Is Alzheimer's Disease Type 3 Diabetes?

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Is Alzheimer's Disease Type 3 Diabetes?

Tuesday, October 27, 2009

The New York Academy of Sciences

The two hallmarks of Alzheimer’s Disease (AD) are amyloid plaque deposition and hyperphosphorylated tau-mediated tangle formation. While inhibitors of these processes are now being studied in the clinic, currently available therapies such as cholinesterase inhibitors and the NMDA antagonist memantine only treat symptoms of AD. A less-studied aspect of AD etiology involves insulin dysregulation in the brain.

Recent studies of postmortem brains from AD patients suggest that sporadic AD may result from a cascade involving dysregulated neuronal insulin signaling systems. This cascade is associated with generation of reactive oxygen and nitrogen species, mitochondrial dysfunction and cholinergic neuronal degeneration, in addition to plaque and tangle formation. Whether AD is Type 3 diabetes, unique to the brain, or whether diabetes is a risk factor for AD remains to be elucidated. Understanding the connection between insulin function and AD might enable discovery of a drug-combination that prevents, delays, or halts progression of sporadic AD.

Agenda


Tuesday, October 27, 2009

12:30 pm

Registration

1:00 pm

Introduction
Barbara Petrack, Drew University

1:10 pm

Adiposity, Hyperinsulinemia, Diabetes, and Alzheimer's Disease: an Epidemiological Perspective
José A. Luchsinger, Columbia University

1:50 pm

Mechanisms by Which a Couch Potato Lifestyle Predisposes to Alzheimer’s Disease
Mark Mattson, National Institute on Aging, NIH

2:30 pm

Refreshments

3:00 pm

A Synaptic Struggle for Survival: Insulin Signaling versus Alzheimer's Toxic Aß Oligomers
William L. Klein, Northwestern University

3:40 pm

Insulin Resistance and Neurodegeneration: Type 2 versus Type 3 Diabetes Mellitus
Suzanne M. de la Monte, Brown Medical School

4:20 pm

Panel Discussion

Speakers

Organizers

Barbara Petrack

Drew University

Dr. Barbara Petrack received her Ph.D. from New York University Medical Center and completed a Post-Doctoral Fellowship at Rockefeller University. She had an extensive career in biochemical research at Geigy/CIBA-GEIGY/Novartis before joining Drew University in1997 She is a Fellow of the NYAS, was a charter member of the BPDG and is still on its steering committee, and was Chair of the Biochemistry Section. Currently she is Chair of the ACS-NY Section’s Biochemical Topical Group.

Jean Lachowicz

Schering-Plough Research Institute

Dr. Lachowicz joined the Schering Plough Research Institute in 1996 as an Associate Principal Scientist in the CNS/Cardiovascular Therapy Area, and she now serves as a Director in the Cardiovascular and Metabolic Disease Therapy Area. She has worked on several drug targets within these areas, including Alzheimer's Disease, Parkinson's Disease, Depression, Obesity, Type 2 Diabetes, and Thrombosis. While her group is focused mainly on drug discovery, Dr. Lachowicz has also been involved in early development of drug products through proof-of-concept. Educated at Brown and Duke Universities with postdoctoral training at NIH, she held a faculty position at Indiana University School of Medicine before joining Schering-Plough.

Speakers

Suzanne M. de la Monte

Brown Medical School

Dr. Suzanne M. de la Monte received her undergraduate degree from Cornell University, MD from Cornell University Medical College, and MPH from The Johns Hopkins Bloomberg School of Public Health. She completed her Anatomic Pathology residency at Johns Hopkins Hospital, and Neuropathology fellowship at the Massachusetts General Hospital/Harvard Medical School. She developed her academic career in basic and translational research working at the Mass General, and in 2000, she joined the faculty at Rhode Island Hospital and the Alpert Medical School of Brown University, where she is currently Professor of Pathology (Division of Neuropathology) and Neurology, and holds an appointment in the Dept. of Medicine. Dr. de la Monte’s research is supported by several grants from the NIH. Her major research efforts are focused on mechanisms and consequences of brain insulin resistance. Her research helped lead to the novel concept that Alzheimer's is a form of brain diabetes. Apart from her research, Dr. de la Monte directs courses in molecular neuroscience, neuropathology, and research methodology, and serves on a number of academic committees at Brown and the Rhode Island Hospital.

