supports the hypothesis that it is the production, aggregation and 42) thatbdeposition of the 42-amino acid isoform of the beta amyloid peptide (A initiates the cascade of events leading to neuronal dysfunction and death and Alzheimer’s Disease (AD) progression. This presentation will review the nonclinical and clinical data to date of the investigational compound tarenflurbil which acts, via allosteric -secretase, as agmodulation of Selective A42-bLowering Agent (SALA). Tarenflurbil has an attractive therapeutic and safety profile in patients with mild AD and the compound is now being studied in two very large Phase 3 trials as a potentially disease modifying AD treatment.

Novel protein labeling technologies to image protein interactions and trafficking at neuronal synapses
Amar Thyagarajan, PhD., Postdoctoral Associate in the Lab of Dr. Alice Ting, Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, USA

Studies of protein interactions and trafficking at neuronal synapses usually involve imaging of fluorescent protein fusions. To overcome problems of large tag size, dim signal, slow maturation, photobleaching, and limited functional readout, we have developed new hybrid genetic/chemical protein tagging methodology based on engineered forms of E. coli biotin and lipoic acid ligases. We applied these technologies to study the trafficking and interactions of neurexin and neuroligin proteins in living neurons during synapse development.

Kinetic properties of cathepsin D and BACE 1 indicate the need to search for additional b-secretase candidate(s)
Israel Schechter, M.D., Ph.D., Professor of Immunology, The Weizmann Institute of Science, Rehovot, Israel

Many studies suggest that BACE 1 is the genuine b-secretase; however, this is not undisputed. The wildtype (WT) b-site of the amyloid precursor protein (APP) present in the worldwide population is cleaved very slowly (kcat/Km: approx. 50 M-1 s-1), while proteases acting on relevant substrates are much more efficient (kcat/Km:104–106 M-1 s-1). Knock-out of BACE 1 in mouse markedly reduces Ab formation. Nevertheless, studies in other systems show that knock-out experiments in rodents and corresponding genetic defects in human may reveal different phenotypes. Considering these issues, we searched for other b-secretase candidate(s), identified cathepsin D, and evaluated properties of cathepsin D related to BACE 1 that were not examined previously. The kinetic constants (kcat, Km, kcat/Km) for cleaving peptides with b-sites of the WT or the mutated Swedish families (SW) APP by human BACE 1 and cathepsin D were determined and found to be similar. Western blots reveal that in human brain cathepsin D is approximately 280- fold more abundant than BACE 1. Furthermore, pepstatin A strongly inhibits the cleavage of SW and WT peptides by both brain extracts and cathepsin D, but not by BACE 1. These findings indicate that b-secretase activity observed in brain extracts is mainly due to cathepsin D. Nevertheless, as both BACE 1 and cathepsin D show poor activity towards the WT b-site sequence, it is necessary to continue the search for additional b-secretase candidate(s).

Development of monoclonal antibodies against beta-amyloid
Trine Veje Axelsen, MS. Industry PhD-student, Loke Diagnostics ApS
Risskov, Denmark
Trine Veje Axelsen1,2), Arne Holm2), Gunna Christiansen2), Svend Birkelund2) and Ida Elisabeth Holm3)

1)Clinical Institute, Faculty of Health , Aarhus University, Denmark
2)Loke Diagnostics ApS, Sindalsvej 17, 8240 Risskov, Denmark
3)Department of Pathology, Aalborg Hospital, Aarhus University Hospital, Denmark

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the presence of neurofibrillary tangles and deposition of the protein β-amyloid (Aβ) in the brain. The Aβ aggregates are often composed of Aβ1-42 known to be the neurotoxic element in AD. A possible treatment for AD is by removing already formed aggregates of Aβ or preventing their formation using immunotherapy with antibodies against Aβ. We describe the development of highly specific monoclonal antibodies recognizing different lengths of Aβ-peptides. The effect of immunotherapy will be tested in transgenic AD mice models that develop the pathological changes seen in the human AD brains.

