The endotoxin hypothesis of Alzheimer’s disease
Abstract Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via periph...
| Main Authors: | , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-04-01
|
| Series: | Molecular Neurodegeneration |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13024-024-00722-y |
| _version_ | 1797219612336586752 |
|---|---|
| author | Guy C. Brown Michael T. Heneka |
| author_facet | Guy C. Brown Michael T. Heneka |
| author_sort | Guy C. Brown |
| collection | DOAJ |
| description | Abstract Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response. |
| first_indexed | 2024-04-24T12:36:25Z |
| format | Article |
| id | doaj.art-a186532d14ce434591744ec80c896f08 |
| institution | Directory Open Access Journal |
| issn | 1750-1326 |
| language | English |
| last_indexed | 2024-04-24T12:36:25Z |
| publishDate | 2024-04-01 |
| publisher | BMC |
| record_format | Article |
| series | Molecular Neurodegeneration |
| spelling | doaj.art-a186532d14ce434591744ec80c896f082024-04-07T11:30:45ZengBMCMolecular Neurodegeneration1750-13262024-04-0119111410.1186/s13024-024-00722-yThe endotoxin hypothesis of Alzheimer’s diseaseGuy C. Brown0Michael T. Heneka1Department of Biochemistry, University of CambridgeLuxembourg Centre for Systems Biomedicine, University of LuxembourgAbstract Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.https://doi.org/10.1186/s13024-024-00722-yLipopolysaccharideAlzheimer’s diseaseEndotoxinInflammationMicrogliaGut |
| spellingShingle | Guy C. Brown Michael T. Heneka The endotoxin hypothesis of Alzheimer’s disease Molecular Neurodegeneration Lipopolysaccharide Alzheimer’s disease Endotoxin Inflammation Microglia Gut |
| title | The endotoxin hypothesis of Alzheimer’s disease |
| title_full | The endotoxin hypothesis of Alzheimer’s disease |
| title_fullStr | The endotoxin hypothesis of Alzheimer’s disease |
| title_full_unstemmed | The endotoxin hypothesis of Alzheimer’s disease |
| title_short | The endotoxin hypothesis of Alzheimer’s disease |
| title_sort | endotoxin hypothesis of alzheimer s disease |
| topic | Lipopolysaccharide Alzheimer’s disease Endotoxin Inflammation Microglia Gut |
| url | https://doi.org/10.1186/s13024-024-00722-y |
| work_keys_str_mv | AT guycbrown theendotoxinhypothesisofalzheimersdisease AT michaeltheneka theendotoxinhypothesisofalzheimersdisease AT guycbrown endotoxinhypothesisofalzheimersdisease AT michaeltheneka endotoxinhypothesisofalzheimersdisease |