Abstract
Alzheimer's disease (AD) is characterized by an accumulation of Amyloid-β (Aβ), released by sequential proteolytic processing of the amyloid precursor protein (APP) by β - and γ-secretase. Aβ peptides can aggregate, leading to toxic Aβ oligomers and amyloid plaque formation. Aβ accumulation is not only dependent on de novo synthesis but also on Aβ degradation. Neprilysin (NEP) is one of the major enzymes involved in Aβ degradation. Here we investigate the molecular mechanism of NEP regulation, which is up to now controversially discussed to be affected by APP processing itself. We found that NEP expression is highly dependent on the APP intracellular domain (AICD), released by APP processing. Mouse embryonic fibroblasts devoid of APP processing, either by the lack of the catalytically active subunit of the γ-secretase complex [presenilin (PS) 1/2] or by the lack of APP and the APP-like protein 2 (APLP2), showed a decreased NEP expression, activity and protein level. Similar results were obtained by utilizing cells lacking a functional AICD domain (APPΔCT15) or expressing mutations in the genes encoding for PS1. AICD supplementation or retransfection with an AICD encoding plasmid could rescue the down-regulation of NEP further strengthening the link between AICD and transcriptional NEP regulation, in which Fe65 acts as an important adaptor protein. Especially AICD generated by the amyloidogenic pathway seems to be more involved in the regulation of NEP expression. In line, analysis of NEP gene expression in vivo in six transgenic AD mouse models (APP and APLP2 single knock-outs, APP/APLP2 double knock-out, APP-swedish, APP-swedish/PS1Δexon9, and APPΔCT15) confirmed the results obtained in cell culture. In summary, in the present study we clearly demonstrate an AICD-dependent regulation of the Aβ-degrading enzyme NEP in vitro and in vivo and elucidate the underlying mechanisms that might be beneficial to develop new therapeutic strategies for the treatment of AD.
Highlights
Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disease of the central nervous system and the most common cause of dementia in the aged population
NEP Gene Expression, Protein Level and Enzyme Activity is Decreased in Absence of presenilin 1 (PS1)/PS2 or amyloid precursor protein (APP)/APP-like protein 2 (APLP2) To investigate a potential role of the catalytically active part of the γ-secretase complex in the regulation of NEP, we used PS1/PS2deficient MEFs (MEF PS1/2−/−) and PS1 wt retransfected control cells (MEF PS1rescue) to obtain clonal homogeneity
The effect in respect of NEP expression was confirmed by comparing MEF devoid of PS with PS1rescue, and with wt cells, further emphasizing that the effects are independent of the used control
Summary
Alzheimer’s disease (AD) is a progressive, irreversible neurodegenerative disease of the central nervous system and the most common cause of dementia in the aged population. Processing of α-CTF and β-CTF fragments by the γ-secretase complex results in the release of the APP intracellular domain (AICD) to the cytosol which is discussed to be involved in gene transcription (Passer et al, 2000; Gao and Pimplikar, 2001; Cao and Sudhof, 2004; von Rotz et al, 2004; Pardossi-Piquard and Checler, 2012). We found further evidences supporting the underlying mechanisms of AICD mediated NEP regulation These mechanisms might be involved in the regulation of other transcriptional targets discussed in literature, which are mentioned above. In respect to AD it is important to notice that NEP has been shown to be reduced in brain areas early affected in AD and characterized by extensive plaque load (Akiyama et al, 2001; Yasojima et al, 2001; Carpentier et al, 2002; Russo et al, 2005; Wang et al, 2005; Miners et al, 2006) indicating the significance of understanding the regulation of this Aβ degrading enzyme
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