Neuroinflammatory Cytokines Induce Amyloid Beta Neurotoxicity through Modulating Amyloid Precursor Protein Levels/Metabolism

Abstract

Neuroinflammation has been observed in association with neurodegenerative diseases including Alzheimer's disease (AD). In particular, a positive correlation has been documented between neuroinflammatory cytokine release and the progression of the AD, which suggests these cytokines are involved in AD pathophysiology. A histological hallmark of the AD is the presence of beta-amyloid (Aβ) plaques and tau neurofibrillary tangles. Beta-amyloid is generated by the sequential cleavage of beta (β) and gamma (γ) sites in the amyloid precursor protein (APP) by β- and γ-secretase enzymes and its accumulation can result from either a decreased Aβ clearance or increased metabolism of APP. Previous studies reported that neuroinflammatory cytokines reduce the efflux transport of Aβ, leading to elevated Aβ concentrations in the brain. However, less is known about the effects of neuroinflammatory mediators on APP expression and metabolism. In this article, we review the modulatory role of neuroinflammatory cytokines on APP expression and metabolism, including their effects on β- and γ-secretase enzymes.

Figure 1

Schematic diagram for the effects of neuroinflammatory cytokines on amyloid precursor protein (APP) processing and beta-amyloid (Aβ) production. Amyloid precursor proteins (APP) are cleaved by beta (β) and gamma (γ) sites in the APP by β- and γ-secretase enzymes producing Aβ in the brain. (a) Normal levels and activity of APP, APP metabolic enzymes, and neuroinflammatory cytokines in control brain. (b) In Alzheimer disease (AD), Aβ is accumulated in the brain leading to formation of Aβ oligomers. This effect leads to activation of microglia, which increases the production of neuroinflammatory cytokines. These cytokines increase APP levels, upregulate β-secretase and γ-secretase, and decrease Aβ clearance in the brain. These effects result in further increase in Aβ concentrations and formation of Aβ oligomers and plaques.