Transgenic Inducible and reversible inhibition of synaptic transmission reveals role of CA3 output in hippocampal learning and memory
Toshiaki Nakashiba, PhD., Research Scientist in the lab of Prof. Susumu Tonegawa,
The Picower Institute for Learning and Memory, RIKEN-MIT Neuroscience Research Center, Howard Hughes Medical Institute, Dept. of Brain & Cognitive Sciences, MIT, Cambridge, MA, USA

The hippocampus is the highest integration center of multimodal sensory information and is involved in formation of spatial and episodic memory. It carries information from the entorhinal cortex (EC) via parallel excitatory pathways. In the main excitatory pathway, referred as the trisynaptic pathway (TSP), information is processed through the three major hippocampal subregions—the dentate gyrus, CA3 and CA1—before returning to the EC. In the second pathway, referred as the monosynaptic pathway (MSP), EC sends information directly to CA1 via the temporoammonic pathway (TA). Thus, CA1 neurons receive two excitatory inputs, Schaffer collateral input from the CA3 and TA input from the EC. To experimentally address the role of these two pathways in hippocampal learning and memory, we developed a generally applicable tetanus toxin-based method for transgenic mice that permits inducible and reversible inhibition of synaptic transmission and applied it to the TSP. We found that the MSP alone is sufficient for the acquisition and recall of spatial learning and memory in the Morris water maze, where over repeated trials mice learn to associate the position of an escape platform location. But the TSP is crucial to the acquisition and recall of memory in tasks where rapid learning is required such as rapid formation and recall of contextual representations.

Visual Cycle Modulation - An Approach to the Treatment of Age-Related
Macular Degeneration
Ian L. Scott, PhD., Senior Director of Chemistry, Acucela, Inc., Bothell, WA, USA

Macular Degeneration affects ten to fifteen million patients in the United States and is the leading cause of blindness in aging populations worldwide. Although the exact cause of the disease is unknown, links have been established between progression of this disease with the accumulation of lipofuscin pigments in retinal pigment epithelium (RPE) cells. A major component of lipofuscin is A2E, a toxic condensation product of all-trans retinaldehyde. All trans retinaldehyde is a key component of the visual cycle. This talk focuses on an approach to the treatment of AMD through modulation of the visual cycle.

Role of epidemiology in neurodegeneration research: Lessons from Parkinson's disease
Alberto Ascherio, MD., Dr.Ph., Associate Professor of Nutrition and Epidemiology
Harvard School of Public Health, Boston, MA, USA

The neurodegenerative process that leads to Parkinson’s disease (PD) starts many years before the onset of the characteristic motor symptoms that lead to the diagnosis. Further, the disease is progressive. It seems likely, therefore, that those factors that decrease the risk of developing the disease may also have a positive effect on its progression. We have tested this concept by examining whether serum level of urate, which is a strong negative risk factor for PD development, is also related to the rate of disease progression. Using data from two large previously completed randomized clinical trials in patients with early PD, we have shown that patients with higher serum urate reached the trial endpoint later than patients with lower urate and had a slower clinical and radiological rate of disease progression. We are now starting a phase 2 randomized trial to examine the safety of administering inosine, a urate precursor, to increase serum urate in patients with PD.

ADDL-Mediated synaptic signaling causes AD memory deficits: New Therapeutic strategies to restore cognitive function
Grant. A. Krafft, PhD. Chairman and Chief Science Officer, Acumen Pharmaceuticals, Inc., South San Francisco, CA, USA

Key research findings over the past decade have established a clear connection between ADDLs, Alzheimer’s disease and AD-related memory deficits. ADDLs affect memory by binding to post-synaptic receptors on specific subsets of neurons, leading to disruption of long-term potentiation (LTP). Surprisingly, this LTP inhibition does not involve compromise of normal neurotransmission, but rather occurs via activation of specific signaling pathways. In animal behavioral models, LTP signaling deficits can be induced transiently by ADDL administration and reversed by ADDL-neutralizing antibodies. Although memory deficits occur long before frank neurodegeneration, prolonged exposure to ADDLs can lead to degenerative cellular pathology via activation of tau hyperphosphorylation and other transcriptional processes. In this presentation, recent work on ADDL signaling and specific ADDL binding to dendritic spines will be summarized, and ADDL-directed intervention strategies will be discussed.

Stem Cell Therapies for Treating Temporal Lobe Epilepsy
Janice R. Naegele, PhD., Professor and Chair of Biology, Wesleyan University, Middletown, CT, USA

This lecture focuses on pathological cell death and aberrant neurogenesis in the hippocampus in temporal lobe epilepsy and the potential applications of stem cell therapy for treating seizure disorders. Current research in cell-based therapies will be discussed with a focus on comparing the efficacy of transplanting endogenous neural stem cell-derived GABAergic interneurons or embryonic stem cell-derived neural precursors for controlling seizures in mouse models of temporal lobe epilepsy. Additional applications of stem cell grafts for drug delivery in epilepsy will be discussed.

