Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Yao, Meicun; Nguyen, Thuy‐Vi V.; Rosario, Emily R.; Ramsden, Martin; Pike, Christian J.

doi:10.1111/j.1471-4159.2008.05341.x

Cited by 78 publications

(66 citation statements)

References 67 publications

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“…Because the injection of testosterone has been shown to reduce deposits of β-amyloid protein in vitro through the enhanced effects of neprilysin (42), it might be that mild exercise, in mediating paracrine effects through androgens and/or DHT, may, in turn, also reduce the deposits of β-amyloid protein and protect cognitive functions.…”

Section: Discussionmentioning

confidence: 99%

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Okamoto

Hojo

Inoue

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

134

105

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Mild exercise activates hippocampal neurons through the glutamatergic pathway and also promotes adult hippocampal neurogenesis (AHN). We hypothesized that such exercise could enhance local androgen synthesis and cause AHN because hippocampal steroid synthesis is facilitated by activated neurons via N-methyl-D-aspartate receptors. Here we addressed this question using a mild-intense treadmill running model that has been shown to be a potent AHN stimulator. A mass-spectrometric analysis demonstrated that hippocampal dihydrotestosterone increased significantly, whereas testosterone levels did not increase significantly after 2 wk of treadmill running in both orchidectomized (ORX) and sham castrated (Sham) male rats. Furthermore, analysis of mRNA expression for the two isoforms of 5α-reductases (srd5a1, srd5a2) and for androgen receptor (AR) revealed that both increased in the hippocampus after exercise, even in ORX rats. All rats were injected twice with 5′-bromo-2′deoxyuridine (50 mg/kg body weight, i.p.) on the day before training. Mild exercise significantly increased AHN in both ORX and Sham rats. Moreover, the increase of doublecortin or 5′-bromo-2′deoxyuridine/NeuN-positive cells in ORX rats was blocked by s.c. flutamide, an AR antagonist. It was also found that application of an estrogen receptor antagonist, tamoxifen, did not suppress exercise-induced AHN. These results support the hypothesis that, in male animals, mild exercise enhances hippocampal synthesis of dihydrotestosterone and increases AHN via androgenenic mediation.neurosteroid | exercise-induced neurogenesis | low intensity exercise | de novo synthesis | paracrine

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Section: Discussionmentioning

confidence: 99%

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Okamoto

Hojo

Inoue

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

134

105

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“…Last year, Yao et al (37) found that androgen up-regulates neprilysin gene expression, and their study suggests that androgen treatment could reduce accumulation of A␤, as a therapeutic approach for AD. This study demonstrates positive regulation of neprilysin expression by 17␤-estradiol, leading to A␤ degradation.…”

Section: Discussionmentioning

confidence: 99%

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

Liang

Yang

Yin

et al. 2010

Journal of Biological Chemistry

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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...

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“…Testosterone was found to downregulate β-secretase to reduce Aβ accumulation [69] by upregulating neprilysin, a primary protease involved in the regulation of Aβ breakdown [70]. Another study reported that testosterone reduced the Aβ accumulation by offsetting the age-related decline in neprilysin expression [71]. Decreased levels of testosterone result in an increased risk for the development of AD in men since it also acts as an endogenous regulator of Aβ [72].…”

Section: Endocrinal Dysregulations In the Ad Pathophysiologymentioning

confidence: 99%

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

Ahmad

Fatima

Mondal³

2019

Neuropsychobiology

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Alzheimer’s disease (AD), the commonest progressive neurodegenerative disorder of the brain, is clinically characterized by the formation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Recent studies suggest a relationship between the endocrinal dysregulation and the neuronal loss during the AD pathology. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis regulating circulating levels of glucocorticoid hormones has been implicated in the pathophysiology of AD. Likewise, dysregulated insulin signaling, impaired glucose uptake and insulin resistance are some of the prime factors in the onset/progression of AD. In this review, we have discussed the changes in HPA and HPG axes, implicated insulin resistance/signaling and glucose regulation during the onset/progression of AD. Therefore, simultaneous detection of these endocrinal markers in the early or presymptomatic stages may help in the early diagnosis of AD. This evidence for implicated endocrinal functions supports the fact that modulation of endocrinal pathways can be used as therapeutic targets for AD. Future studies need to determine how the induction or inhibition of endocrinal targets could be used for predictable neuroprotection in AD therapies.

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Androgens regulate neprilysin expression: role in reducing β‐amyloid levels

Cited by 78 publications

References 67 publications

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

Mild exercise increases dihydrotestosterone in hippocampus providing evidence for androgenic mediation of neurogenesis

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

Role of Hypothalamic-Pituitary-Adrenal Axis, Hypothalamic-Pituitary-Gonadal Axis and Insulin Signaling in the Pathophysiology of Alzheimer’s Disease

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