scholarly journals Luteinizing Hormone, a Reproductive Regulator That Modulates the Processing of Amyloid-β Precursor Protein and Amyloid-β Deposition

2004 ◽  
Vol 279 (19) ◽  
pp. 20539-20545 ◽  
Author(s):  
Richard L. Bowen ◽  
Giuseppe Verdile ◽  
Tianbing Liu ◽  
Albert F. Parlow ◽  
George Perry ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Sex Steroids ◽  
Early Adulthood ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Leuprolide Acetate ◽  
Precursor Protein ◽  
Aging Brain ◽  
Hormonal Changes ◽  
Age Related

Hormonal changes associated with the dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis following menopause/andropause have been implicated in the pathogenesis of Alzheimer's disease (AD). Experimental support for this has come from studies demonstrating an increase in amyloid-β (Aβ) deposition following ovariectomy/castration. Because sex steroids and gonadotropins are both part of the HPG feedback loop, any loss in sex steroids results in a proportionate increase in gonadotropins. To assess whether Aβ generation was due to the loss of serum 17β-estradiol or to the up-regulation of serum gonadotropins, we treated C57Bl/6J mice with the anti-gonadotropin leuprolide acetate, which suppresses both sex steroids and gonadotropins. Leuprolide acetate treatment resulted in a 3.5-fold (p< 0.0001) and a 1.5-fold (p< 0.024) reduction in total brain Aβ1-42 and Aβ1-40 concentrations, respectively, after 8 weeks of treatment. To further explore the role of gonadotropins in promoting amyloidogenesis, M17 neuroblastoma cells were treated with the gonadotropin luteinizing hormone (LH) at concentrations equivalent to early adulthood (10 mIU/ml) or post-menopause/andropause (30 mIU/ml). LH did not alter amyloid-β precursor protein (AβPP) expression but did alter AβPP processing toward the amyloidogenic pathway as evidenced by increased secretion and insolubility of Aβ, decreased αAβPP secretion, and increased AβPP-C99 levels. These results suggest the marked increases in serum LH following menopause/andropause as a physiologically relevant signal that could promote Aβ secretion and deposition in the aging brain. Suppression of the age-related increase in serum gonadotropins using anti-gonadotropin agents may represent a novel therapeutic strategy for AD.

scholarly journals EDEM1 Regulates Amyloid Precursor Protein (APP) Metabolism and Amyloid-β Production

2021 ◽  
Vol 23 (1) ◽  
pp. 117
Author(s):  
Jowita Nowakowska-Gołacka ◽  
Justyna Czapiewska ◽  
Hanna Sominka ◽  
Natalia Sowa-Rogozińska ◽  
Monika Słomińska-Wojewódzka
Keyword(s):  
Endoplasmic Reticulum ◽  
Neuroblastoma Cells ◽  
Amyloid Β ◽  
Proteasomal Degradation ◽  
Precursor Protein ◽  
Control Factor ◽  
Regulatory Factor ◽  
Human Embryonic Kidney ◽  
App Metabolism ◽  
Dependent Transport

Endoplasmic reticulum (ER) degradation-enhancing α-mannosidase-like protein 1 (EDEM1) is a quality control factor directly involved in the endoplasmic reticulum-associated degradation (ERAD) process. It recognizes terminally misfolded proteins and directs them to retrotranslocation which is followed by proteasomal degradation in the cytosol. The amyloid-β precursor protein (APP) is synthesized and N-glycosylated in the ER and transported to the Golgi for maturation before being delivered to the cell surface. The amyloidogenic cleavage pathway of APP leads to production of amyloid-β (Aβ), deposited in the brains of Alzheimer’s disease (AD) patients. Here, using biochemical methods applied to human embryonic kidney, HEK293, and SH-SY5Y neuroblastoma cells, we show that EDEM1 is an important regulatory factor involved in APP metabolism. We find that APP cellular levels are significantly reduced after EDEM1 overproduction and are increased in cells with downregulated EDEM1. We also report on EDEM1-dependent transport of APP from the ER to the cytosol that leads to proteasomal degradation of APP. EDEM1 directly interacts with APP. Furthermore, overproduction of EDEM1 results in decreased Aβ40 and Aβ42 secretion. These findings indicate that EDEM1 is a novel regulator of APP metabolism through ERAD.

