Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Pacheco‐Quinto, Javier; Eckman, Elizabeth A.

doi:10.1074/jbc.m112.422964

Cited by 77 publications

(80 citation statements)

References 50 publications

(54 reference statements)

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“…ECE2 is predominantly localized within the endolysosomal pathway and is responsible for the cleavage of Aβ destined for lysosomal degradation 43. The elevated production of EDN1 may be an unfortunate side effect of over‐activation of this pathway by excessive Aβ42.…”

Section: Discussionmentioning

confidence: 99%

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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The earliest decline in cerebral perfusion in Alzheimer's disease (AD) is in the medial parietal cortex (precuneus). We have analyzed precuneus in post‐mortem tissue from 70 AD and 37 control brains to explore the pathophysiology of the hypoperfusion: the contribution of arteriolosclerotic small vessel disease (SVD) and cerebral amyloid angiopathy (CAA), and of the vasoconstrictors endothelin‐1 (EDN1) and angiotensin II (Ang II), and the association with Aβ. The myelin‐associated glycoprotein:proteolipid protein‐1 ratio (MAG:PLP1) was used as an indicator of oxygenation of the precuneus prior to death. MAG:PLP1 was reduced ∼50% in early AD (Braak stage III–IV). Although MAG:PLP1 remained low in advanced AD (stage V–VI), the reduction was less pronounced, possibly reflecting falling oxygen demand. Reduction in cortical MAG:PLP1 correlated with elevation in vascular endothelial growth factor (VEGF), another marker of hypoperfusion. Cortical MAG:PLP1 declined nonsignificantly with increasing SVD and CAA, but significantly with the concentration of EDN1, which was elevated approximately 75% in AD. In contrast, with reduction in cortical MAG:PLP1, Ang II level and angiotensin‐converting enzyme (ACE) activity declined, showing a normal physiological response to hypoperfusion. MAG:PLP1 was reduced in the parietal white matter (WM) in AD but here the decline correlated positively (ie, physiologically) with WM EDN1. However, the decline of MAG:PLP1 in the WM was associated with increasing cortical EDN1 and perhaps reflected vasoconstriction of perforating arterioles, which traverse the cortex to perfuse the WM. EDN1 in the cortex correlated highly significantly with both soluble and insoluble Aβ42, shown previously to upregulate neuronal endothelin‐converting enzyme‐2 (ECE2), but not with Aβ40. Our findings demonstrate reduced oxygenation of the precuneus in early AD and suggest that elevated EDN1, resulting from Aβ42‐mediated upregulation of ECE2, is a contributor.

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Section: Discussionmentioning

confidence: 99%

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

2015

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“…We assumed that in spite of the elevation of both peptide and copper ion concentrations during the ionization process than in the incubation buffer, the ratio between the copper ion and Aβ(1-16) would be fixed even after evaporation of the solvent as shown by other studies. 12,22 Moreover, since there is an increase in the copper content of Cu 2+ -Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) complexes from fractions with higher copper to peptide ratios, this would suggest that the metal was attached to the peptide prior to ESI-MS analysis. We demonstrate here that Aβ(1-16) is able to bind up to three Cu 2+ ions at pH 7.4, and up to four Cu 2+ ions when the pH value decreased to 6.6.…”

Section: Resultsmentioning

confidence: 99%

“…Copper binding to Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) peptide. Using ESI-MS, we found that the binding of Cu : peptide molar ratio was 10:1 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…10 Nevertheless, short and easy-to-handle peptides have been used to study the structures and mechanisms that are also relevant for the native and longer peptides involved in neurodegenerative diseases. 11,12 Moreover, some previous ESI-MS studies have reported on the binding of Cu 2+ to Aβ (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16) at physiological pH and its effect on peptide conformation and oligomerisation. 12 The copper binding sites are located in the N-terminal region of Aβ peptides.…”

Section: Introductionmentioning

confidence: 99%

“…2,6 Recent data suggest that the intracellular pool of Aβ is regulated by the activity of endothelinconverting enzymes at the sites of production. 7 However, the deregulation of copper seems to be intimately involved in the pathogenesis of AD. 8,9 Copper is known to accelerate the aggregation of Aβ and Aβ(1-42) peptides, the major components of Aβ deposits.…”

Section: Introductionmentioning

confidence: 99%

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Time- and pH-Dependent Copper Binding to Aβ(1–16) Peptide: An Electrospray Ionization-Mass Spectrometric Approach

Manea

Schlosser

Murariu

2014

Int J Pept Res Ther

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CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

et al. 2018

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Although there are changes in gene expression and alterations in neuronal density and afferent inputs in the forebrain of trisomic mouse models of Down syndrome (DS) and Alzheimer's disease (AD), there is a lack of systematic assessments of gene expression and encoded proteins within individual vulnerable cell populations, precluding translational investigations at the molecular and cellular level. Further, no effective treatment exists to combat intellectual disability and basal forebrain cholinergic neurodegeneration seen in DS. To further our understanding of gene expression changes before and following cholinergic degeneration in a well-established mouse model of DS/AD, the Ts65Dn mouse, we assessed RNA expression levels from CA1 pyramidal neurons at two adult ages (∼6 months of age and ∼11 months of age) in both Ts65Dn and their normal disomic (2N) littermates. We further examined a therapeutic intervention, maternal choline supplementation (MCS), which has been previously shown to lessen dysfunction in spatial cognition and attention, and have protective effects on the survival of basal forebrain cholinergic neurons in the Ts65Dn mouse model. Results indicate that MCS normalized expression of several genes in key gene ontology categories, including synaptic plasticity, calcium signaling, and AD-associated neurodegeneration related to amyloid-beta peptide (Aβ) clearance. Specifically, normalized expression levels were found for endothelin converting enzyme-2 (Ece2), insulin degrading enzyme (Ide), Dyrk1a, and calcium/calmodulin-dependent protein kinase II (Camk2a), among other relevant genes. Single population expression profiling of vulnerable CA1 pyramidal neurons indicates that MCS is a viable therapeutic for long-term reprogramming of key transcripts involved in neuronal signaling that are dysregulated in the trisomic mouse brain which have translational potential for DS and AD.

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Endothelin-converting Enzymes Degrade Intracellular β-Amyloid Produced within the Endosomal/Lysosomal Pathway and Autophagosomes*

Cited by 77 publications

References 50 publications

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Pathophysiology of Hypoperfusion of the Precuneus in Early Alzheimer's Disease

Time- and pH-Dependent Copper Binding to Aβ(1–16) Peptide: An Electrospray Ionization-Mass Spectrometric Approach

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

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