New approaches to the treatment of neurodegenerative diseases
Peter T. Lansbury, Jr. PhD., Professor of Neurology, Harvard Medical School and
Chief Scientific Officer and Chairman, Link Medicine Corporation, Cambridge, MA, USA

Existing drugs for neurodegenerative disorders like Parkinson’s and Alzheimer’s diseases act by temporarily masking selected symptoms, but do not change the rate of progression of the underlying disease. The availability of novel drugs to slow disease progression would have an enormous impact on the public health. This talk will focus on our efforts at Link Medicine to develop disease-modifying drugs for Parkinson’s and Alzheimer’s disease. Several strategies to reduce the accumulation of protein aggregates in the brain will be discussed.

Inert C-terminal Ab antibody efficacy in an Alzheimer’s model
Dione Kobayashi, PhD., Principal scientist, Rinat Labs, Pfizer, Inc., South San Francisco, USA

Dione T. Kobayashi1*, Thomas A. Lanz2, Danielle A. Pappas1, Erene W. Mina1, Ons Harrabi1, Jo-Ann Wentland2, Daniel Malashock1, Sangeetha Subbarao2, Jeanette Dilley1, Yasmina Abdiche1, Wei-Hsien Ho1, Jaume Pons1, Barbara A. Tate2, John C. Lin1

1 Rinat Laboratories, Pfizer Inc. 230 East Grand Avenue, South San Francisco, CA 94080

2 Pfizer Global Research And Development Eastern Point Road, Groton CT 06340

The central accumulation of Ab peptide is implicated as a causal factor in the development of Alzheimer’s Disease, the most prevalent neurological disorder of the industrialized world’s aging population. Excess Ab peptides can aggregate to form oligomeric to larger fibrillar deposits that have been described to promote inflammation, synaptic dysfunction and neuronal toxicity. Passive immunotherapy with antibodies directed against the Ab peptide is a promising therapeutic concept for AD treatment. While there is controversy surrounding the mechanism by which Ab antibodies influence Ab accumulations in the brain, as well as the Ab species that underlies the dysfunctions of AD, most of these investigations have focused on antibodies that trigger immune effector function and bind N-terminal or mid-domain Ab epitopes. In this article we describe the biochemical and behavioral efficacy of an antibody directed against the C-terminus of the Ab peptide engineered to have minimal ability to trigger immune effector function. The antibody is proposed to operate largely via a peripheral sink mechanism without major contribution from phagocytosis of CNS Abeta, and has a greater affinity for oligomeric than fibrillar forms of Ab. Finally, we demonstrate that cognitive rescue is attainable with or without significant reduction of brain Ab burdens, suggesting the molecular basis of the cognitive dysfunction in AD may be attributed to a minority species of Ab.

The Use of Biomarkers in Clinical Development of Alzheimer’s Disease
Holly D. Soares, PhD., Director in Translational Medicine, Pfizer Global Research and Development

The development of effective treatments for Alzheimer’s disease (AD) continues to be a major goal in AD drug development. Although consensus remains elusive around accepted clinical trial designs for disease modification, current trends suggests that biomarkers reflective of AD neuropathology, early stages of disease and treatment response would provide effective clinical tools to assess pharmacology activity and for early drug development decisions. Recent advances suggest that biochemical biomarker endpoints may have some utility as tools to identify patients in early stages of AD and as tools to monitor treatment response. This session will:
Review available biochemical based biomarkers for AD
Present novel findings on the use of multiplex panels to identify AD biomarkers that alter in response to treatment.

Genetic Risk Assessment for Alzheimer’s Disease
Robert C. Green, MD, MPH., Professor of Neurology, Genetics and Epidemiology
Boston University Schools of Medicine and Public Health, Boston, MA, USA

