<i>β</i>‐Amyloid Degradation and Alzheimer′s Disease

Wang, Deng Shun; Dickson, Dennis W.; Malter, James S.

doi:10.1155/jbb/2006/58406

Cited by 155 publications

(129 citation statements)

References 180 publications

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“…However, other mechanisms might account for the contribution of the ACE gene to the development of AD. A cell culture study showed that the ACE protein degrades beta-amyloid [14] , which is one of the pathological hallmarks of AD [11] . The degradation of [28] .…”

Section: Discussionmentioning

confidence: 99%

“…The function of the ACE protein is thought to be related to cardiovascular events [7][8][9] that contribute to AD, inflammatory processes, oxidative stress, cell growth, matrix deposition, and the interference of acetylcholine release in neurons involved in cognitive processing [10] . In addition, the ACE protein has been shown to degrade beta-amyloid, which is one of the pathological hallmarks of AD [11] , in a cell culture study [12] . These results have suggested that the ACE protein might be beneficial as a treatment for patients with AD [13] .…”

Section: Introductionmentioning

confidence: 99%

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Is the role of the angiotensin-converting enzyme gene in Alzheimer's disease independent of hypertension?

Yang

Huang

et al. 2017

Transl. Neurosci. Clin.

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Objective: Angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms are considered biomarkers of late-onset Alzheimer's disease (AD). However, the results of studies of these polymorphisms have been inconsistent. The ACE protein directly degrades beta-amyloid and thereby slows the progression of AD and its onset. However, it also activates the renin-angiotensin-aldosterone system, which can contribute to hypertension and/or cardiovascular events that increase the risk for developing AD. Methods: In this study, we examined the bidirectional association of the ACE gene and AD in patients with AD with and without hypertension.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Is the role of the angiotensin-converting enzyme gene in Alzheimer's disease independent of hypertension?

Yang

Huang

et al. 2017

Transl. Neurosci. Clin.

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“…Thus, it would be interesting to co-crystallize IDE with pA␤ or npA␤ to further elucidate the structural basis of the inhibitory effect of phosphorylation on A␤ degradation. In addition to IDE, several other proteases involved in A␤ degradation that contribute to the regulation of A␤ levels in the human brain have been identified (52). In particular, NEP, ACE, and plasmin are considered to be physiologically and pathologically relevant in sporadic AD.…”

Section: Maldi-tof-ms Analysis Of Cleavage Products Of Npa␤ and Pa␤mentioning

confidence: 99%

“…NEP is a membrane-bound zinc metallopeptidase localized at the cell surface and in cytoplasmic vesicles preferentially hydrolyzing extracellular oligopeptides on the amino side of hydrophobic residues (53) and has been shown to be capable of degrading A␤ both in vivo (54,55) and in vitro (55)(56)(57). NEP is also reported to be expressed on neuronal pre-and postsynaptic membranes (52). However, only very little concentrations of NEP are found in extracellular fluids (58).…”

