Immunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid β-protein (Aβ) deposition

doi:10.1016/S0006-8993(01)02390-3

Brain Research

Volume 902, Issue 2, 1 June 2001, Pages 277-281

https://doi.org/10.1016/S0006-8993(01)02390-3 Get rights and content

Abstract

We investigated the immunohistochemical localization of neprilysin, a putative amyloid β-protein (Aβ)-degrading enzyme, in postmortem human brain tissues. In the cerebral cortex, neprilysin immunoreactivity was weak, but relatively dense distribution was found in the primary somatosensory and visual cortices compared with the hippocampus and association cortices. In Alzheimer brain, neprilysin-positive dystrophic neurites occurred in senile plaques in the primary cortices, an observation that supports the relative abundance of neprilysin-positive neuronal processes. A paucity of neprilysin in the hippocampus and association cortices may contribute to the vulnerability of these areas to Aβ deposition.

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Acknowledgements

This research was supported by grants-in-aid from the Ministry of Education, Science and Culture of Japan (10670618).

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2017, Toxicology and Applied Pharmacology
Citation Excerpt :
Given that CSF concentrations of Aβ1-40 and Aβ1-42 were unaltered in healthy volunteers administered sacubitril/valsartan (400 mg QD for 2 weeks), this may suggest a limited contribution of NEP to the Aβ degrading capacity and/or a possible up-regulation of redundant pathways for Aβ clearance in humans, which may differ in non-human primates. Across species, there is weak to no expression of NEP in the regions associated with Aβ plaque formation, namely the cerebral cortex and hippocampus (Matsas et al., 1985; Matsas et al., 1986; Pollard et al., 1987; Bourne et al., 1989; Gaudoux et al., 1993; Akiyama et al., 2001; Takeuchi et al., 2008; Chambers et al., 2010), potentially reinforcing the importance of other Aβ clearance pathways in these areas; immunostaining for Aβ in the cynomolgus monkey brain showed no evidence of Aβ accumulation in these regions. The brain regions with the highest NEP expression included the basal ganglia (caudate nucleus, putamen and globus pallidus) and some thalamic, pontine, cerebellar, and medullary nuclei.
Sacubitril/valsartan (LCZ696) is the first angiotensin receptor neprilysin inhibitor approved to reduce cardiovascular mortality and hospitalization in patients with heart failure with reduced ejection fraction. As neprilysin (NEP) is one of several enzymes known to degrade amyloid-β (Aβ), there is a theoretical risk of Aβ accumulation following long-term NEP inhibition. The primary objective of this study was to evaluate the potential effects of sacubitril/valsartan on central nervous system clearance of Aβ isoforms in cynomolgus monkeys using the sensitive Stable Isotope Labeling Kinetics (SILK™)-Aβ methodology.
The in vitro selectivity of valsartan, sacubitril, and its active metabolite sacubitrilat was established; sacubitrilat did not inhibit other human Aβ-degrading metalloproteases. In a 2-week study, sacubitril/valsartan (50 mg/kg/day) or vehicle was orally administered to female cynomolgus monkeys in conjunction with SILK™-Aβ. Despite low cerebrospinal fluid (CSF) and brain penetration, CSF exposure to sacubitril was sufficient to inhibit NEP and resulted in an increase in the elimination half-life of Aβ1-42 (65.3%; p = 0.026), Aβ1-40 (35.2%; p = 0.04) and Aβtotal (29.8%; p = 0.04) acutely; this returned to normal as expected with repeated dosing for 15 days. CSF concentrations of newly generated Aβ (AUC_(0–24 h)) indicated elevations in the more aggregable form Aβ1-42 on day 1 (20.4%; p = 0.039) and day 15 (34.7%; p = 0.0003) and in shorter forms Aβ1-40 (23.4%; p = 0.009), Aβ1-38 (64.1%; p = 0.0001) and Aβtotal (50.45%; p = 0.00002) on day 15. However, there were no elevations in any Aβ isoforms in the brains of these monkeys on day 16. In a second study cynomolgus monkeys were administered sacubitril/valsartan (300 mg/kg) or vehicle control for 39 weeks; no microscopic brain changes or Aβ deposition, as assessed by immunohistochemical staining, were present. Further clinical studies are planned to address the relevance of these findings.
Recombinant soluble neprilysin reduces amyloid-beta accumulation and improves memory impairment in Alzheimer's disease mice
2013, Brain Research
Accumulation of amyloid-β (Aβ) is thought to be a central pathology in the brain of patients with Alzheimer's disease (AD). Neprilysin (NEP), a plasma membrane glycoprotein of the neutral zinc metalloendopeptidase family, is known as a major Aβ-degrading enzyme in the brain. The level of NEP is reduced in the brains of patients with AD; therefore, NEP is under intense investigation as a potential therapeutic source for degradation of deposited Aβ in AD. Previous studies have utilized viral vectors expressing NEP for reduction of Aβ deposition in the brain. However, viral vectors have disadvantages regarding difficulty in control of insert size, expression desired (short- or long-term), and target cell type. Here, in order to overcome these disadvantages, we produced recombinant soluble NEP from insect cells using an NEP expression vector, which was administered by intracerebral injection into AD mice, resulting in significantly reduced accumulation of Aβ. In addition, AD mice treated with NEP showed improved behavioral performance on the water maze test. These data support a role of recombinant soluble NEP in improving memory impairment by regulation of Aβ deposition and suggest the possibility that approaches using protein therapy might have potential for development of alternative therapies for treatment of AD.
Neprilysin
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Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model
