Estrogen Stimulates Degradation of β-Amyloid Peptide by Up-regulating Neprilysin

Abstract

Postmenopausal estrogen depletion is a characterized risk factor for Alzheimer disease (AD), a human disorder linked to high levels of ␤-amyloid peptide (A␤) in brain tissue. Previous studies suggest that estrogen negatively regulates the level of A␤ in the brain, but the molecular mechanism is unknown. Here, we provide evidence that estrogen promotes A␤ degradation mainly through a principal A␤ degrading enzyme, neprilysin, in neuroblastoma SH-SY5Y cells. We also demonstrate that upregulation of neprilysin by estrogen is dependent on both estrogen receptor ␣ and ␤ (ER␣ and ER␤), and ligand-activated ER regulates expression of neprilysin through physical interactions between ER and estrogen response elements (EREs) identified in the neprilysin gene. These results were confirmed by in vitro gel shift and in vivo chromatin immunoprecipitation analyses, which demonstrate specific binding of ER␣ and ER␤ to two putative EREs in the neprilysin gene. The EREs also enhance ER␣-and ER␤-dependent reporter gene expression in a yeast model system. Therefore, the study described here provides a putative mechanism by which estrogen positively regulates expression of neprilysin to promote degradation of A␤, reducing risk for AD. These results may lead to novel approaches to prevent or treat AD.Alzheimer disease (AD) 3 is a progressive neurodegenerative disease characterized by declarative memory impairment and progressive dementia. The level of ␤-amyloid peptide (A␤) is elevated in the brains of AD patients, and A␤ is believed to play a critical role in the pathology of AD (1, 2). Recent studies show that aggregated oligomers of A␤ (protofibrils) play a direct role in neuronal and behavioral deficits in AD patients (3).The rate of A␤ degradation could influence the risk of developing AD, and it has been proposed that stimulation of proteolytic degradation of A␤ could be used as a therapeutic approach for AD (4, 5). Neprilysin is thought to be the primary A␤-degrading enzyme in the brain (6) because degradation of radiolabeled synthetic A␤42 in rat brain is largely inhibited by the neprilysin inhibitor, phosphoramidon (PA) (7, 8) and because neprilysin degrades both monomeric and oligomeric forms of A␤40 and A␤42 in intracellular and extracellular compartments of the brain (9). Moreover, the level of neprilysin mRNA and protein is lower in the hippocampus and temporal gyrus of AD patients (10, 11), which correlates with higher levels of A␤ as A␤ tends to accumulate in these regions (12).Neprilysin activity is also lower in the hippocampus, cerebellum, and caudate of ovariectomized rats than in non-ovariectomized rats, and this effect can be reversed by exogenous 17␤-estradiol (13). These data indicate that 17␤-estradiol positively regulates neprilysin activity in the brain. 17␤-Estradiol was also reported to reduce the generation of A␤ peptides in neuroblastoma cells and neurons (14). The positive regulation of neprilysin by 17␤-estradiol might be a crucial factor in protecting normal adult brain from A␤ damage and in improving...

Estrogen and Brain Protection

“…Alternatively, estrogen may reduce available amyloid precursor protein by stimulating the formation of vesicles that uptake this precursor-protein, thereby precluding maximal generation of Amyloid (Greenfield et al, 2002). These findings suggest another mechanism underlying estrogen's protection against Alzheimer's disease involving Amyloid degredation (Liang et al, 2010). Estrogen may also protect the signaling function of protein kinases from Amyloid .…”

“…In vitro estrogen treatment inhibited the formation of toxic Amyloid oligomers (Morinaga et al, 2007). Finally, estrogen activated Neprilysin, the primary enzyme that degrades Amyloid , thereby facilitating Amyloid degradation in human neuroblastoma cells (Liang et al, 2010). It is possible that this effect of estrogen is preceded by estrogen's action on amyloid precursor protein.…”

Neprilysin Is Suppressed by Dual-Specificity Tyrosine-Phosphorylation Regulated Kinase 1A (DYRK1A) in Down-Syndrome-Derived Fibroblasts

“…1) Given that in general elderly women have a higher prevalence of AD than elderly men, 32) gender difference is one of key factors in development of AD. Because a representative female sex hormone, 17β-estradiol, induces the expression of MME gene, 33) gender-specific regulatory mechanism of MME gene expression in the brains may be implicated in higher prevalence of AD in elderly women. In fact, it is reported that in AD-model mice NEP expression levels are declined from 16 month of age.…”

Hormone replacement therapy and Alzheimers disease in older women: A systematic review of literature

“…(3) Influencing the glutamate system, a second neurotransmitter involved in learning and memory, via the expression of proteins of the NMDA receptors that are involved in glutamate activation and the enhancement of long-term potentiation (Gazzaley et al, 1996;Grodstein, 2017). (4) Promotion of the non-amyloidogenic metabolism of the amyloid precursor protein through increasing the activity of amyloid-β degrading enzymes (ADE) by enhanced activity of Neprilysin (NEP-1 and NEP-2) enzymes (Jaffe et al, 1994;Xiao et al, 2009;Liang et al, 2010;Yoon and Jo, 2012) (5) Increasing cerebral glucose transportation and regional blood flow which are all decreased in AD (Bishop and Simpkins, 1985;Ohkura et al, 1995;Resnick et al, 1998;Maki and Resnick, 2000).…”