Age, inflammation and Abeta itself influence Abeta degradation in Alzheimer’s Disease

Abstract

It is well established that AD is caused by accumulation of amyloid-beta (Aβ) peptides in the brain. The cause of this accumulation in late-onset AD is, however, still uncertain. An increasing amount of evidence on the subject points towards a defective clearance of Aβ peptides from the brain. Furthermore, because both microglia and astrocytes are shown to accumulate around Aβ plaques, multiple studies focused on the role of these cells in Aβ clearance. Interestingly, these cells produce Aβ-degrading enzymes and are thus potential mediators in Aβ-clearance. In this review, various factors are discussed which can influence the expression and activity of Aβ-degrading enzymes in microglia and astrocytes. To provide a concise overview of recent studies, this article is limited to the effects of aging, cytokines, and Aβ itself on the Aβ-degrading enzymes NEP, IDE and MMP-9. By comparing recent studies, it becomes clear that a major influence on the expression of Aβ-degrading enzymes is the production of pro- and anti-inflammatory cytokines. Factors promoting inflammation in the brain generally lower the expression of NEP and IDE, while anti-inflammatory cytokines counter this effect. Aβ itself influences the expression of Aβ-degrading enzymes by heightening the expression of these enzymes in microglia and astrocytes that are in direct contact with Aβ plaques. Strikingly, recent evidence indicates that AD patients do not show a response of their glial cells under the same conditions, thereby suggesting a defect in this process. Lastly, although age is the most prominent risk factor for late-onset AD, the precise effect of aging on AD progression remains controversial.