The Biology of Aging: Novel Drug Targets for Neurodegenerative Disease

Agenda

* Presentation titles and times are subject to change.

Abstracts

Delaying the Biology of Aging to Prevent Alzheimer's Disease
Nir Barzilai, MD, Institute for Aging Research at Albert Einstein College of Medicine

Aging is the major risk not only for AD but also for other diseases such as cancer, type 2 Diabetes mellitus and cardiovascular disease. We hypothesize that a progress in preventing these diseases will occur only if we can understand the reason people age at different rates, and develop strategy to delay aging. We present 2 examples. We study the genome of centenarians, whose aging and onset of its diseases have been delayed. We have implicated a longevity genotype, cholesterol ester transfer protein (CETP), in the preservation of cognitive function in centenarians and their families. CETP inhibitor is in phase III trial to prevent CVD but offers an approach for prevention of AD. We have discovered line of, previously un-noted mitochondrial derived peptides, whose expression declines with aging. Those peptides have roles in metabolism and stress response. One of those peptides, humanin, has been directly implicated in neuronal toxicity relevant to AD. Derivation of this molecule is tested for potential drug development for AD. These examples suggest an approach of delaying aging and several of its disease, rather than focus on one organ-specific drug at a time.

Autophagy, Cell Health and Aging
Eric H. Baehrecke, Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605

Autophagy is a catabolic process that targets cytoplasmic components for degradation by the lysosome. Autophagy is an important cellular response to stress, and plays essential roles in development, aging, immunity, cancer and neurodegeneration. Thus, autophagy is considered a promising target for disease therapies. Studies of yeast led to the identification of conserved factors that regulate autophagy, but the role of autophagy in specific cell contexts during aging of multi-cellular organisms has not been rigorously studied. Recent studies of autophagy and how this process contributes to stem cell, tissue and organism health during aging will be presented.

Aging and Mtor: Challenges In Sustaining Metabolic And Protein Homeostasis
Brendan D. Manning, Ph.D, Harvard School of Public Health, Boston, MA

Metabolic processes within cells must be managed by integrated control mechanisms that sense the nutrient status of both the cell and organism. The mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) is a key signaling node, universal to eukaryotic cells, which links the sensing of nutrients to the coordinated regulation of cellular metabolism. mTORC1 has the ability to sense and integrate signals from a variety of sources, including intracellular nutrients and secreted growth factors. The physiological and pathological activation of mTORC1 results in downstream changes in cellular metabolism, with a shift from catabolic processes to anabolic biosynthetic processes. mTORC1 activity has been found in multiple species from yeast to mammals to contribute to aging, and mTORC1 is chronically activated in a variety of aging-related diseases. Through unbiased genomic and metabolomic approaches, we have found that, in addition to its established roles in promoting protein synthesis and inhibiting autophagy, mTORC1 stimulates changes in specific metabolic pathways through transcriptional and posttranslational effects on metabolic enzymes. In this manner, mTORC1 serves to link growth signals to metabolic processes that promote the growth of cells, tissues, and organisms, including the de novo synthesis of proteins, lipids, and nucleic acids. In addition, we have recently uncovered a novel and surprising role for mTORC1 in controlling cellular protein and amino acid homeostasis through the coordinated regulation of protein synthesis and degradation. This seemingly paradoxical function of mTORC1 serves as both a quality control mechanism to handle the increase in misfolded proteins that accompanies elevated rates of protein synthesis and as a means of maintaining adequate pools of intracellular amino acids to sustain new protein synthesis. The potential implications of these downstream functions of mTORC1 in understanding the pathological manifestations of aging will be discussed.

Proteostasis In Biology, Aging, And Disease
Richard I. Morimoto, Department of Molecular Biosciences, Rice Institute for Biomedical Research, Northwestern University, Evanston, IL 60208, USA

The proteostasis network (PN) is essential for the health of the proteome, optimal tissue function, and lifespan.  Under ideal conditions, the PN prevents misfolding and aggregation that arises from genetic polymorphisms, error-prone synthesis, and mutations, that are exacerbated by stress, aging, and disease.  Critical components of the PN include the heat shock response (HSR), the unfolded protein responses, and antioxidant response that function in concert to protect the proteome against damage.  Despite these protective networks, the expression of 1/3^rd of the human chaperome declines during brain aging and further in Alzheimer's, Huntington's and Parkinson's disease.  Functional RNAi assays with C. elegans models of Ab and polyQ expression revealed that a core chaperome of 16 genes are essential to prevent misfolding and proteotoxicity.  In C. elegans, this age-dependent decline in the HSR and other stress responses occurs abruptly upon reproductive maturity and appears to be regulated by epigenetic chromatin repressive marks that restricts the accessibility of HSF-1 to the promoter regions of HS genes.  At the organismal level, the transmission of stress signals across tissues involves cell non-autonomous signaling from the environment to sensory neurons to regulate the HSR of somatic tissues, and by transcellular chaperone signaling to achieve balanced organismal expression of chaperones between tissues expressing different levels of damaged proteins and altered levels of chaperones.  Orchestration of chaperone networks, therefore communicates the proteostatic state among cells and surrounding tissues, to adjust the PN throughout development and adulthood and to prevent the consequences of stress-induced proteotoxic damage.

