Scenes from the Summit: PPAR-y and Metabolic Pathways in Alzheimer's Disease
Posted August 28, 2007
In recent years, Alzheimer's disease research has been focused on the pathways associated with the proteins amyloid-β (Aβ) and tau in the brain. But the well-characterized buildup of amyloid plaques and tangles of tau are not the only biochemical phenomena wrought by this neurodegenerative disease. A May 21, 2007, meeting of the Neurodegenerative Diseases Discussion Group focused on alternative ideas about AD, inspired by reports of the biological activity of PPAR-γ (peroxisome proliferator-activated receptor gamma), the main target of insulin-sensitizing drugs such as rosiglitazone.
More broadly, the discussion considered the roles of metabolic dysregulation, insulin resistance, oxidative stress, and cell death signaling in the molecular mechanisms of AD. Talks looked at metabolic disturbances involved in many of the pathologic processes seen in Alzheimer's disease; connections between insulin resistance, diabetes, and AD; a Phase 2 trial of the diabetes drug and PPAR-γ agonist rosiglitazone (Avandia) in Alzheimer's patients; and evidence that glucagon-like peptide-1 (GLP-1) and the GLP-1 agonist exenatide (the diabetes drug known as Byetta) promote neuronal survival in models of AD, Parkinson's disease, and stroke. Tests also showed that using treatment with a p53 inhibitor in these models reduced cell death, much to the same effect.
Use the tabs above to find a meeting report and multimedia from this event.
Alzforum, the master site for research information on Alzheimer's Disease, takes on the question of whether AD should be considered a type of diabetes at in a discussion led by de la Monte. An older discussion about the role of NSAIDs and inflammation in AD is also available.
The Web site for Amylin Pharmaceuticals, the manufacturer of Byetta, includes some clinical and mechanistic information, including clinical data, education briefs for clinical professionals on the activity incretin hormones, and a description of activity of GLP-1.
A compendium of information on GLP-1, GLP-2, DPP-IV, the origins of exendin-4, and other related subjects can be found at this website maintained by Daniel J. Drucker, a professor of medicine in the division of endocrinology at the University of Toronto.
An interactive map of PPAR-γ pathways can be found at the Web site of Penn State University molecular toxicologist Jack Vanden Heuvel.
Brain Insulin Deficiency and Insulin Resistance in Alzheimer's Disease
De la Monte SM, Tong M, Lester-Coll N, et al. 2006. Therapeutic rescue of neurodegeneration in experimental type 3 diabetes: relevance to Alzheimer's disease. J. Alzheimers Dis. 10: 89-109.
De la Monte SM, Wands JR. 2005. Review of insulin and insulin-like growth factor expression, signaling, and malfunction in the central nervous system: relevance to Alzheimer's disease. J. Alzheimers Dis. 7: 45-61. 14 (PDF, 148 KB) Full Text
Kinoshita J, Fagan A, Ewbank D, et al. 2006. Alzheimer Research Forum live discussion: Insulin resistance: a common axis linking Alzheimer's, depression, and metabolism? J. Alzheimers Dis. 9: 89-93.
Lester-Coll N, Rivera EJ, Soscia SJ, et al. 2006. Intracerebral streptozotocin model of type 3 diabetes: relevance to sporadic Alzheimer's disease. J. Alzheimers Dis. 9: 13-33.
Rivera EJ, Goldin A, Fulmer N, et al. 2005. Insulin and insulin-like growth factor expression and function deteriorate with progression of Alzheimer's disease: link to brain reductions in acetylcholine. J. Alzheimers Dis. 8: 247-268.
Steen E, Terry BM, Rivera EJ, et al. 2005. Impaired insulin and insulin-like growth factor expression and signaling mechanisms in Alzheimer's disease—is this type 3 diabetes? J. Alzheimers Dis. 7: 63-80. (PDF, 273 KB) Full Text
Dietary Lifestyle Factors and Alzheimer's Disease
Ho L, Qin W, Pompl PN, et al. 2004. Diet-induced insulin resistance promotes amyloidosis in a transgenic mouse model of Alzheimer's disease. FASEB J. 18: 902-904. (PDF, 126 KB) Full Text
Patti ME, Butte AJ, Crunkhorn S, Cusi K. 2003. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. PNAS 100: 8466-8471. Full TextQin W, Chachich M, Lane M, et al. 2006. Calorie restriction attenuates Alzheimer's disease type brain amyloidosis in Squirrel monkeys (Saimiri sciureus). J. Alzheimers Dis. 10: 417-422.
Qin W, Yang T, Ho L, et al. 2006. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 281: 21745-21754. Full Text
Wang J, Ho L, Qin W, et al. 2005. Caloric restriction attenuates β-amyloid neuropathology in a mouse model of Alzheimer's disease. FASEB J. 19: 659-661. (PDF, 505 KB) Full Text
Efficacy Pharmacogenetics Of Rosiglitazone In Alzheimer's Disease
Nicodemus KK, Stenger JE, Schmechel DE, et al. 2004. Comprehensive association analysis of APOE regulatory region polymorphisms in Alzheimer disease. Neurogenetics 5: 201-208.
Risner ME, Saunders AM, Altman JF, et al. 2006. Efficacy of rosiglitazone in a genetically defined population with mild-to-moderate Alzheimer's disease. Pharmacogenomics J. 6: 246-254.
Roses AD. 2006. On the discovery of the genetic association of Apolipoprotein E genotypes and common late-onset Alzheimer disease. J. Alzheimers Dis. 9 (3 Suppl): 361-366.
