Alzheimer's Amyloid Precursor Protein α-Secretase Is Inhibited by Hydroxamic Acid-Based Zinc Metalloprotease Inhibitors:  Similarities to the Angiotensin Converting Enzyme Secretase†

Biochemistry ◽  
1998 ◽  
Vol 37 (6) ◽  
pp. 1680-1685 ◽  
Author(s):  
S. Parvathy ◽  
Ishrut Hussain ◽  
Eric H. Karran ◽  
Anthony J. Turner ◽  
Nigel M. Hooper
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Hydroxamic Acid ◽  
Precursor Protein ◽  
Converting Enzyme ◽  
Zinc Metalloprotease ◽  
Metalloprotease Inhibitors

scholarly journals A clinical dose of angiotensin-converting enzyme (ACE) inhibitor and heterozygous ACE deletion exacerbate Alzheimer's disease pathology in mice

2019 ◽  
Vol 294 (25) ◽  
pp. 9760-9770 ◽  
Author(s):  
Shuyu Liu ◽  
Fujiko Ando ◽  
Yu Fujita ◽  
Junjun Liu ◽  
Tomoji Maeda ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Ace Inhibitors ◽  
Ace Inhibitor ◽  
Precursor Protein ◽  
Causative Role ◽  
Converting Enzyme ◽  
Clinical Dose

Inhibition of angiotensin-converting enzyme (ACE) is a strategy used worldwide for managing hypertension. In addition to converting angiotensin I to angiotensin II, ACE also converts neurotoxic β-amyloid protein 42 (Aβ42) to Aβ40. Because of its neurotoxicity, Aβ42 is believed to play a causative role in the development of Alzheimer's disease (AD), whereas Aβ40 has neuroprotective effects against Aβ42 aggregation and also against metal-induced oxidative damage. Whether ACE inhibition enhances Aβ42 aggregation or impairs human cognitive ability are very important issues for preventing AD onset and for optimal hypertension management. In an 8-year longitudinal study, we found here that the mean intelligence quotient of male, but not female, hypertensive patients taking ACE inhibitors declined more rapidly than that of others taking no ACE inhibitors. Moreover, the sera of all AD patients exhibited a decrease in Aβ42-to-Aβ40–converting activity compared with sera from age-matched healthy individuals. Using human amyloid precursor protein transgenic mice, we found that a clinical dose of an ACE inhibitor was sufficient to increase brain amyloid deposition. We also generated human amyloid precursor protein/ACE+/− mice and found that a decrease in ACE levels promoted Aβ42 deposition and increased the number of apoptotic neurons. These results suggest that inhibition of ACE activity is a risk factor for impaired human cognition and for triggering AD onset.

Angiotensin converting enzyme and the amyloid precursor protein secretases

1999 ◽  
Vol 27 (1) ◽  
pp. A23-A23
Author(s):  
Nigel M. Hooper ◽  
S. Parvathy ◽  
Eric H. Karran ◽  
Anthony J. Turner
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Converting Enzyme

scholarly journals The role of ADAM10 and ADAM17 in the ectodomain shedding of angiotensin converting enzyme and the amyloid precursor protein

2004 ◽  
Vol 271 (12) ◽  
pp. 2539-2547 ◽  
Author(s):  
Tobias M. J. Allinson ◽  
Edward T. Parkin ◽  
Thomas P. Condon ◽  
Sylva L. U. Schwager ◽  
Edward D. Sturrock ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Ectodomain Shedding ◽  
Converting Enzyme

Angiotensin-converting enzyme and the amyloid precursor protein secretases

1999 ◽  
Vol 27 (2) ◽  
pp. 229-234 ◽  
Author(s):  
N. M. Hooper ◽  
S. Parvathy ◽  
E. H. Karran ◽  
A. J. Turner
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Converting Enzyme

scholarly journals Angiotensin-converting enzyme secretase is inhibited by zinc metalloprotease inhibitors and requires its substrate to be inserted in a lipid bilayer