Role of Complement Cascade in Synapse Loss and Cognitive Aging
Beth Stevens, Kirby Neurobiology Center, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115

Early synapse loss is a hallmark of aging and Alzheimer's disease (AD) but what makes synapses vulnerable remains elusive. During development, synapse pruning is a normal and highly regulated process, required for proper brain wiring and synaptic connectivity. Recent work has revealed unexpected roles for proteins of the classical complement cascade, an innate immune pathway, and microglia, immune cells that reside in the CNS, for elimination and refinement of synaptic connections in postnatal mouse brains. In developing brain, C1q and C3 are deposited onto less active synapses for elimination by microglia that express CR3. We hypothesized that similar mechanisms of synapse pruning may be involved to drive synapse loss in the aging brain and in the early stages of AD pathogenesis. We found an early, region-specific up regulation and deposition of complement (C1q) onto synapses in hippocampus and regions vulnerable to synapse loss, in two mouse models of Alzheimer's disease.  Preliminary results suggest genetic deletion of classical complement cascade components protect against early synapse loss and dysfunction in AD mouse models. Together our results suggest that aberrant reactivation of a normal developmental pruning pathway may work together to mediate early synapse loss in AD. . This study also has broad therapeutic implications for AD and other age dependent neurodegenerative diseases involving synaptic loss and dysfunction.

The Anti-Aging Protein Klotho as a New Target for Treating Neurodegenerative Diseases
Carmela R. Abraham, PhD¹

In Alzheimer’s disease (AD), amyloid beta peptides (Ab) accumulate in the brain and are toxic to neurons and synapses. Strategies either to interfere with Aβ formation or enhance its clearance have not succeeded in slowing the progression of the disease. We propose a novel approach intended to protect neurons from the toxicity of Aβ and other age-related insults. Studying the anti-aging protein Klotho, our group has made four important discoveries that have profound relevance to AD and likely other neurodegenerative disorders. We found that: 1) the levels of Klotho, which protects mice and humans from aging and disease, are much lower in the aged healthy brain, in brains of AD patients and animal models of AD, 2) Klotho is able to rescue hippocampal neurons from Aβ and from oxidative stress and death induced by the excitotoxic amino acid glutamate, 3) a potentially novel molecular mechanism is responsible for the Klotho-induced neuroprotection, and 4) small molecule compounds that were developed from hits from a high throughput screen to enhance Klotho expression, can mimic Klotho’s neuroprotective functions and rescue neurons from death. Furthermore, Klotho induces the differentiation of oligodendrocyte progenitor cells (OPCs) into myelinating oligodendrocytes. This is particularly important for multiple sclerosis (MS) where there are plenty of OPCs around MS plaques, but where they fail to differentiate into mature myelin-forming cells. In summary, Klotho exhibits neuroprotective properties to neurons and promotes differentiation of oligodendrocytes and, therefore, Klotho enhancing small molecule compounds that cross the blood-brain barrier could become novel therapeutics for AD and MS.
 
Coauthors: Ci-Di Chen, PhD¹, Marcie A. Glicksman, PhD², Kevin Hodgetts, PhD², Satish Medicetty, DVM, PhD³, and Ella Zeldich, PhD^1
1Boston University School of Medicine, Boston, MA
²Laboratory for Drug Discovery in Neurodegeneration, Brigham and Women’s Hospital, Boston, MA
³Renovo Neural, Inc., Cleveland, OH

Stimulation of macroautophagy with small molecules
Haung Yu, PhD, Yasir Qureshi, MD, Amanda L Chi, Matthieu Herman,
Taub Institute, Department of Pathology and Cell Biology, Columbia University

Autophagy is a major pathway for the clearance of redundant and aberrant proteins in cells, in addition to removal of defective organelles, like mitochondria. In neurodegenerative diseases like Alzheimer’s disease, this process may be inefficient and this can be attributed to a reduction in the amount of autophagy or a downstream disruption of autophagic-lysosomal processing. Using models of tauopathy, an investigation of small molecule activators of were investigated for their capacity to reduce phospho- and aggregated tau in cells and organotypic brain slice cultures from tau transgenic models. This presentation will discuss use of an organic molecule, trehalose, in addition to the identification of a lead compound and a series of modified structures for their capacity to induce autophagy. This study also demonstrates that upregulation of autophagy can successfully ameliorate proteinopathy and reduce the physiological and behavioral deficits associated with tauopathy.

