Neprilysin and Aβ Clearance: Impact of the APP Intracellular Domain in NEP Regulation and Implications in Alzheimer’s Disease

Abstract

One of the characteristic hallmarks of Alzheimer’s disease (AD) is an accumulation of amyloid β (Aβ) leading to plaque formation and toxic oligomeric Aβ complexes. Besides the de novo synthesis of Aβ caused by amyloidogenic processing of the amyloid precursor protein (APP), Aβ levels are also highly dependent on Aβ degradation. Several enzymes are described to cleave Aβ. In this review we focus on one of the most prominent Aβ degrading enzymes, the zinc-metalloprotease Neprilysin (NEP). In the first part of the review we discuss beside the general role of NEP in Aβ degradation the alterations of the enzyme observed during normal aging and the progression of AD. In vivo and cell culture experiments reveal that a decreased NEP level results in an increased Aβ level and vice versa. In a pathological situation like AD, it has been reported that NEP levels and activity are decreased and it has been suggested that certain polymorphisms in the NEP gene result in an increased risk for AD. Conversely, increasing NEP activity in AD mouse models revealed an improvement in some behavioral tests. Therefore it has been suggested that increasing NEP might be an interesting potential target to treat or to be protective for AD making it indispensable to understand the regulation of NEP. Interestingly, it is discussed that the APP intracellular domain (AICD), one of the cleavage products of APP processing, which has high similarities to Notch receptor processing, might be involved in the transcriptional regulation of NEP. However, the mechanisms of NEP regulation by AICD, which might be helpful to develop new therapeutic strategies, are up to now controversially discussed and summarized in the second part of this review. In addition, we review the impact of AICD not only in the transcriptional regulation of NEP but also of further genes.

PS Dependent APP Cleavage Regulates Glucosylceramide Synthase and is Affected in Alzheimer's Disease

“…Beside AICD regulated gene transcription of lipid-related genes, AICD is discussed to be involved in the transcriptional regulation of several other proteins, e.g. neprilysin, an Aβ degrading enzyme [69], and the mitochondrial master transcriptional coactivator PGC-1α, affecting mitochondrial energy metabolism [30]. As we found in the present study increased gene transcription of GCS in absence of PS or the APP family, one might speculate that AICD down regulates GCS gene expression.…”

Activation of 5-HT2C Receptor Promotes the Expression of Neprilysin in U251 Human Glioma Cells

“…APPs secretion can be stimulated by 5-HT 2C receptor coupled with phospholipase A2 (PLA2) and protein kinase C (PKC) (Nistch et al 1996), and serotoninmediated activation of extracellular regulated kinase (ERK) was necessary for this regulation (Cirrito et al 2011). The zinc-metalloprotease neprilysin (NEP) is one of the most prominent Ab degrading enzymes, which is a ubiquitously occurring type II integral membrane protein consisting of 742 amino acid (Grimm et al 2013). NEP is distributed over neurons, astrocytes, and microglia in the central nervous system (Grimm et al 2013).…”

“…The zinc-metalloprotease neprilysin (NEP) is one of the most prominent Ab degrading enzymes, which is a ubiquitously occurring type II integral membrane protein consisting of 742 amino acid (Grimm et al 2013). NEP is distributed over neurons, astrocytes, and microglia in the central nervous system (Grimm et al 2013). Neprilysin seems to be reduced in brain areas early affected in AD and characterized by high plaque load (Grimm et al 2013).…”

“…Knockout of NEP results in increased Ab level and impaired synaptic plasticity in wild and APP transgenic mice (Huang et al 2006;Madani et al 2006). Conversely, overexpression of NEP in AD mouse models decreases Ab level and inhibits formation of plaque (Grimm et al 2013;Iwata et al 2004). All these results suggest that AD progress could be inhibited by the increased expression or activity of NEP.…”

Prospective Comparison of ARNi With ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF)

“…This also needs further careful assessment in weighing up risks and benefits of this new therapy. In addition, amyloid β is also a substrate for neprilysin, 7 and inhibition may block breakdown of this key peptide implicated in Alzheimer disease pathogenesis and progression. , in a similar patient population) will assess this (thus far) theoretical concern, via evaluations such as cognitive function testing.…”