Abstract
Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
Keywords: Alzheimer’s disease, down syndrome, mitosis, aneuploidy, trisomy 21, neurogenesis.
Current Alzheimer Research
Title:Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease
Volume: 13 Issue: 1
Author(s): Huntington Potter, Antoneta Granic and Julbert Caneus
Affiliation:
Keywords: Alzheimer’s disease, down syndrome, mitosis, aneuploidy, trisomy 21, neurogenesis.
Abstract: Trisomy 21 and the consequent extra copy of the amyloid precursor protein (APP) gene and increased beta-amyloid (Aβ) peptide production underlie the universal development of Alzheimer’s disease (AD) pathology and high risk of AD dementia in people with Down syndrome (DS). Trisomy 21 and other forms of aneuploidy also arise among neurons and peripheral cells in both sporadic and familial AD and in mouse and cell models thereof, reinforcing the conclusion that AD and DS are two sides of the same coin. The demonstration that 90% of the neurodegeneration in AD can be attributed to the selective loss of aneuploid neurons generated over the course of the disease indicates that aneuploidy is an essential feature of the pathogenic pathway leading to the depletion of neuronal cell populations. Trisomy 21 mosaicism also occurs in neurons and other cells from patients with Niemann-Pick C1 disease and from patients with familial or sporadic frontotemporal lobar degeneration (FTLD), as well as in their corresponding mouse and cell models. Biochemical studies have shown that Aβ induces mitotic spindle defects, chromosome mis-segregation, and aneuploidy in cultured cells by inhibiting specific microtubule motors required for mitosis. These data indicate that neuronal trisomy 21 and other types of aneuploidy characterize and likely contribute to multiple neurodegenerative diseases and are a valid target for therapeutic intervention. For example, reducing extracellular calcium or treating cells with lithium chloride (LiCl) blocks the induction of trisomy 21 by Aβ. The latter finding is relevant in light of recent reports of a lowered risk of dementia in bipolar patients treated with LiCl and in the stabilization of cognition in AD patients treated with LiCl.
Export Options
About this article
Cite this article as:
Potter Huntington, Granic Antoneta and Caneus Julbert, Role of Trisomy 21 Mosaicism in Sporadic and Familial Alzheimer’s Disease, Current Alzheimer Research 2016; 13 (1) . https://dx.doi.org/10.2174/156720501301151207100616
DOI https://dx.doi.org/10.2174/156720501301151207100616 |
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
-
Editorial (Thematic Issue: Mitochondria and Subcellular Organelles as Treatment Targets Against Pathological Conditions)
Current Pharmaceutical Design Editorial [Hot topic: Polyunsaturated Fatty Acids and Human Health: A Critical Appraisal of the Evidence (Executive Editor: Antonio Cherubini)]
Current Pharmaceutical Design Simvastatin and Other HMG-CoA Reductase Inhibitors on Brain Cholesterol Levels in Alzheimers Disease
Current Alzheimer Research MicroRNAs in Atrial Fibrillation
Current Medicinal Chemistry Hypothalamic and Neuroendocrine Changes in Huntingtons Disease
Current Drug Targets Pharmacogenetic Modulation of Platelet Inhibition
Current Pharmacogenomics and Personalized Medicine Impaired Neural Transmission and Synaptic Plasticity in Superior Cervical Ganglia from β-Amyloid Rat Model of Alzheimers Disease
Current Alzheimer Research Complement C4A and C4B Gene Copy Number Study in Alzheimer's Disease Patients
Current Alzheimer Research Sensory-Dependent Knowledge in Young and Elderly Adults: Argument from the Cross-Modal Priming Effect
Current Aging Science Novel Targets for Drugs in Schizophrenia
CNS & Neurological Disorders - Drug Targets Omega-3 Polyunsaturated Fatty Acids in Alzheimers Disease: Key Questions and Partial Answers
Current Alzheimer Research Cellular Reservoirs of HIV-1 and their Role in Viral Persistence
Current HIV Research Nutraceuticals in Psychiatric Practice
Recent Patents on CNS Drug Discovery (Discontinued) Treatment of Large Vessel Vasculitis
Current Immunology Reviews (Discontinued) Sex-Genetic Interaction in the Risk for Cerebrovascular Disease
Current Medicinal Chemistry Diabetes of the Brain: Computational Approaches and Interventional Strategies
CNS & Neurological Disorders - Drug Targets Didehydro-Cortistatin A Inhibits HIV-1 Tat Mediated Neuroinflammation and Prevents Potentiation of Cocaine Reward in Tat Transgenic Mice
Current HIV Research Cardiovascular Toxicity of Cyclooxygenase Inhibitors and Promising Natur a l Substitutes
Current Pharmaceutical Design Preparation and Evaluation of Gliptin Liposomes for Targetting Ocular Region in Neurodegeneration
Nanoscience & Nanotechnology-Asia Discovering New Treatments for Alzheimer's Disease by Repurposing Approved Medications
Current Topics in Medicinal Chemistry