Toxic mechanisms of amyloid oligomers and therapeutic strategies
Magdalena I Ivanova1,2, Carmelo La Rosa3, Ayyalusamy Ramamoorthy1,4,5,6,7
1Biophysics Program, University of Michigan, Ann Arbor, Michigan, USA.
Abstract:
Amyloid oligomers are increasingly recognized as the major toxic contributors across protein-misfolding disorders. In this review, we cover mechanistic evidence showing how these transient and structurally heterogeneous oligomers disrupt cellular homeostasis by: (i) permeabilizing lipid membranes and forming ion-conducting pores; (ii) triggering endoplasmic reticulum (ER) stress and unfolded protein response (UPR), thereby compromising proteostasis via dysfunction of the ubiquitin-proteasome system (UPS) and autophagy; (iii) impairing mitochondrial function and disrupting redox balance; (iv) interfering with endosomal-lysosomal as well as axonal and synaptic trafficking; and (v) activating stress-kinase signaling and apoptotic pathways. In relation to therapeutic intervention, we review secretase-targeting strategies, conformation-selective antibodies, and their mixed clinical outcomes. An in-depth understanding of the toxic action of pathogenic oligomeric species will be critical for translating these mechanistic insights into effective therapies that comprehensively target oligomer toxicity.
Insights
Amyloid oligomers disrupt cell function by damaging membranes and stress pathways. Understanding these toxic mechanisms is key to developing effective therapies for protein-misfolding disorders.
Area of Science:
- Biochemistry
- Cell Biology
- Neuroscience
Background:
- Protein-misfolding disorders are linked to toxic amyloid oligomers.
- These oligomers are transient and structurally diverse.
- Understanding their cellular impact is crucial for therapeutic development.
Purpose of the Study:
- To review the mechanistic evidence of how amyloid oligomers disrupt cellular homeostasis.
- To discuss therapeutic strategies targeting amyloid oligomers and their clinical outcomes.
- To highlight the importance of understanding oligomer toxicity for future therapies.
Main Methods:
- Mechanistic review of existing literature.
- Analysis of cellular disruption pathways.
- Evaluation of therapeutic interventions and clinical trial results.
Main Results:
- Amyloid oligomers permeabilize lipid membranes, forming ion channels.
- They induce endoplasmic reticulum stress and compromise proteostasis (ubiquitin-proteasome system and autophagy).
- Oligomers impair mitochondrial function, disrupt redox balance, interfere with trafficking, and activate apoptotic pathways.
Conclusions:
- Amyloid oligomers exhibit diverse toxic mechanisms affecting cellular homeostasis.
- Current therapeutic strategies like secretase inhibitors and antibodies show mixed results.
- A comprehensive understanding of oligomer toxicity is essential for developing effective treatments.
Related Concept Videos
01:22Alzheimer's Disease: Treatment
03:03Amyloid Fibrils
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
03:03Amyloid Fibrils
01:26Pharmaceutical Poisoning: Treatment Strategies
01:26Alzheimer's Disease: Overview
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
01:17Antidotes
Specific antidotes operate by inhibiting the enzymes that control biochemical pathways, reducing the production of harmful metabolites.
An example of an antidote is atropine, which counteracts the detrimental effects of cholinesterase inhibitors. It achieves this by deactivating muscarinic receptors,...