Inflammatory process in Alzheimer's Disease

Marco A Meraz-Ríos, Danira Toral-Rios, Diana Franco-Bocanegra, Juana Villeda-Hernández, Victoria Campos-Peña, Marco A Meraz-Ríos, Danira Toral-Rios, Diana Franco-Bocanegra, Juana Villeda-Hernández, Victoria Campos-Peña

Abstract

Alzheimer Disease (AD) is a neurodegenerative disorder and the most common form of dementia. Histopathologically is characterized by the presence of two major hallmarks, the intracellular neurofibrillary tangles (NFTs) and extracellular neuritic plaques (NPs) surrounded by activated astrocytes and microglia. NFTs consist of paired helical filaments of truncated tau protein that is abnormally hyperphosphorylated. The main component in the NP is the amyloid-β peptide (Aβ), a small fragment of 40-42 amino acids with a molecular weight of 4 kD. It has been proposed that the amyloid aggregates and microglia activation are able to favor the neurodegenerative process observed in AD patients. However, the role of inflammation in AD is controversial, because in early stages the inflammation could have a beneficial role in the pathology, since it has been thought that the microglia and astrocytes activated could be involved in Aβ clearance. Nevertheless the chronic activation of the microglia has been related with an increase of Aβ and possibly with tau phosphorylation. Studies in AD brains have shown an upregulation of complement molecules, pro-inflammatory cytokines, acute phase reactants and other inflammatory mediators that could contribute with the neurodegenerative process. Clinical trials and animal models with non-steroidal anti-inflammatory drugs (NSAIDs) indicate that these drugs may decrease the risk of developing AD and apparently reduce Aβ deposition. Finally, further studies are needed to determine whether treatment with anti-inflammatory strategies, may decrease the neurodegenerative process that affects these patients.

Keywords: Alzheimer disease; amyloid-β; anti-inflammatory strategies; astrocyte; microglia; neurodegeneration; neuroinflammation; pro-inflammatory cytokine.

Figures

Figure 1
Figure 1
Inflammation in Alzheimer's disease. The Aβ peptide produced by APP processing, form aggregates that activate microglia through TLRs and RAGE receptors. These receptors in turn, activate NF-κ B and AP-1 transcription factors, which induce the reactive oxygen species (ROS) production and the expression of inflammatory cytokines (IL-1, IL-6, TNF). These inflammatory factors directly acting on the neurons and also stimulate the astrocytes, which amplify the pro-inflammatory signals, inducing a neurotoxic effects. The inflammatory mediators generate by resident CNS cells, induce the production of adhesion molecules and chemokines, which recruit peripheral immune cells.
Figure 2
Figure 2
Neuronal damage and Aβ deposition triggers microglial and astrocytes activation and the generation of inflammation molecular mediators. The acute production of molecules of the complement system (C1q, C3, and C5), pro-inflammatory cytokines (IL-1, IL-6, TNF-α), chemokines (CCL2, MIP-1α, MIP-1β, and IL-8) mediate the Aβ clearance. However, in a chronic stage these molecules could promote an increased expression and alteration of APP processing, Aβ deposition, Tau phosphorylation and neurodegeneration. Also, another effect of glial cells includes the generation of NO that promotes oxidative stress. The inflammatory microenvironment favors the production of COX-2 in neurons that leads to apoptosis. In contrast, it has been proposed that glial cells could mediate neuronal survival, by the production of TGF-β and neurotrophic factors (BDNF and NGF), but the disease progression results in failure to repair neurons.

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