William L. Klein

Northwestern University

Dr. William L. Klein is Professor of Neurobiology and Physiology at Northwestern University, Evanston, Illinois. He and his colleagues have pioneered the concept that memory loss in Alzheimer’s disease is initiated by soluble amyloid beta oligomers, small neurotoxins that target particular synapses and cause their functional and structural degeneration. Formerly Director of Northwestern’s Interdepartmental Graduate Program in Neuroscience, Dr. Klein currently is a member of the university’s Cognitive Neurology and Alzheimer’s Disease Center and the Nanoscale Science and Engineering Center. Dr. Klein serves on the editorial board of the Journal of Biological Chemistry and the scientific advisory board of Acumen Pharmaceuticals, a biotech he co-founded. After graduating from MIT in biology, Dr. Klein carried out predoctoral studies in protein biochemistry at UCLA with Paul Boyer (Nobel Prize, Chemistry) and postdoctoral studies in molecular neurobiology at NIH with Marshall Nirenberg (Nobel Prize, Physiology and Medicine). His research team at Northwestern has provided new insights into physiological synaptic signal transduction and cell biology and more recently into the patholobiology of synapses in Alzheimer’s disease. In a seminal contribution, Dr. Klein’s team discovered that amyloid fibrils are not the only neurotoxins formed by Aβ peptide and likely not the most important ones: Aβ also generates small, soluble oligomers that are long-lived CNS neurotoxins capable of destroying the synaptic basis for memory and ultimately causing nerve cell death. Klein’s team established toxic oligomers (also known as ADDLs) as a major feature of AD neuropathology through use of unique toxin-sensitive antibodies now under development for therapeutics. Their discovery that ADDLs are highly elevated in CSF of Alzheimer’s patients offers promise as a diagnostic biomarker. Mechanistic studies have revealed ADDLs to be gain-of-function ligands that attack particular synapses, provoking neuronal changes that account for both memory loss and major features of AD neuropathology. As described in the Progress Report on Alzheimer’s Disease published by the US Department of Health and Human Services, Aβ oligomers are now widely regarded as the primary cause of Alzheimer’s nerve cell damage and memory loss. Investigations into toxic oligomers have provided an archetypal mechanism now considered applicable to multiple diseases of fibrillogenic protein. By explaining why Alzheimer’s is a disease of memory and accounting for major pathological changes of Alzheimer’affected brain, ADDL toxicity provides a unifying molecular mechanism for pathogenesis, underscoring the importance of ADDLs as targets for new clinical diagnostics and disease-modifying therapeutics.

José A. Luchsinger

Columbia University

José Alejandro Luchsinger, MD MPH is a Florence Irving Associate Professor of Medicine and Epidemiology at the Gertrude H. Sergievsky Center at Columbia University Medical Center in New York City. His area of interest is the role of vascular risk factors and diet in cognitive disorders, with particular emphasis on type 2 diabetes and related conditions such as obesity and insulin resistance. He is the principal investigator of several related studies including a clinical trial of a diabetes medication in mild cognitive impairment, a cohort study of cognitive impairment in persons with diabetes, a cohort study of risk factors of Alzheimer’s disease, and ancillary studies of cognition in 2 clinical trials of the prevention of diabetes. He has received funding from the National Institutes of Health, the New York Academy of Medicine, the Fidelity Foundation, the Alzheimer’s Association, the American Diabetes Association, the Alzheimer’s Disease Drug Discovery Foundation, and the Florence and Herbert Irving Clinical Research Scholars Program.

