Abstract
Alzheimers disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.
Keywords: Alzheimer's disease, dementia, neurofibrillary tangles, neurodegeneration cascade, hyperphosphorylated tau, energy metabolism, endoplasmic reticulum, neurotoxic, neuro-imaging
Current Alzheimer Research
Title: Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease
Volume: 9 Issue: 1
Author(s): Suzanne M. de la Monte
Affiliation:
Keywords: Alzheimer's disease, dementia, neurofibrillary tangles, neurodegeneration cascade, hyperphosphorylated tau, energy metabolism, endoplasmic reticulum, neurotoxic, neuro-imaging
Abstract: Alzheimers disease [AD] is the most common cause of dementia in North America. Despite 30+ years of intense investigation, the field lacks consensus regarding the etiology and pathogenesis of sporadic AD, and therefore we still do not know the best strategies for treating and preventing this debilitating and costly disease. However, growing evidence supports the concept that AD is fundamentally a metabolic disease with substantial and progressive derangements in brain glucose utilization and responsiveness to insulin and insulin-like growth factor [IGF] stimulation. Moreover, AD is now recognized to be heterogeneous in nature, and not solely the end-product of aberrantly processed, misfolded, and aggregated oligomeric amyloid-beta peptides and hyperphosphorylated tau. Other factors, including impairments in energy metabolism, increased oxidative stress, inflammation, insulin and IGF resistance, and insulin/IGF deficiency in the brain should be incorporated into all equations used to develop diagnostic and therapeutic approaches to AD. Herein, the contributions of impaired insulin and IGF signaling to AD-associated neuronal loss, synaptic disconnection, tau hyperphosphorylation, amyloid-beta accumulation, and impaired energy metabolism are reviewed. In addition, we discuss current therapeutic strategies and suggest additional approaches based on the hypothesis that AD is principally a metabolic disease similar to diabetes mellitus. Ultimately, our ability to effectively detect, monitor, treat, and prevent AD will require more efficient, accurate and integrative diagnostic tools that utilize clinical, neuroimaging, biochemical, and molecular biomarker data. Finally, it is imperative that future therapeutic strategies for AD abandon the concept of uni-modal therapy in favor of multi-modal treatments that target distinct impairments at different levels within the brain insulin/IGF signaling cascades.
Export Options
About this article
Cite this article as:
M. de la Monte Suzanne, Brain Insulin Resistance and Deficiency as Therapeutic Targets in Alzheimers Disease, Current Alzheimer Research 2012; 9 (1) . https://dx.doi.org/10.2174/156720512799015037
DOI https://dx.doi.org/10.2174/156720512799015037 |
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
-
Developing Novel Therapeutic Approaches to Frailty
Current Pharmaceutical Design Biocatalysis in the Preparation of the Statin Side Chain
Current Organic Synthesis Bipolar Spectrum Disorder: Origins and State of the Art
Current Psychiatry Reviews Recent Advances in Visualizing Alzheimers Plaques by Magnetic Resonance Imaging
Current Medical Imaging Neuroimmune Crosstalk in CNS Disorders: The Histamine Connection
Current Pharmaceutical Design Oral Antidiabetic Agents: Anti-Atherosclerotic Properties Beyond Glucose Lowering?
Current Pharmaceutical Design Risk-Benefit Perspectives in COX-2 Blockade
Current Drug Safety Antigonadotropins: A Novel Strategy to Halt Alzheimers Disease Progression
Current Pharmaceutical Design L-Dopa Related Hyperhomocysteinemia: A Possible Mediator of Toxicity?
Letters in Drug Design & Discovery Retrospective Results on the Treatment of Chronic Hepatitis C with Different Interferon Regimes in a General Hospital
Current Drug Therapy Vitamin D and Cardiovascular Disease
Current Vascular Pharmacology “SLY AS A FOXO”: New Paths with Forkhead Signaling in the Brain
Current Neurovascular Research A Computational Approach to Finding RNA Tertiary Motifs in Genomic Sequences: A Case Study
Recent Patents on DNA & Gene Sequences The Molecular Mechanism of <i>Scutellaria baicalensis</i> Georgi Stems and Leaves Flavonoids in Promoting Neurogenesis and Improving Memory Impairment by the PI3K-AKT-CREB Signaling Pathway in Rats
Combinatorial Chemistry & High Throughput Screening An Overview on Inventions Related to Ginger Processing and Products for food and Pharmaceutical Applications
Recent Patents on Food, Nutrition & Agriculture The Role of α7 Nicotinic Acetylcholine Receptors and α7-Specific Antibodies in Neuroinflammation Related to Alzheimer Disease
Current Pharmaceutical Design Ability of older people with dementia or cognitive impairment to manage medicine regimens: a narrative review
Current Clinical Pharmacology Metformin: Repurposing Opportunities for Cognitive and Mood Dysfunction
CNS & Neurological Disorders - Drug Targets Pharmacological Interventions and Rehabilitation Approach for Enhancing Brain Self-repair and Stroke Recovery
Current Neuropharmacology Role of Transcranial Doppler Ultrasonography in Cerebrovascular Disease
Recent Patents on CNS Drug Discovery (Discontinued)