Turnover of Amyloid β-Protein in Mouse Brain and Acute Reduction of Its Level by Phorbol Ester

Savage, Mary J.; Trusko, Stephen P.; Howland, David; Pinsker, Leonard R.; Mistretta, Suzanne; Reaume, Andrew G.; Greenberg, Barry D.; Siman, Robert; Scott, Richard W.

doi:10.1523/jneurosci.18-05-01743.1998

Cited by 208 publications

(154 citation statements)

References 66 publications

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“…A␤ X-40 and A␤ X-42 ELISAs were performed by using the well characterized BNT-77͞BA-27 (A␤ X-40) and BNT-77͞BC-05 (A␤ X-42) systems (36). To measure brain A␤, each cerebral hemisphere was homogenized in 9 vol (wt͞vol) of 0.2% diethylamine in 50 mM NaCl (16,37) by using a Potter-Elvehjem homogenizer. After centrifugation at 100,000 ϫ g for 1 h, the supernatant was neutralized with 1͞10 vol of 500 mM Tris⅐HCl (pH 6.8), then A␤ ELISAs were performed.…”

Section: Methodsmentioning

confidence: 99%

“…Although cerebral accumulation of A␤ is believed to play a central role in Alzheimer's disease (AD) pathogenesis, in the vast majority of cases the underlying causes for this elevation are unknown. Several lines of evidence demonstrate that newly generated A␤ is rapidly cleared from the brain (16,17), suggesting that A␤-degrading proteases could play a role in regulating cerebral levels of the peptide. Two proteases, neprilysin (NEP) and endothelin-converting enzyme, have recently been shown to degrade A␤ in vivo (18,19), validating the role of proteolysis in regulating endogenous A␤ levels.…”

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confidence: 99%

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Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Farris

Mansourian

Chang

et al. 2003

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

1,340

1,040

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Two substrates of insulin-degrading enzyme (IDE), amyloid ␤-protein (A␤) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of A␤ levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases A␤ and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE ؊͞؊). IDE deficiency resulted in a >50% decrease in A␤ degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE ؊͞؊ mice showed increased cerebral accumulation of endogenous A␤, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the ␤-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. Together with emerging genetic evidence, our in vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD. I nsulin-degrading enzyme (IDE, insulysin) is an Ϸ110-kDa thiol zinc-metalloendopeptidase located in cytosol, peroxisomes, endosomes, and on the cell surface (1-4) that cleaves small proteins of diverse sequence, many of which share a propensity to form ␤-pleated sheet-rich amyloid fibrils under certain conditions [e.g., amyloid ␤-protein (A␤), insulin, glucagon, amylin, atrial natriuretic factor, and calcitonin] (5, 6). IDE is the major enzyme responsible for insulin degradation in vitro (1), but the extent to which it mediates insulin catabolism in vivo has been controversial, with doubts expressed that IDE has any physiological role in insulin catabolism (7). Insulin, which is critical for glucose, lipid, and protein metabolism, as well as for cell growth and differentiation, is cleared mainly by the liver and kidney, but most other tissues also degrade the hormone. It was recently shown that transferring an Ϸ3.7-cM chromosomal region containing the IDE gene from an inbred rat model of type 2 diabetes mellitus (DM2) (the GK rat) to a normoglycemic rat recapitulated several features of the diabetic phenotype, including hyperinsulinemia and postprandial hyperglycemia (8). The GK allele of IDE in this chromosomal region was found to bear two missense mutations that, when transfected into COS-1 cells, resulted in 31% less insulin degradation compared with cells transfected with the WT allele. Furthermore, the IDE region of chromosome 10q has been genetically linked to DM2 (9, 10) and to elevated fasting glucose levels [20-year means (1...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Farris

Mansourian

Chang

et al. 2003

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

1,340

1,040

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“…However, there is evidence to suggest that there are such mechanisms. For example, although CSF is regularly released into the venous system through the arachnoid villi, the half lives of proteins in the CSF differ from protein to protein, and even differ between various proteolytic fragments of the same original protein (Savage et al, 1998), suggesting a selective mechanism of removal. Recently it was proposed that there is an extracellular protein quality control system consisting of abundant secreted ECs that recognise and facilitate the disposal of non-native or dangerously hydrophobic proteins via receptor-mediated cell uptake .…”

Section: Potential Control Mechanisms?mentioning

confidence: 99%

Extracellular Chaperones and Amyloids

Wilson¹,

Yerbury²,

Poon³

2008

Heat Shock Proteins and the Brain: Implications for Neurodegenerative Diseases and Neuroprotection

