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 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.

Keywords: Alzheimer’s disease; Endotoxin; Gut; Inflammation; Lipopolysaccharide; Microglia; Neurodegeneration; Neuroinflammation.

Fig. 1

Summary of the endotoxin hypothesis of Alzheimer’s disease. LPS from gut, lungs or gums may increase blood LPS, which may directly or indirectly increase the pathology of Aβ, TAU and microglia, to exacerbate Alzheimer’s disease

Fig. 2

Serum and CSF (cerebralspinal fluid) measurements of LPS endotoxin by sandwich ELISA in AD and MCI patients and age-matched controls. Reprinted from Andreadou EG et al. , with permission from Elsevier. A405 is the absorbance measurement proportional to the amount of LPS

Fig. 3

LPS increases amyloid pathology at multiple points

Fig. 4

LPS increase TAU pathology at multiple points

Fig. 5

Microglia may mediate the synergy between LPS, Aβ and TAU to induce neurodegeneration. Exposure of microglia to Aβ or LPS can prime microglia, such that subsequent exposure to LPS or Aβ results in a different quantity or quality of inflammation. These inflamed microglia may induce: i) hyperphosphorylation and aggregation of TAU in neurons, ii) phagocytosis of stressed synapses and neurons, and iii) neurotoxicity. All of these may promote TAU spreading to other brain regions