Chromaffin cells express Alzheimer amyloid precursor protein in the same manner as brain cells

Takeda, Misa; Tanaka, Shigeru; Kido, Hiroshi; Daikoku, Sigeo; Oka, M.; Sakai, Kentaro; Katunuma, Nobuhiko

doi:10.1016/0304-3940(94)90415-4

Cited by 9 publications

(6 citation statements)

References 9 publications

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“…CA074Me treatment abolished levels of activity-dependent pGlu-Aβ(3-40) released, but had no effect on constitutive levels secreted; these data suggest that CatB may produce pGlu-Aβ(3-40) in the regulated but not constitutive secretory pathway. Neuronal-like chromaffin cells (bovine) are an excellent model of human AβPPwt processing because they express AβPP-695 having the wt β-secretase and wt Aβ sequences identical to that in man [61, 62]. These chromaffin cell data, which are from an entirely natural model of human AβPPwt processing, are consistent with that we obtained here in the unnatural transgenic AβPPLon mouse model.…”

Section: Discussionsupporting

confidence: 86%

“…Moreover, unlike AβPPLon mice, chromaffin cells are a natural model and, thus, provide a control for potential transgene artifacts. Bovine chromaffin cells express AβPP-695 having the wt β-secretase site and flAβ(1-40/42) sequences found in man [61, 62] and as such model human wt β-secretase activity. Therefore, neuronal-like chromaffin cells were used to study the effects of CatB inhibition on pGlu-Aβ levels released from regulated and constitutive secretory pathways.…”

Section: Introductionmentioning

confidence: 99%

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Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

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Toneff

et al. 2014

JAD

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Pyroglutamate amyloid-β peptides (pGlu-Aβ) are particularly pernicious forms of amyloid-β peptides (Aβ) present in Alzheimer’s disease (AD) brains. pGlu-Aβ peptides are N-terminally truncated forms of full-length Aβ peptides (flAβ(1-40/42)) in which the N-terminal glutamate is cyclized to pyroglutamate to generate pGlu-Aβ(3-40/42). β-secretase cleavage of amyloid-β precursor protein (AβPP) produces flAβ(1-40/42), but it is not yet known whether the β-secretase BACE1 or the alternative β-secretase cathepsin B (CatB) participate in the production of pGlu-Aβ. Therefore, this study examined the effects of gene knockout of these proteases on brain pGlu-Aβ levels in transgenic AβPPLon mice, which express AβPP isoform 695 and have the wild-type (wt) β-secretase activity found in most AD patients. Knockout or overexpression of the CatB gene reduced or increased, respectively, pGlu-Aβ(3-40/42), flAβ(1-40/42), and pGlu-Aβ plaque load, but knockout of the BACE1 gene had no effect on those parameters in the transgenic mice. Treatment of AβPPLon mice with E64d, a cysteine protease inhibitor of CatB, also reduced brain pGlu-Aβ(3-42), flAβ(1-40/42), and pGlu-Aβ plaque load. Treatment of neuronal-like chromaffin cells with CA074Me, an inhibitor of CatB, resulted in reduced levels of pGlu-Aβ(3-40) released from the activity-dependent, regulated secretory pathway. Moreover, CatB knockout and E64d treatment has been previously shown to improve memory deficits in the AβPPLon mice. These data illustrate the role of CatB in producing pGlu-Aβ and flAβ that participate as key factors in the development of AD. The advantages of CatB inhibitors, especially E64d and its derivatives, as alternatives to BACE1 inhibitors in treating AD patients are discussed.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

Hook

Toneff

et al. 2014

JAD

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“…As a result, CG-mediated secretion has been used extensively as a model for the regulation of neuronal secretion (9). In addition, primary chromaffin cell cultures express various APP isoforms in a manner similar to neurons (24), and…”

Section: Resultsmentioning

confidence: 99%

Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells.

Efthimiopoulos

Vassilacopoulou

Ripellino

et al. 1996

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

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“…High APP levels are found in brain stem neurons, 40 the medullae chromaffin cells of the adrenal gland, 41 the heart, 28 and soluble APP is present in plasma. 29 We assayed catecholamine levels in these tissues, which are important for the sympathetic nervous system.…”

Section: Increased Catecholamines In App Knockout Micementioning

confidence: 99%

Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels

et al. 2012

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The catecholamines dopamine (DA), norepinephrine (NE) and epinephrine (E) are neurotransmitters and hormones that mediate stress responses in tissues and plasma. The expression of β-amyloid precursor protein (APP) is responsive to stress and is high in tissues rich in catecholamines. We recently reported that APP is a ferroxidase, subsuming, in neurons and other cells, the iron-export activity that ceruloplasmin mediates in glia. Here we report that, like ceruloplasmin, APP also oxidizes synthetic amines and catecholamines catalytically (K(m) NE=0.27 mM), through a site encompassing its ferroxidase motif and selectively inhibited by zinc. Accordingly, APP knockout mice have significantly higher levels of DA, NE and E in brain, plasma and select tissues. Consistent with this, these animals have increased resting heart rate and systolic blood pressure as well as suppressed prolactin and lymphocyte levels. These findings support a role for APP in extracellular catecholaminergic clearance.

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Chromaffin cells express Alzheimer amyloid precursor protein in the same manner as brain cells

Cited by 9 publications

References 9 publications

Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

Brain Pyroglutamate Amyloid-β is Produced by Cathepsin B and is Reduced by the Cysteine Protease Inhibitor E64d, Representing a Potential Alzheimer's Disease Therapeutic

Cholinergic agonists stimulate secretion of soluble full-length amyloid precursor protein in neuroendocrine cells.

Amine oxidase activity of β-amyloid precursor protein modulates systemic and local catecholamine levels

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