Roses AD, Saunders AM, Huang Y, et al. 2007. Complex disease-associated pharmacogenetics: drug efficacy, drug safety, and confirmation of a pathogenetic hypothesis (Alzheimer's disease). Pharmacogenomics J. 7: 10-28.
New Strategies to Treat Neurodegenerative Diseases
Doyle ME, McConville P, Theodorakis MJ, et al. 2005. In vivo biological activity of exendin (1-30). Endocrine 27: 1-9.
Perry T, Greig NH. 2002. The glucagon-like peptides: a new genre in therapeutic targets for intervention in Alzheimer's disease. J. Alzheimers Dis. 4: 487-496.
Perry T, Greig NH. 2003. The glucagon-like peptides: a double-edged therapeutic sword? Trends Pharmacol Sci. 24(7): 377-83.
Perry T, Greig NH. 2004. A new Alzheimer's disease interventive strategy: GLP-1. Curr. Drug Targets 5: 565-571.
Perry T, Greig NH. 2005. Enhancing central nervous system endogenous GLP-1 receptor pathways for intervention in Alzheimer's disease. Curr. Alzheimer Res. 2: 377-385.
Perry T, Holloway HW, Weerasuriya A, et al. 2007. Evidence of GLP-1-mediated neuroprotection in an animal model of pyridoxine-induced peripheral sensory neuropathy. Exp. Neurol. 203: 293-301. Full Text
Perry T, Lahiri DK, Sambamurti K, et al. 2003. Glucagon-like peptide-1 decreases endogenous amyloid-β peptide (Aβ) levels and protects hippocampal neurons from death induced by Aβ and iron. J. Neurosci. Res. 72: 603-612.
Suzanne de la Monte, MD, MPH
Suzanne de la Monte is a research professor of pathology and medicine in the division of gastroenterology at the Warren Alpert Medical School of Brown University, and pathologist and neuropathologist at Rhode Island Hospital and Miriam Hospital. Her research investigates the role of insulin in neurodegeneration, including the role of insulin deficiency and resistance in Alzheimer's disease, the effects of chronic ethanol exposure on fetal development as mediated through insulin-stimulated signaling in neuronal development and migration, and the process of neurodegeneration in alcoholics.
De la Monte received her MD from Cornell University Medical College in 1977 and an MPH from Johns Hopkins in 1984. Following residencies in pathology and neuropathology at Johns Hopkins Hospital, she joined Massachusetts General Hospital as a pathology fellow. In 1989 she joined Harvard Medical School as an assistant professor in pathology, and in 2000 was appointed to the faculty of the pathobiology graduate program at Brown University and became an associate pathologist and neuropathologist at Rhode Island Hospital. De la Monte was awarded the Alzheimer Medal in 2000 for demonstrating the role that cerebrovascular injury plays in manifestations of Alzheimer's disease, and an award from the Tan Yan Kee Foundation in 2005 for the study of insulin resistance in AD.
Giulio Maria Pasinetti, MD, PhD
Giulio Maria Pasinetti is professor of psychiatry, neuroscience, and geriatrics and adult development at Mount Sinai School of Medicine in New York. Using microarrays and other gene-expression techniques, his lab explores the biological changes that underlie Alzheimer's Disease, particularly in its earliest stages. His group has generated a profile of early gene expression changes in AD, and is studying the functional role of these abnormally expressed genes in the brain.
Pasinetti received his MD in 1982 from the University of Milan Medical School in Milan, Italy and his PhD in pharmacology from the University of Milan in 1988. He joined the University of Southern California as a research associate in gerontology in 1984, and was appointed an assistant professor in gerontology and biological sciences in 1990. In 1996 he came to Mount Sinai as assistant professor of psychiatry. In addition to his current role at Mount Sinai, Pasinetti is also director of the Translational Neuroscience Laboratories at Bronx Veterans Affairs Medical Center. His awards include the Temple Foundation Discovery Award from the Alzheimer's Association in 1999 and the Dana Alliance for Brain Initiatives Award in 2002.
Anthony Akkari, PhD
Anthony Akkari is human genetics manager in the Genetics Research Department of GlaxoSmithKline USA. He is also director of research at Molecular Research Technologies Pty Ltd. Akkari has conducted genetic studies of susceptibility to Parkinson’s disease, ALS, and pulmonary fibrosis, and is currently involved in the design, implementation, and communication about pharmacogenetic studies related to early and late-stage development of pharmaceutical treatments of Parkinson’s. Born in Australia, he earned his PhD at Curtin University and held positions at the Center for Neuromuscular and Neurological Disorders and the University of Western Australia.
Nigel Greig, PhD
Nigel Greig is senior investigator and chief of the Drug Design & Development Section in the Laboratory of Neurosciences within the Intramural Research Program of the National Institute on Aging, National Institutes of Health. His laboratory investigates neurodegenerative and neuroprotective signaling pathways to identify potential drug targets, and designs and synthesizes new candidate drugs to protect against age-related cognitive decline, neurodegenerative disease and diabetes.
Greig received his PhD in pharmacology from the University of London in 1982. He joined the National Institute on Aging, NIH, the same year. Discoveries from his research there were licensed from the National Institutes of Health and helped form the basis of several companies, including Athena Neurosciences (now Elan) and Axonyx. His research has resulted in experimental drugs that have translated from concept to the clinic, as well as pharmacological tools to elucidate disease mechanisms. The work of Greig and his collaborators has resulted in numerous publications and patents and was recently recognized in the form of the 2007 Sato Memorial International Award.
Kathleen McGowan is a freelance magazine writer specializing in science and medicine.