Mark Mattson

National Institute on Aging, NIH

After receiving his PhD degree from the University of Iowa, Dr. Mattson completed a postdoctoral fellowship in Developmental Neuroscience at Colorado State University. He then joined the Sanders-Brown Center on Aging and the Department of Anatomy and Neurobiology at the University of Kentucky College of Medicine as an Assistant Professor. Dr. Mattson was promoted to the rank of Associate Professor with tenure and then to Full Professor. In 2000, Dr. Mattson took the position of Chief of the Laboratory of Neurosciences at the National Institute on Aging in Baltimore, where he leads a multi-faceted research team that applies cutting-edge technologies in research aimed at understanding molecular and cellular mechanisms of brain aging and the pathogenesis of neurodegenerative disorders. He is also a Professor in the Department of Neuroscience at Johns Hopkins University School of Medicine. Dr. Mattson is considered a leader in the area of cellular and molecular mechanisms underlying neuronal plasticity and neurodegenerative disorders, and has made major contributions to understanding the pathogenesis of Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, and to their prevention and treatment. Dr. Mattson is the most highly cited neuroscientist in the world according to the ISI information database. He has published more than 400 original research articles and numerous review articles in leading journals and books, and has edited 10 books in the areas of neuronal signal transduction, neurodegenerative disorders and mechanisms of aging. He has received many awards including the Metropolitan Life Foundation Medical Research Award, the Alzheimer’s Association Zenith Award, the Jordi Folch Pi Award, the Santiago Grisolia Chair Prize, and several Grass Lectureship Awards. He is Editor-in-Chief of two journals and on the editorial boards of more than 20 journals. Dr. Mattson has trained more than 60 postdoctoral and predoctoral scientists, and has made major contributions to the education of undergraduate, graduate and medical students.

Abstracts

Adiposity, Hyperinsulinemia, Diabetes, and Alzheimer's Disease: an Epidemiological Perspective

José A. Luchsinger, Columbia University

This presentation will provide a comprehensive review of the epidemiologic evidence linking the continuum of adiposity, hyperinsulinemia, and type 2 diabetes (T2D) with Alzheimer’s disease (AD). Most of the data shown is from a longitudinal study of aging in Northern New York City. The mechanisms linking this continuum to AD may include hyperinsulinemia, advanced products of glycosilation, cerebrovascular disease, and products of adipose tissue metabolism. Elevated adiposity in middle age is related to a higher risk of AD1 but the data on this association in old age is conflicting2. The relation of adiposity with AD is attenuated in older ages, and measures of central adiposity may capture this relationship better than classical measures such as body mass index2, 3. Hyperinsulinemia, a consequence of higher adiposity and insulin resistance is also related to a higher risk of AD4. Hyperinsulinemia is a risk factor for T2D, and T2D is also related with higher AD risk5. The association between this continuum and AD has strong biologic plausibility. This continuum is a cause of cerebrovascular disease, which has an important role in the precipitation of AD. In addition, hyperinsulinemia has been shown to be important in the clearance of amyloid beta, the putative culprit of AD. The implication of these associations is that a large proportion of the world population may be at increased risk of AD given the trends for increasing prevalence of elevated adiposity, hyperinsulinemia, and T2D. However these associations may present a unique opportunity for prevention and treatment of AD. Several studies in the prevention and treatment of T2D are currently conducting or have planned cognition ancillary studies. In addition, clinical trials using insulin sensitizers in the treatment or prevention of AD are under way.

1. Whitmer RA, Gunderson EP, Barrett-Connor E, et al. 2005. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ bmj.38446.466238.E466230.
2. Luchsinger JA, Patel B, Tang MX, et al. 2007. Measures of adiposity and dementia risk in elderly persons. Arch. Neurol. 64(3):392-398.
3. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. 2008. Central obesity and increased risk of dementia more than three decades later. Neurology 71(14):1057-1064.
4. Luchsinger JA, Tang M-X, Shea S, Mayeux R. 2004. Hyperinsulinemia and risk of Alzheimer disease. Neurology 63(7):1187-1192.
5. Luchsinger JA, Reitz C, Honig LS, et al. 2005. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 65(4):545-551.

Mechanisms by Which a Couch Potato Lifestyle Predisposes to Alzheimer’s Disease

Mark P. Mattson, National Institute on Aging

Advancing age and diabetes are major risk factors for cognitive impairment and Alzheimer’s disease (AD). Because average lifespan and the prevalence of diabetes are both increasing, it is important to aggressively pursue novel preventative strategies. Regular exercise, cognitive challenges and dietary moderation may reduce the risk of cognitive decline. Each of the latter lifestyle factors may protect neurons by activating adaptive cellular stress response signaling pathways involving transcription factors (Nrf-2, FOXO and CREB) that induce the expression of neurotrophic factors (BDNF, bFGF, GDNF…), antioxidant enzymes (MnSOD, HO-1, NQO1…) and protein chaperones (HSP-70, GRP-78…). Some of these pathways may also mediate the enhancement of hippocampal neurogenesis and synaptic plasticity in response to exercise, dietary energy restriction and cognitive stimulation. Conversely, diabetes suppresses neurotrophic factor signaling, and may also reduce levels of endogenous antioxidants and protein degradations pathways. Sustained elevations of adrenal glucocorticoid levels may contribute to the adverse effects of diabetes on neuronal plasticity and cognitive function. Our recent findings suggest that it is possible to activate beneficial adaptive stress response signaling pathways in neurons using natural products and synthetic analogs thereof. The translation of such basic research findings into preventative and therapeutic treatments for human subjects is being pursued.

