Abstract
Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer’s disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4 corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or “infects” Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.
Keywords: Alzheimer's disease, amyloid beta, amylin, blood, brain, immunohistochemistry, metabolic dysfunction, oligomers, plaques, type 2 diabetes.
Current Alzheimer Research
Title:Islet Amyloid Polypeptide (IAPP): A Second Amyloid in Alzheimer's Disease
Volume: 11 Issue: 10
Author(s): Janelle N. Fawver, Yonatan Ghiwot, Catherine Koola, Wesley Carrera, Jennifer Rodriguez-Rivera, Caterina Hernandez, Kelly T. Dineley, Yu Kong, Jianrong Li, Jack Jhamandas, George Perry and Ian V.J. Murray
Affiliation:
Keywords: Alzheimer's disease, amyloid beta, amylin, blood, brain, immunohistochemistry, metabolic dysfunction, oligomers, plaques, type 2 diabetes.
Abstract: Amyloid formation is the pathological hallmark of type 2 diabetes (T2D) and Alzheimer’s disease (AD). These diseases are marked by extracellular amyloid deposits of islet amyloid polypeptide (IAPP) in the pancreas and amyloid β (Aβ) in the brain. Since IAPP may enter the brain and disparate amyloids can cross-seed each other to augment amyloid formation, we hypothesized that pancreatic derived IAPP may enter the brain to augment misfolding of Aβ in AD. The corollaries for validity of this hypothesis are that IAPP [1] enters the brain, [2] augments Aβ misfolding, [3] associates with Aβ plaques, and most importantly [4] plasma levels correlate with AD diagnosis. We demonstrate the first 3 corollaries that: (1) IAPP is present in the brain in human cerebrospinal fluid (CSF), (2) synthetic IAPP promoted oligomerization of Aβ in vitro, and (3) endogenous IAPP localized to Aβ oligomers and plaques. For the 4 corollary, we did not observe correlation of peripheral IAPP levels with AD pathology in either an African American cohort or AD transgenic mice. In the African American cohort, with increased risk for both T2D and AD, peripheral IAPP levels were not significantly different in samples with no disease, T2D, AD, or both T2D and AD. In the Tg2576 AD mouse model, IAPP plasma levels were not significantly elevated at an age where the mice exhibit the glucose intolerance of pre-diabetes. Based on this negative data, it appears unlikely that peripheral IAPP cross-seeds or “infects” Aβ pathology in AD brain. However, we provide novel and additional data which demonstrate that IAPP protein is present in astrocytes in murine brain and secreted from primary cultured astrocytes. This preliminary report suggests a potential and novel association between brain derived IAPP and AD, however whether astrocytic derived IAPP cross-seeds Aβ in the brain requires further research.
Export Options
About this article
Cite this article as:
Fawver N. Janelle, Ghiwot Yonatan, Koola Catherine, Carrera Wesley, Rodriguez-Rivera Jennifer, Hernandez Caterina, Dineley T. Kelly, Kong Yu, Li Jianrong, Jhamandas Jack, Perry George and Murray V.J. Ian, Islet Amyloid Polypeptide (IAPP): A Second Amyloid in Alzheimer's Disease, Current Alzheimer Research 2014; 11 (10) . https://dx.doi.org/10.2174/1567205011666141107124538
DOI https://dx.doi.org/10.2174/1567205011666141107124538 |
Print ISSN 1567-2050 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5828 |
Call for Papers in Thematic Issues
New Advances in the Prevention, Diagnosis, Treatment, and Rehabilitation of Alzheimer's Disease
Aims and Scope: Introduction: Alzheimer's disease (AD) poses a significant global health challenge, with an increasing prevalence that demands concerted efforts to advance our understanding and strategies for prevention, diagnosis, treatment, and rehabilitation. This thematic issue aims to bring together cutting-edge research and innovative approaches from multidisciplinary perspectives to address ...read more
Current updates on the Role of Neuroinflammation in Neurodegenerative Disorders
Neuroinflammation is an invariable hallmark of chronic and acute neurodegenerative disorders and has long been considered a potential drug target for Alzheimer?s disease (AD) and dementia. Significant evidence of inflammatory processes as a feature of AD is provided by the presence of inflammatory markers in plasma, CSF and postmortem brain ...read more
Deep Learning for Advancing Alzheimer's Disease Research
Alzheimer's disease (AD) poses a significant global health challenge, with an increasing number of individuals affected yearly. Deep learning, a subfield of artificial intelligence, has shown immense potential in various domains, including healthcare. This thematic issue of Current Alzheimer Research explores the application of deep learning techniques in advancing our ...read more
Diagnostic and therapeutic biomarkers of dementia
Dementia affects 18 million people worldwide. Dementia is a syndrome of symptoms caused by brain disease, usually chronic or progressive, clinically characterized by multiple impairments of higher cortical functions such as memory, thinking, orientation, and learning. In addition, in the course of dementia, cognitive deficits are observed, which often hinder ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
The Role of the Immune System in the Pathogenesis of Hypertension
Current Hypertension Reviews Nitric Oxide and Protection against Cardiac Ischemia
Current Pharmaceutical Design Pharmacology of Recombinant Low-Voltage Activated Calcium Channels
Current Drug Targets - CNS & Neurological Disorders Physiological and Molecular Role of Ranpirnase on Cancer Treatment
Current Cancer Therapy Reviews Novel Peptides: An Alternative Approach for the Treatment of Diabetes Mellitus
Current Drug Therapy Inflammation in Atherosclerosis: A New Therapeutic Target
Current Medicinal Chemistry - Anti-Inflammatory & Anti-Allergy Agents Inflammatory Related Cardiovascular Diseases: From Molecular Mechanisms to Therapeutic Targets
Current Pharmaceutical Design Recent Patents Relating to siRNAs and Therapeutic Strategies for Genetic Diseases
Recent Patents on DNA & Gene Sequences Recreational Use, Analysis and Toxicity of Tryptamines
Current Neuropharmacology Antioxidant Potentials and Xanthine Oxidase Inhibitory Effect of Two Furanocoumarins Isolated from <i>Tamus communis</i> L
Medicinal Chemistry Management of Hypertension in the Acute Phase of Stroke
Current Hypertension Reviews Role of Oxidative-Nitrosative Stress and Downstream Pathways in Various Forms of Cardiomyopathy and Heart Failure
Current Vascular Pharmacology Attention Deficit Hyperactive Disorder and Occurrence of Tic Disorders in Children and Adolescents—What is the Verdict
Current Pediatric Reviews Editorial [Hot Topic: Targeted Cancer Therapies: Current Status and Future Directions (Guest Editors: Ioannis Starakis)]
Current Medicinal Chemistry Impact of Dendritic Cells on Vascular Biology
Current Hypertension Reviews Role of the Decreased Nitric Oxide Bioavailability in the Vascular Complications of Diabetes Mellitus
Current Pharmaceutical Biotechnology Dural Venous Sinuses: What We Need to Know
Current Medical Imaging Sesamin and Sesamolin: Natures Therapeutic Lignans
Current Enzyme Inhibition The Role of Omega-3 Polyunsaturated Fatty Acids Supplementation in Childhood: A Review
Recent Patents on Cardiovascular Drug Discovery Early Vascular Aging: A New Target for Hypertension Treatment
Current Pharmaceutical Design