A New Mitochondrial Target for Neurodegenerative Disease
Jerry R. Colca, Ph.D.Metabolic Solutions Development Company, Kalamazoo Michigan

Alzheimer's disease and other neurodegenerative diseases have a contributing metabolic dysfunction that includes a progressive loss of mitochondrial function.  This likely is a key reason while these diseases progress with aging.  It is also commonly observed that neurodegenerative diseases are associated with a phenomenon known as insulin resistance, where growth factor signaling is impaired.  Over the years, "insulin sensitizers" have shown positive results in preclinical models of neurodegeneration. We have recently found a previously unappreciated protein complex in the internal mitochondrial membrane that binds insulin sensitizing molecules.  This complex, which we have termed mTOT (mitochondrial target of the thiazolidinediones), includes key components of the mitochondrial pyruvate carrier as well as other important machinery that coordinates oxidative metabolism.  We have shown that treatment with a prototype mTOT modulator insulin sensitizer (MSDC-0160) maintains FDG-PET patterns patients with mild to moderate Alzheimer's in a three month clinical trial, indicative of central effects.  This presentation will summarize the results from this clinical trial and provide an update on the understanding of this new mitochondrial target. It is possible that modulation of metabolism with this pharmacology could provide a pathway to modify the course of neurodegenerative diseases.

Targeting Neuroinflammation by Inhibiting Glial Cell Cytokine Overproduction
D. Martin Watterson, PhD, Northwestern University Feinberg School of Medicine

Perturbation of homeostasis mechanisms critical to synaptic function is a component of pathology progression in diverse neurodegenerative diseases and the neurologic sequelae to brain injury. Stressor induced upregulation of proinflammatory cytokine production and the associated synaptic dysfunction is considered a key player in these mechanisms due to disruption of the glia-neuronal axis. Attenuation of the pathology progression offers the potential of disease modifying therapeutic intervention. We have applied a CNS focused drug discovery engine to the development of novel small molecule candidates that attenuate this injurious proinflammatory cytokine overproduction and the associated synaptic dysfunction. The discovery engine is a recursive, biology-driven chemistry platform that leverages small molecule pharmacoinformatics at the design and synthesis planning stage, and includes early pharmacological parsing of the novel synthesized compounds. The presentation will cover two distinct classes of drug candidates emerging from the application of this discovery engine. One class is a preclinical deliverable at the IND enabling stage that uses the popular single molecular target approach and employs high resolution co-crystallography and pharmacoinformatics based on small molecule CNS drugs. The second class that is in clinical trials stage emerged from the classical and more unbiased phenotypic approach with heavy dependence on pharmacoinformatics based on small molecule CNS drugs and re-utilization of validated CNS drug scaffolds. Both classes of compounds are orally active, brain-penetrant, small molecules that are selective, efficacious and safe in preclinical animal models of Alzheimer's disease. Our data suggest that selective targeting of the dysregulated cytokine response, a component of the neuroinflammation that contributes to synaptic dysfunction, is an attractive therapeutic strategy for neurodegenerative disorders such as Alzheimer's disease.

Biological and Chemical Approaches to Adapt Proteostasis to Ameliorate Protein Aggregation Diseases
Jeffery W. Kelly, Departments of Chemistry and Molecular and Experimental Medicine, and The Skaggs Institute of Chemical Biology, The Scripps Research Institute

The cellular protein homeostasis, or proteostasis network, regulates proteome function by controlling ribosomal protein synthesis, chaperone and enzyme mediated protein folding, protein trafficking, protein degradation and the like. Stress responsive signaling pathways match proteostasis network capacity with demand in each subcellular compartment to maintain cellular homeostasis. The beginning of the seminar will focus on how the proteostasis network can be adapted through unfolded protein response arm-selective signaling to alleviate gain-of-toxic-function diseases where excessive secretion of misfolding and aggregation of proteins leads to the amyloid diseases. The second part of the seminar will focus on a chemical strategy to achieve protein homeostasis, wherein small molecule kinetic stabilizers produced by structure-based drug design are employed to halt the progression of peripheral neuropathy in the human disease familial amyloid polyneuropathy linked to transthyretin amyloidogenesis. I will explain how delineating the molecular mechanism of transthyretin aggregation linked to pathology led to a regulatory agency approved drug. Since this is the first pharmacologic evidence supporting the amyloid hypothesis, the notion that protein aggregation causes degeneration of the heart and the nervous system, the last part of the seminar will focus on what we have learned about the etiology of these diseases vis-à-vis a successful clinical trial.

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