How adolescents and adults translate motivational value to action: Age-related shifts in strategic physical effort exertion for monetary rewards

2019 ◽  
Author(s):  
Alexandra M Rodman ◽  
Katherine Powers ◽  
Catherine Insel ◽  
Erik K Kastman ◽  
Katherine Kabotyanski ◽  
...  
Keyword(s):  
Young Adults ◽  
Early Adulthood ◽  
Theoretical Models ◽  
Incentive Motivation ◽  
Reward Processing ◽  
Monetary Reward ◽  
Physical Effort ◽  
Monetary Rewards ◽  
Age Related ◽  
Adolescents And Adults

Adults titrate the degree of physical effort they are willing to expend according to the magnitude of reward they expect to obtain, a process guided by incentive motivation. However, it remains unclear whether adolescents, who are undergoing normative developmental changes in cognitive and reward processing, translate incentive motivation into action in a way that is similarly tuned to reward value and economical in effort utilization. The present study adapted a classic physical effort paradigm to quantify age-related changes in motivation-based and strategic markers of effort exertion for monetary rewards from adolescence to early adulthood. One hundred and three participants aged 12-23 years completed a task that involved exerting low or high amounts of physical effort, in the form of a hand grip, to earn low or high amounts of money. Adolescents and young adults exhibited highly similar incentive-modulated effort for reward according to measures of peak grip force and speed, suggesting that motivation for monetary reward is consistent across age. However, young adults expended energy more economically and strategically: whereas adolescents were prone to exert excess physical effort beyond what was required to earn reward, young adults were more likely to strategically prepare before each grip phase and conserve energy by opting out of low reward trials. This work extends theoretical models of development of incentive-driven behavior by demonstrating that layered on similarity in motivational value for monetary reward, there are important differences in the way behavior is flexibly adjusted in the presence of reward from adolescence to young adulthood.

scholarly journals Role of amyloid β-peptide in the pathogenesis of age-related macular degeneration

2021 ◽  
Vol 6 (1) ◽  
pp. e000774
Author(s):  
Minwei Wang ◽  
Shiqi Su ◽  
Shaoyun Jiang ◽  
Xinghuai Sun ◽  
Jiantao Wang
Keyword(s):  
Mitochondrial Dysfunction ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Cell Structure ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Amyloid Β Peptide ◽  
Age Related

Age-related macular degeneration (AMD) is the most common eye disease in elderly patients, which could lead to irreversible vision loss and blindness. Increasing evidence indicates that amyloid β-peptide (Aβ) might be associated with the pathogenesis of AMD. In this review, we would like to summarise the current findings in this field. The literature search was done from 1995 to Feb, 2021 with following keywords, ‘Amyloid β-peptide and age-related macular degeneration’, ‘Inflammation and age-related macular degeneration’, ‘Angiogenesis and age-related macular degeneration’, ‘Actin cytoskeleton and amyloid β-peptide’, ‘Mitochondrial dysfunction and amyloid β-peptide’, ‘Ribosomal dysregulation and amyloid β-peptide’ using search engines Pubmed, Google Scholar and Web of Science. Aβ congregates in subretinal drusen of patients with AMD and participates in the pathogenesis of AMD through enhancing inflammatory activity, inducing mitochondrial dysfunction, altering ribosomal function, regulating the lysosomal pathway, affecting RNA splicing, modulating angiogenesis and modifying cell structure in AMD. The methods targeting Aβ are shown to inhibit inflammatory signalling pathway and restore the function of retinal pigment epithelium cells and photoreceptor cells in the subretinal region. Targeting Aβ may provide a novel therapeutic strategy for AMD.

scholarly journals 4-(Phenylsulfanyl) Butan-2-One Attenuates the Inflammatory Response Induced by Amyloid-β Oligomers in Retinal Pigment Epithelium Cells

Marine Drugs ◽  
2020 ◽  
Vol 19 (1) ◽  
pp. 1
Author(s):  
Peeraporn Varinthra ◽  
Shun-Ping Huang ◽  
Supin Chompoopong ◽  
Zhi-Hong Wen ◽  
Ingrid Y. Liu
Keyword(s):  
Retinal Pigment Epithelium ◽  
Inflammatory Response ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Amyloid Β ◽  
Age Related Macular Degeneration ◽  
Epithelial Cell Line ◽  
Age Related ◽  
Tnf Α ◽  
Cox 2

Age-related macular degeneration (AMD) is a progressive eye disease that causes irreversible impairment of central vision, and effective treatment is not yet available. Extracellular accumulation of amyloid-beta (Aβ) in drusen that lie under the retinal pigment epithelium (RPE) has been reported as one of the early signs of AMD and was found in more than 60% of Alzheimer’s disease (AD) patients. Extracellular deposition of Aβ can induce the expression of inflammatory cytokines such as IL-1β, TNF-α, COX-2, and iNOS in RPE cells. Thus, finding a compound that can effectively reduce the inflammatory response may help the treatment of AMD. In this research, we investigated the anti-inflammatory effect of the coral-derived compound 4-(phenylsulfanyl) butan-2-one (4-PSB-2) on Aβ1-42 oligomer (oAβ1-42) added to the human adult retinal pigment epithelial cell line (ARPE-19). Our results demonstrated that 4-PSB-2 can decrease the elevated expressions of TNF-α, COX-2, and iNOS via NF-κB signaling in ARPE-19 cells treated with oAβ1-42 without causing any cytotoxicity or notable side effects. This study suggests that 4-PSB-2 is a promising drug candidate for attenuation of AMD.

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