Abstract
The sporadic, late onset form of Alzheimer's disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased β-amyloid (Aβ) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of Aβ. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted Aβ. Furthermore, accumulation of improperly degraded Aβ in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric Aβ can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, Aβ accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of Aβ causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced Aβ clearance and subsequent Aβ spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated Aβ, it can be possible to remove it and avoid Aβ-induced neurodegeneration without disturbing the endogenously important pool of secreted Aβ. Additionally, drugs targeted to inhibit the spread of intracellular toxic Aβ aggregates may also be useful in stopping the progression of pathology, without affecting the level of Aβ that normally occurs in the brain.
Keywords: Alzheimer's disease, lysosome, proteasome, β-amyloid, neuron-to-neuron transfer, degradation.
Current Pharmaceutical Design
Title:Getting Rid of Intracellular Aβ - Loss of Cellular Degradation Leads to Transfer Between Connected Neurons
Volume: 20 Issue: 15
Author(s): Lotta Agholme and Martin Hallbeck
Affiliation:
Keywords: Alzheimer's disease, lysosome, proteasome, β-amyloid, neuron-to-neuron transfer, degradation.
Abstract: The sporadic, late onset form of Alzheimer's disease (AD) shares pathological hallmarks with the familial form; however, no clear reason for increased β-amyloid (Aβ) generation has been found in the former. It has long been speculated that the late onset form of AD is caused by reduced degradation and/or clearance of Aβ. Indeed, both intracellular degradation systems, the proteasomal and lysosomal systems, have been shown to be defective in AD. Reduced proteasome activity increases levels of intracellular and secreted Aβ. Furthermore, accumulation of improperly degraded Aβ in the lysosomes causes lysosomal disruption and cell death. We recently showed that oligomeric Aβ can be transmitted from one neuron to another, which causes neurotoxicity. In both the donating and receiving cells, Aβ accumulates in the endo-lysosomal compartment. It is possible that ineffective degradation of Aβ causes its transfer to neighboring neurons, thereby spreading AD pathology. This review summarizes the data underlying the idea of reduced Aβ clearance and subsequent Aβ spread in AD, and also suggests new therapeutic methods, which are aimed at targeting the degradation systems and synaptic transfer. By enhancing degradation of intracellular accumulated Aβ, it can be possible to remove it and avoid Aβ-induced neurodegeneration without disturbing the endogenously important pool of secreted Aβ. Additionally, drugs targeted to inhibit the spread of intracellular toxic Aβ aggregates may also be useful in stopping the progression of pathology, without affecting the level of Aβ that normally occurs in the brain.
Export Options
About this article
Cite this article as:
Agholme Lotta and Hallbeck Martin, Getting Rid of Intracellular Aβ - Loss of Cellular Degradation Leads to Transfer Between Connected Neurons, Current Pharmaceutical Design 2014; 20 (15) . https://dx.doi.org/10.2174/13816128113199990501
DOI https://dx.doi.org/10.2174/13816128113199990501 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
Call for Papers in Thematic Issues
"Tuberculosis Prevention, Diagnosis and Drug Discovery"
The Nobel Prize-winning discoveries of Mycobacterium tuberculosis and streptomycin have enabled an appropriate diagnosis and an effective treatment of tuberculosis (TB). Since then, many newer diagnosis methods and drugs have been saving millions of lives. Despite advances in the past, TB is still a leading cause of infectious disease mortality ...read more
Current Pharmaceutical challenges in the treatment and diagnosis of neurological dysfunctions
Neurological dysfunctions (MND, ALS, MS, PD, AD, HD, ALS, Autism, OCD etc..) present significant challenges in both diagnosis and treatment, often necessitating innovative approaches and therapeutic interventions. This thematic issue aims to explore the current pharmaceutical landscape surrounding neurological disorders, shedding light on the challenges faced by researchers, clinicians, and ...read more
Emerging and re-emerging diseases
Faced with a possible endemic situation of COVID-19, the world has experienced two important phenomena, the emergence of new infectious diseases and/or the resurgence of previously eradicated infectious diseases. Furthermore, the geographic distribution of such diseases has also undergone changes. This context, in turn, may have a strong relationship with ...read more
Melanoma and Non-Melanoma Skin Cancer Treatment: Standard of Care and Recent Advances
In this thematic issue, we aim to provide a standard of care of the diagnosis and treatment of melanoma and non-melanoma skin cancer. The editor will invite authors from different countries who will write review articles of melanoma and non-melanoma skin cancers. The Diagnosis, Staging, Surgical Treatment, Non-Surgical Treatment all ...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
-
Alzheimers Disease and Non-Steroidal Anti-Inflammatory Drugs: Old Therapeutic Tools with Novel Mechanisms of Action?
Current Medicinal Chemistry - Central Nervous System Agents Ethanolamine: A Potential Promoiety with Additional Effects on the Brain
CNS & Neurological Disorders - Drug Targets Iron Chelators in Medicinal Applications - Chemical Equilibrium Considerations in Pharmaceutical Activity
Current Medicinal Chemistry Therapeutic Gene Products Delivery by Neuron Stem Cells
Current Pharmaceutical Biotechnology Neurokinin Receptors and Subtypes as Potential Targets in Breast Cancer: Relevance to Bone Marrow Metastasis
Drug Design Reviews - Online (Discontinued) Functional Characterization of the In Vitro Folded Human Y1 Receptor in Lipid Environment
Protein & Peptide Letters Role of Complement Systems in IVIG Mediated Attenuation of Cognitive Deterioration in Alzheimer's Disease
Current Alzheimer Research Decoding the Inter-Relationship between Sleep Disorders and Alzheimer’s Disease Pathogenesis
CNS & Neurological Disorders - Drug Targets Human Papillomavirus E7 Oncoprotein Promotes Proliferation and Migration through the Transcription Factor E2F1 in Cervical Cancer Cells
Anti-Cancer Agents in Medicinal Chemistry 4-Substituted-2-Methoxyphenol: Suitable Building Block to Prepare New Bioactive Natural-like Hydroxylated Biphenyls
Letters in Drug Design & Discovery Immunomodulation and Anti-inflammatory Roles of Polyphenols as Anticancer Agents
Anti-Cancer Agents in Medicinal Chemistry Antiepileptics and the Treatment of Neuropathic Pain: Evidence from Animal Models
Current Pharmaceutical Design Polyphenols as Potential Inhibitors of Amyloid Aggregation and Toxicity:Possible Significance to Alzheimers Disease
Mini-Reviews in Medicinal Chemistry Plasticity of T Cell Differentiation and Cytokine Signature: A Double-Edged Sword for Immune Responses
Immunology, Endocrine & Metabolic Agents in Medicinal Chemistry (Discontinued) Current Prodrug Design for Drug Discovery
Current Pharmaceutical Design Review of and Perspectives on the Toxicology of Graphene-based Materials
Current Drug Metabolism A Neuroinformatics Study Describing Molecular Interaction of Cisplatin with Acetylcholinesterase: A Plausible Cause for Anticancer Drug Induced Neurotoxicity
CNS & Neurological Disorders - Drug Targets Targeting βIII-Tubulin in Glioblastoma Multiforme: From Cell Biology and Histopathology to Cancer Therapeutics
Anti-Cancer Agents in Medicinal Chemistry Neurotrophic Actions of Mood-Stabilizers: A Recent Research Discovery and its Potential Clinical Applications
Current Psychiatry Reviews Voltage-Gated Calcium Channels as Targets for the Treatment of Chronic Pain
Current Drug Targets - CNS & Neurological Disorders