Section: Maldi-tof-ms Analysis Of Cleavage Products Of Npa␤ and Pa␤mentioning

confidence: 99%

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

Kumar

Singh

Hinze

et al. 2012

Journal of Biological Chemistry

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Background: Amyloid-␤ peptide (A␤) is degraded by different proteases. We recently demonstrated phosphorylation of A␤. Results: Phosphorylation of A␤ decreases its clearance by microglial BV-2 cells and selectively inhibits the cleavage by insulindegrading and angiotensin-converting enzymes. Conclusion: Phosphorylation at Ser-8 negatively regulates A␤ degradation. Significance: Phosphorylation could play a dual role in A␤ metabolism. It decreases the clearance by microglial cells and also promotes A␤ aggregation. Accumulation of amyloid-␤ peptides (A␤) in the brain is a common pathological feature of Alzheimer disease (AD).Aggregates of A␤ are neurotoxic and appear to be critically involved in the neurodegeneration during AD pathogenesis. Accumulation of A␤ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the ␥-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD. However, recent data also indicate a decreased clearance rate of A␤ in AD brains. We recently demonstrated that A␤ undergoes phosphorylation by extracellular or cell surface-localized protein kinase A, leading to increased aggregation. Here, we provide evidence that phosphorylation of monomeric A␤ at Ser-8 also decreases its clearance by microglial cells. By using mass spectrometry, we demonstrate that phosphorylation at Ser-8 inhibited the proteolytic degradation of monomeric A␤ by the insulin-degrading enzyme, a major A␤-degrading enzyme released from microglial cells. Phosphorylation also decreased the degradation of A␤ by the angiotensin-converting enzyme. In contrast, A␤ degradation by plasmin was largely unaffected by phosphorylation. Thus, phosphorylation of A␤ could play a dual role in A␤ metabolism. It decreases its proteolytic clearance and also promotes its aggregation. The inhibition of extracellular A␤ phosphorylation, stimulation of protease expression and/or their proteolytic activity could be explored to promote A␤ degradation in AD therapy or prevention.Alzheimer disease (AD) 3 is characterized by the progressive deposition of amyloid-␤ peptides (A␤) in the brain (1, 2). A␤ derives from proteolytic processing of the amyloid precursor protein involving sequential cleavages by enzymes called ␤-and ␥-secretases (3, 4). A critical role of A␤ in the pathogenesis of AD is strongly supported by several mutations within the genes encoding the amyloid precursor protein itself or the two presenilins that represent the proteolytically active components of the ␥-secretase complex. All of these mutations affect the production and/or aggregation of A␤ and cause early-onset forms of familial AD (5-7). Although early-onset familial AD appears to be commonly associated with an elevated production of aggregation-prone A␤ variants, it remains unclear whether increased A␤ generation also contributes to the much more common form of late-onset AD. Recent evidence rather indicated a decreased clearance rate of A␤ in AD compared with control brains (8 -10).Several...

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“…Currently, 12 million people are affected with AD and the number is predicted to triple by 2050 world-wide (1,2). The common pathogenic figures of AD are senile plaques, neurofibrillary tangles (NFTs), dystrophic neurites, extensive neuronal loss, and gliosis (3). Currently, the most credible hypothesis regarding senile plaques is that they form by reversible aggregation of Aß in clusters (4,5).…”

Section: Introductionmentioning

confidence: 99%

Characterization of changes in global gene expression in the brain of neuron-specific enolase/human Tau23 transgenic mice in response to overexpression of Tau protein

Woo

Park²,

Kang³

et al. 2010

Int J Mol Med

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Abstract. Tau is a neuronal phosphoprotein responsible for the formation of the neurofibrillary tangles in Alzheimer's disease. To characterize the changes in global gene expression in the brain of transgenic mice that overexpress human Tau23 protein in response to the increase of Tau23 phosphorylation, total RNA extracted from the hippocampus of 12-month-old transgenic and wild-type mice was converted to cDNA, labeled with biotin and hybridized to oligonucleotide microarrays. The microarray results were confirmed by real-time RT-PCR and Western blotting method. It was determined that 43 genes were up-regulated and 8 genes were down-regulated by Tau23 in transgenic mice compared to controls, based on the arbitrary difference in the 2-fold change. Among the up-regulated transcripts, those encoding for transporter and oxidoreductase were dramatically over-represented, followed by those related to regulatory molecule, cytoskeletal protein, signaling molecule, and extracellular matrix protein. Genes encoding for transcription factor, regulatory molecule, miscellaneous function, and chaperone were significantly reduced in the downregulated group. The major genes in the up-regulated categories included Ecrg4, Folr1, Defb11, Aqp1 and Soctdc1. The major genes in the down-regulated categories were Ncor1, Gpm6a, and Hspd1. These results indicate that the microarray analysis identifies several gene functional groups and individual genes that respond to a sustained increase in Tau23 phosphorylation levels in the brain of transgenic mice. In addition, the results suggest the microarray test is a useful tool for increased understanding of the role of Tau23 protein in regulating neurodegenerative disorders.

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β‐Amyloid Degradation and Alzheimer′s Disease

Cited by 155 publications

References 180 publications

Is the role of the angiotensin-converting enzyme gene in Alzheimer's disease independent of hypertension?

Is the role of the angiotensin-converting enzyme gene in Alzheimer's disease independent of hypertension?

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

Characterization of changes in global gene expression in the brain of neuron-specific enolase/human Tau23 transgenic mice in response to overexpression of Tau protein

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