Explaining Insulin Resistance in the Alzheimer's Brain: The Attack on CNS Insulin Receptors by Abeta Oligomers (ADDLs)

William L. Klein, Northwestern University

Brain insulin signaling appears to be compromised in Alzheimer’s disease, leading to the intriguing suggestion that Alzheimer’s constitutes a type 3 diabetes. This idea is strongly supported by the relationship between CNS insulin receptors and the soluble neurotoxins now thought to initiate Alzheimer’s neuronal damage and dementia. These neurotoxins comprise diffusible oligomers of the amyloid beta peptide (Aβ). Abeta oligomers (also referred to as ADDLs) have emerged as prominent alternatives to amyloid plaque fibrils in providing a molecular basis for Alzheimer’s pathogenesis. ADDLs accumulate extracellularly in the CNS and act as synaptotoxic ligands, binding with specificity to particular synapses, where they cause damage to synapse composition, morphology, and plasticity. Recently, it has been found that the attack on synapses by ADDLs results in a striking loss of insulin receptors from synaptic membranes. Impaired brain insulin signaling has ramifications for energy use as well as for synaptic information processing germane to learning and memory. Loss of insulin receptors from the surface membrane appears to be an ADDL-induced deficiency in trafficking, seen as well for certain other receptors involved in synaptic plasticity. Insulin resistance in AD brain putatively may be considered a key facet of the overall pathological impact of ADDLs on CNS synapses. Somewhat remarkably, insulin signal transduction is capable of protecting itself against ADDL toxicity, with receptor activity causing down-regulation of ADDL binding sites. Insulin and ADDL signaling thus engage in a struggle for synapse survival. These findings give rise to the concept that impairments in brain insulin signaling that occur with other diseases or aging should be regarded as potential AD risk factors, with maintenance of robust brain insulin signaling a prerequisite for defending the nervous system against Alzheimer’s disease.

Insulin Resistance and Neurodegeneration: Type 2 versus Type 3 Diabetes Mellitis

Suzanne M. de la Monte, Brown Medical School

Evidence suggests that Alzheimer’s Disease (AD), like Type 2 diabetes mellitus (T2DM), is caused by insulin resistance. Human brain studies revealed significant deficits in insulin polypeptide and receptor gene expression and impaired receptor binding in AD. These abnormalities worsen as AD progresses, and correlate with cholinergic deficits. We suggested that AD be regarded as T3DM. Correspondingly, an experimental model of T3DM was produced by intracerebral injection of Streptozocin, and the associated neurodegeneration and cognitive impairment were ameliorated by early treatment with insulin sensitizer drugs. However, the significant correlations between obesity or T2DM and cognitive impairment, and the two-fold increased risk for AD in people with T2DM, prompted additional studies to clarify the role of T2DM in relation to neurodegeneration. Obesity with T2DM and NASH was found sufficient to cause brain atrophy, cognitive impairment, and brain insulin resistance with deficits in acetylcholine, but the structural and biochemical brain abnormalities were considerably less than in AD/T3DM. Therefore, obesity, T2DM, and NASH may contribute to AD progression, but are not sufficient to cause AD. Recent work suggests roles for neurotoxic lipids, i.e. ceramides, generated in liver and capable of crossing the blood-brain barrier, as mediators of brain insulin resistance and neurodegeneration in obesity, T2DM, and NASH. These findings support the concept that T2DM/NASH causes cognitive impairment and brain insulin resistance via a liver-brain axis of neurodegeneration, which is distinct from the primary neurodegeneration in AD/T3DM. This lecture will review the role of brain insulin resistance as a major factor leading to cognitive impairment and neurodegeneration, including Alzheimer's disease. The contributions of Type 2 diabetes and metabolic syndrome to the pathogenesis of Alzheimer's will be discussed.

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