2013, Neuropharmacology
Ageing is associated with a deterioration of cognitive performance and with increased risk of neurodegenerative disorders. Hypertension is the most-prevalent modifiable risk factor for cardiovascular morbidity and mortality worldwide, and clinical data suggest that hypertension is a risk factor for Alzheimer's disease (AD). In the present study we tested whether propranolol, a β-receptor antagonist commonly used as antihypertensive drug, could ameliorate the cognitive impairments and increases in AD-related markers shown by the senescence-accelerated mouse prone-8 (SAMP8). Propranolol administration (5 mg/kg for 3 weeks) to 6-month-old SAMP8 mice attenuated cognitive memory impairments shown by these mice in the novel object recognition test. In the hippocampus of SAMP8 mice it has been found increases in Aβ₄₂ levels, the principal constituent of amyloid plaques observed in AD, accompanied by both an increased expression of the cleaving enzyme BACE1 and a decreased expression of the degrading enzyme IDE. All these effects were reversed by propranolol treatment. Tau hyperphosphorylation (PHF-1 epitope) shown by SAMP8 mice at this age was also decreased in the hippocampus of propranolol-treated mice, an effect probably related to a decrease in JNK1 expression. Interestingly, propranolol also phosphorylated Akt in SAMP8 mice, which was associated with an increase of glycogen synthase kinase-3β phosphorylation, contributing therefore to the reductions in Tau hyperphosphorylation. Synaptic pathology in SAMP8 mice, as shown by decreases in synaptophysin and BDNF, was also counteracted by propranolol treatment. Overall, propranolol might be beneficial in age-related brain dysfunction and could be an emerging candidate for the treatment of other neurodegenerative diseases.
This article is part of a Special Issue entitled ‘Cognitive Enhancers’.
Notch signaling proteins HES-1 and Hey-1 bind to insulin degrading enzyme (IDE) proximal promoter and repress its transcription and activity: Implications for cellular Aβ metabolism
2012, Biochimica et Biophysica Acta - Molecular Cell Research
Cerebral amyloid β (Aβ) accumulation is pathogenically associated with sporadic Alzheimer's disease (SAD). BACE-1 is involved in Aβ generation while insulin-degrading enzyme (IDE) partakes in Aβ proteolytic clearance. Vulnerable regions in AD brains show increased BACE-1 protein levels and enzymatic activity while the opposite occurs with IDE. Another common feature in SAD brains is Notch1 overexpression. Here we demonstrate an increase in mRNA levels of Hey-1, a Notch target gene, and a decrease of IDE transcripts in the hippocampus of SAD brains as compared to controls. Transient transfection of Notch intracellular domain (NICD) in N2aSW cells, mouse neuroblastoma cells (N2a) stably expressing human amyloid precursor protein (APP) Swedish mutation, reduce IDE mRNA levels, promoting extracellular Aβ accumulation. Also, NICD, HES-1 and Hey-1 overexpression result in decreased IDE proximal promoter activity. This effect was mediated by 2 functional sites located at − 379/− 372 and − 310 − 303 from the first translation start site in the − 575/− 19 (556 bp) fragment of IDE proximal promoter. By site-directed mutagenesis of the IDE promoter region we reverted the inhibitory effect mediated by NICD transfection suggesting that these sites are indeed responsible for the Notch-mediated inhibition of the IDE gene expression. Intracranial injection of the Notch ligand JAG-1 in Tg2576 mice, expressing the Swedish mutation in human APP, induced overexpression of HES-1 and Hey-1 and reduction of IDE mRNA levels, respectively. Our results support our theory that a Notch-dependent IDE transcriptional modulation may impact on Aβ metabolism providing a functional link between Notch signaling and the amyloidogenic pathway in SAD.
In vitro Pb exposure disturbs the balance between Aβ production and elimination: The role of AβPP and neprilysin
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Metabolism of β-amyloid peptide (Aβ) is closely associated with the pathology and etiology of Alzheimer's disease (AD). Our previous studies on aging primates and rodents have revealed that early life lead exposure increases the expression of the β-amyloid precursor protein (AβPP), elevates Aβ levels, and promotes neurodegeneration in old age. These effects were attributed to de novo synthetic pathways; however, the impact on Aβ degradation was not explored. Neprilysin (NEP), a rate-limiting catabolic peptidase is involved in Aβ metabolism in vivo. In the present study we sought to investigate whether accumulation of Aβ induced by Pb exposure is partially due to its ability to subdue NEP expression and consequently NEP activity. SH-SY5Y cells were exposed to Pb concentrations of 0, 5, 10, 20, and 50 μM for 48 h and AβPP, NEP protein and mRNA levels were measured. Additionally, NEP enzymatic activity and Aβ levels were also assessed. Western blot and RT-PCR analysis indicated significant increases in the protein and mRNA expression of AβPP, which appeared to be concentration and time-dependent, while the protein and mRNA expression of NEP as well as NEP activity declined. These actions of Pb were specific and were not observed when substituted by another metal. These results suggest that Pb causes both the overexpression of AβPP and repression of NEP resulting in the buildup of Aβ.

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Short communicationImmunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid β-protein (Aβ) deposition

Abstract

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Acknowledgements

J. Neuroimmunol.

Neuroscience

Neuroscience

Neuroscience

Blood

Short communication
Immunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid β-protein (Aβ) deposition