1997 ◽  
Vol 327 (1) ◽  
pp. 37-43 ◽  
Author(s):  
S. PARVATHY ◽  
Sylvester Y. OPPONG ◽  
Eric H. KARRAN ◽  
Derek R. BUCKLE ◽  
Anthony J. TURNER ◽  
...  
Keyword(s):  
Membrane Protein ◽  
Angiotensin Converting Enzyme ◽  
Lipid Bilayer ◽  
Proteolytic Processing ◽  
Full Length ◽  
Converting Enzyme ◽  
Pig Kidney ◽  
Zinc Metalloprotease ◽  
Metalloprotease Inhibitors ◽  
Triton X

Mammalian angiotensin-converting enzyme (ACE; EC 3.4.15.1) is one of several proteins that exist in both membrane-bound and soluble forms as a result of a post-translational proteolytic processing event. For ACE we have previously identified a metalloprotease (secretase) responsible for this proteolytic cleavage. The effect of a range of structurally related zinc metalloprotease inhibitors on the activity of the secretase has been examined. Batimastat (BB94) was the most potent inhibitor of the secretase in pig kidney microvillar membranes, displaying an IC50 of 0.47 μM, whereas TAPI-2 was slightly less potent (IC50 18 μM). Removal of the thienothiomethyl substituent adjacent to the hydroxamic acid moiety or the substitution of the P2′ substituent decreased the inhibitory potency of batimastat towards the secretase. Several other non-hydroxamate-based collagenase inhibitors were without inhibitory effect on the secretase, indicating that ACE secretase is a novel zinc metalloprotease that is related to, but distinct from, the matrix metalloproteases. The full-length amphipathic form of ACE was labelled selectively with 3-trifluoromethyl-3-(m-[125I]iodophenyl)diazirine in the membrane-spanning hydrophobic region. Although trypsin was able to cleave the hydrophobic anchoring domain from the bulk of the protein, there was no cleavage of full-length ACE by a Triton X-100-solubilized pig kidney secretase preparation when the substrate was in detergent solution. In contrast, the Triton X-100-solubilized secretase preparation released ACE from pig intestinal microvillar membranes, which lack endogenous secretase activity, and cleaved the purified amphipathic form of ACE when it was incorporated into artificial lipid vesicles. Thus the secretase has an absolute requirement for its substrate to be inserted in a lipid bilayer, a factor that might have implications for the development of cell-free assays for other membrane protein secretases. ACE secretase could be solubilized from the membrane with Triton X-100 and CHAPS, but not with n-octylβ-D-glucopyranoside. Furthermore trypsin could release the secretase from the membrane, implying that like its substrate, ACE, it too is a stalked integral membrane protein.

Protein processing mechanisms: from angiotensin-converting enzyme to Alzheimer's disease

2000 ◽  
Vol 28 (4) ◽  
pp. 441-446
Author(s):  
N. M. Hooper ◽  
A. J. Turner
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Angiotensin Converting Enzyme ◽  
Amyloid Precursor Protein ◽  
Neuronal Cell ◽  
Precursor Protein ◽  
Soluble Form ◽  
Converting Enzyme ◽  
A Disintegrin And Metalloproteinase ◽  
Factor Α

Angiotensin-converting enzyme (ACE) and the Alzheimer's disease amyloid precursor protein are two examples of membrane-bound proteins that are released in a soluble form by a post-trans-lational proteolytic cleavage event involving a secretase. Site-specific antibodies and matrix-assisted laser desorption ionization-time-of-flight (‘MALDI-TOF’) MS have been used to map the secretase cleavage site in somatic ACE to Arg-1203/Ser-1204, 24 residues proximal to the membrane-anchoring domain. Trypsin, which can solubilize ACE from the membrane, cleaves the protein at the same site. The use of structurally related hydroxamic acid-based zinc metalloproteinase inhibitors indicate that tumour necrosis factor-α convertase, a member of the ADAMs (‘a disintegrin and metalloproteinase’) family of proteins, is not involved in the proteolytic release of ACE, or in the constitutive or regulated α-secretase release of the amyloid precursor protein from a human neuronal cell line.

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