Interactions between APP secretases and inflammatory mediators - PubMed (original) (raw)

Review

Interactions between APP secretases and inflammatory mediators

Magdalena Sastre et al. J Neuroinflammation. 2008.

Abstract

There is now a large body of evidence linking inflammation to Alzheimer's disease (AD). This association manifests itself neuropathologically in the presence of activated microglia and astrocytes around neuritic plaques and increased levels of inflammatory mediators in the brains of AD patients. It is considered that amyloid-beta peptide (Abeta), which is derived from the processing of the longer amyloid precursor protein (APP), could be the most important stimulator of this response, and therefore determining the role of the different secretases involved in its generation is essential for a better understanding of the regulation of inflammation in AD. The finding that certain non-steroidal anti-inflammatory drugs (NSAIDs) can affect the processing of APP by inhibiting beta- and gamma-secretases, together with recent revelations that these enzymes may be regulated by inflammation, suggest that they could be an interesting target for anti-inflammatory drugs. In this review we will discuss some of these issues and the role of the secretases in inflammation, independent of their effect on Abeta formation.

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Figures

Figure 1

Figure 1

Proteolytic processing of APP. Proteolysis of APP by α-secretase or β-secretase leads to the secretion of αAPPs or βAPPs. Both secretases generate C-terminal fragments (CTF) of 10 kDa and 12 kDa respectively, which are inserted in the membrane (grey). These fragments can be cut by γ-secretase to release the peptides P3 and Aβ. Two further cleavage sites, termed ε and ζ, have been identified in the CTF.

Figure 2

Figure 2

Schematic representation of the interactions between inflammatory processes and APP processing. Aβ generation by BACE1 and γ-secretase induces an inflammatory response, which involves the activation of microglia and astrocytes and the release of pro-inflammatory cytokines. This inflammatory response could be enhanced by brain trauma or by PS1 mutations, probably also by increased Aβ production. Inflammatory cytokines have been involved in the aggregation of Aβ [121]. Moreover, cytokines can affect the expression of secretases and APP, influencing their transcription, translation and/or activation [122]. Non-steroidal anti-inflammatory drug treatment could reverse the effect of inflammation on BACE1 transcription, modulate the cleavage site of γ-secretase and decrease the secretion of cytokines and the number of microglia and astrocytes. On the other hand, α-secretase has been involved in the shedding of certain cytokines, potentiating their activity. See text for further details of individual interactions. Numbers on the diagram correspond to the appropriate references in the review.

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References

    1. Selkoe DJ. Folding proteins in fatal ways. Nature. 2003;42:900–904. doi: 10.1038/nature02264. - DOI - PubMed
    1. Selkoe DJ. Alzheimer's disease is a synaptic failure. Science. 2002;298:789–791. doi: 10.1126/science.1074069. - DOI - PubMed
    1. Alzheimer A. Ueber eine eigenartige Erkrankung der Hirnrinde. Centralblatt fur Nervenheilkunde un Psychiatrie. 1907;30:177–179.
    1. Shoji M, Golde TE, Ghiso J, Cheung TT, Estus S, Shaffer LM, Cai XD, McKay DM, Tintner R, Frangione B, Younkin SG. Production of the Alzheimer amyloid beta protein by normal proteolytic processing. Science. 1992;258:126–129. doi: 10.1126/science.1439760. - DOI - PubMed
    1. Haass C, Schlossmacher MG, Hung AY, Vigo-Pelfrey C, Mellon A, Ostaszewski BL, Lieberburg I, Koo EH, Schenk D, Teplow DB, Selkoe DJ. Amyloid beta-peptide is produced by cultured cells during normal metabolism. Nature. 1992;359:322–325. doi: 10.1038/359322a0. - DOI - PubMed

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