As genetic and non-genetic biomarkers are discovered for late onset diseases of aging, it will be important to understand the impact of disclosing susceptibility information to individuals who are at risk. This is a particularly urgent need in Alzheimer’s disease (AD) where we are on the brink of developing disease-modifying therapies that have the potential, if applied presymptomatically, to prevent or delay the onset of the disease. REVEAL (Risk Evaluation and Education for Alzheimer’s) is a series of NIH-funded multi-site randomized trials assessing the impact of genetic risk assessment for AD using APOE disclosure in unaffected first-degree relatives of AD patients.
After screening to exclude psychological vulnerability and cognitive impairment, 421 participants (mean age = 56 ± 10.7 years; 72% female; 15% African-American) completed one of two separate trials. In the first, 162 participants were randomized to receive AD risk assessment with or without disclosure of their APOE genotype. There were no differences between randomization groups or among the disclosure groups in depression or anxiety measures. The ε4- group had lower test-related distress than the ε4+ group at 6 weeks (p=0.01), 6 months (p=0.001), and 12 months (p=0.001).
A separate cohort of 259 participants were randomized to receive APOE-based risk assessment through a traditional education/counseling protocol or a highly condensed protocol, more closely resembling services provided by direct-to-consumer genetic testing companies. Again, there were no differences between randomization groups or among the disclosure groups in depression or anxiety measures. In this trial, the mean test-related distress was lower among those in the traditional protocol than those in the condensed protocol at 6 weeks (2.8 vs. 6.5, p=0.005), a difference that was not considered clinically significant and that was not statistically significant at 6 months and 12 months.
We conclude that in this pre-screened population, and using highly structured protocols, APOE genotype for AD risk assessment can be disclosed safely, and provides psychological benefits to ε4- individuals without undue distress to ε4+ individuals. Caution is warranted for disclosure to larger populations and in different circumstances.

Pyroglutamated Ab peptides-N-terminally blocked Ab variants generated by glutam(in)yl cyclase
Stephan Schilling, PhD., Director of Enzymology, Probiodrug AG, Halle (Saale), Germany

Stephan Schilling2 and Hans-Ulrich Demuth1
1Probiodrug AG, Halle (Saale), Germany
2University of Halle and Leibniz Institute for Plant Biochemistry, Germany

N-terminally truncated and pGlu-modified Ab peptides are highly abundant in sporadic and inherited Alzheimer's Disease. Formation of pGlu confers resistance against cleavage by most aminopeptidases, increases the totoxicity of the peptides and speeds up Ab aggregate formation.
Our in vitro and in vivo studies provide strong evidence for a slow Glutaminyl cyclase (QC, EC 2.3.2.5) catalyzed cyclization of N-terminal glutamic acid, substantiating a crucial role for generation of pGlu-Ab peptides. Those peptides potentially influence the neurodegenerative processes underlying Alzheimer’s Disease caused by its proteolytic stability. The inhibition of glutaminyl cyclase has been proven efficacy in animal model with Alzheimer-like pathology and has thus implications for novel treatment strategies of AD.

From In Silico to Patient; A case study in expedited drug development for Alzheimer’s Disease
J. Thomas Megerian, MD, PhD., Executive Director for Clinical Development, EPIX Pharmaceuticals, Inc., Lexington, MA 02421, USA

Modern drug development is often the result of high throughput screening methods that are time consuming, rely on costly hardware and software, and require the synthesis of sufficient quantities of potential candidates to allow for biological screening.

Using novel in silico techniques, based on the PREDIX computation molecular modeling platform, EPIX Pharmaceuticals, Inc. has been able to cut down the lead time to pre-clinical and clinical testing of candidate small molecules aimed at GPCR therapeutic targets.

The 5HT4 partial agonist PRX-03140 for treatment of Alzheimer’s Disease is one such therapeutic candidate developed through this novel development platform.  We will review the methods used to develop this candidate molecule as well as the results from a recently completed Phase 2A study of the molecule in patients with Alzheimer’s Disease.

Aβ Immunotherapy: Translation of Preclinical Biomarkers into the Clinic
Ronald B. DeMattos, PhD. Research Advisor in Neuroscience Division, Lilly Research Laboratories, Indianapolis, IN, USA

Several active and passive immunization approaches for the treatment Alzheimer’s disease (AD) are currently being tested in the clinic. We have shown that the monoclonal antibody m266 binds soluble Aβ selectively and hence cannot operate via mechanisms that depend upon antibody recognition of deposited Aβ (opsonization). An extensive pre-clinical data package has been assembled for m266 that demonstrates its ability to perturb the CNS/plasma Aβ equilibrium, alter soluble CSF Aβ pools, decrease plaque deposition in PDAPP mice and reverse behavioral impairments in PDAPP mice, while at the same time not exacerbating CAA-related microhemorrhage. Our current studies are focused on the translation of the preclinical biomarkers into the clinic.