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The pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacerabate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies. ABSTRACTThe pathology of more than 40 human degenerative diseases is associated with fibrillar proteinaceous deposits called amyloid. Collectively referred to as protein deposition diseases, many of these affect the brain and the central nervous system. In many cases the amyloid deposits are extracellular and are found associated with newly identified abundant extracellular chaperones (ECs). Evidence is discussed which suggests an important regulatory role for ECs in amyloid formation and disposal in vivo. This is emerging as an exciting field. A model is presented in which it is proposed that, under normal conditions, ECs stabilize extracellular misfolded proteins by binding to them, and then guide them to specific receptors for uptake and subsequent degradation. In this scenario, EC receptors are a critical part of a quality control system which protects the brain against dangerously hydrophobic proteins/peptides. However, it also appears possible that in the presence of a high molar excess of misfolded protein, such as might occur during disease, the limited amounts of ECs available may actually exacebate pathology. Further advances in understanding of the mechanisms that control extracellular protein folding are likely to identify new strategies for effective disease therapies.

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“…For example, one recent study (2) implicated neutrophil PKC␦ in reperfusion injury after experimental stroke, consistent with work from Mochly-Rosen and colleagues (3) showing that a PKC␦ inhibitor reduced infarct size. The present study (1) builds on previous findings that phorbol esters reduce A␤ levels and the number of amyloid plaques in AD-transgenic mice (4) and that PKC decreases A␤ levels in cell culture (5). These and other threads that link PKC and A␤ are discussed in a recent review (6).…”

mentioning

confidence: 78%

Another weapon against amyloid

Greenberg

2006

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

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A lzheimer's disease (AD) is one of those conditions that, like cancer in earlier generations, inspires particular terror among the general public. Therapeutic advances have lagged behind insights into genetics and pathophysiology, and although ␤-amyloid (A␤), the product of amyloid precursor protein (APP) cleavage, remains the leading suspect among proposed pathogenic factors, its causal role in AD has not been established with certainty.At present, patients with AD have access to two approved specific treatments, acetylcholinesterase inhibitors and the glutamate receptor antagonist memantine, neither of which is dramatically effective. Several experimental approaches are also under study, including A␤ vaccines, metal chelators, and derivatives of Congo red dye, which bind A␤. In this issue of PNAS, Robert Messing and colleagues (1) report a finding that suggests a new strategy for stimulating the enzymatic breakdown of A␤, which could produce benefit in AD.This strategy is based on the enzyme PKC, a serine͞threonine kinase that catalyzes the calcium-and phospholipiddependent phosphorylation of protein substrates and is also a receptor for phorbol esters. Messing and colleagues (1) have been studying PKC for many years, especially the neurological effects of PKC isozymes. For example, one recent study (2) implicated neutrophil PKC␦ in reperfusion injury after experimental stroke, consistent with work from Mochly-Rosen and colleagues (3) showing that a PKC␦ inhibitor reduced infarct size. The present study (1) builds on previous findings that phorbol esters reduce A␤ levels and the number of amyloid plaques in AD-transgenic mice (4) and that PKC decreases A␤ levels in cell culture (5). These and other threads that link PKC and A␤ are discussed in a recent review (6).Messing and colleagues (1) crossed two lines of transgenic mice, one that overexpresses PKC in neurons and another that expresses a mutant form of APP (the Indiana or V717F mutation) found in some patients with the rare familial form of AD. The latter mice exhibit some features of clinical AD, including the age-dependent deposition of extracellular amyloid plaques in selected brain regions. Plaque density, astrogliosis, and alterations in neurites were reduced in PKC -transgenic͞ APP V717F compared with APP V717F mutant mice. Similar findings were obtained with other PKC and APP transgenics. Contrary to expectations, however, A␤ synthesis was unaffected by PKC overexpression. Instead, PKC seemed to act by stimulating the degradation of A␤.A␤ is a substrate for several enzymes, including insulin-degrading enzyme and neprilysin, the activities of which were unaltered in PKC transgenics. However, the activity of another A␤-degrading enzyme, endothelin-converting enzyme (ECE) (7), was increased in hippocampus and cerebral neocortex of these mice. Previous cell-culture studies suggested that the effect of phorbol esters on ECE expression was mediated through the transcription factor Ets-1. Messing and colleagues (1) concluded that amyloid deposition was d...

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Turnover of Amyloid β-Protein in Mouse Brain and Acute Reduction of Its Level by Phorbol Ester

Cited by 208 publications

References 66 publications

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo

Extracellular Chaperones and Amyloids

Another weapon against amyloid

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