The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species

Bien, Jessica; Jefferson, Tamara; Čaušević, Mirsada; Jumpertz, Thorsten; Munter, Lisa Marie; Multhaup, Gerd; Weggen, Sascha; Becker‐Pauly, Christoph; Pietrzik, Claus U.

doi:10.1074/jbc.m112.395608

Cited by 119 publications

(104 citation statements)

References 38 publications

(20 reference statements)

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“…This is interesting, because BACE has an acidic pH optimum (35,36) but APP is nevertheless metabolized to Aβ in the presence of bafilomycin A1. This phenomenon, which has been observed by others (37)(38)(39), could result from BACE-like cleavage of APP by cellular proteases that do not require an acidic milieu for activity. Candidate proteases include caspases that may become activated by cathepsins leaked from lysosomes after bafilomycin A1 treatment (40).…”

Section: Discussionmentioning

confidence: 96%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

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

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Neurotoxic amyloid-β peptides (Aβ) are major drivers of Alzheimer's disease (AD) and are formed by sequential cleavage of the amyloid precursor protein (APP) by β-secretase (BACE) and γ-secretase. Our previous study showed that the anticancer drug Gleevec lowers Aβ levels through indirect inhibition of γ-secretase activity. Here we report that Gleevec also achieves its Aβ-lowering effects through an additional cellular mechanism. It renders APP less susceptible to proteolysis by BACE without inhibiting BACE enzymatic activity or the processing of other BACE substrates. This effect closely mimics the phenotype of APP A673T, a recently discovered mutation that protects carriers against AD and age-related cognitive decline. In addition, Gleevec induces formation of a specific set of APP C-terminal fragments, also observed in cells expressing the APP protective mutation and in cells exposed to a conventional BACE inhibitor. These Gleevec phenotypes require an intracellular acidic pH and are independent of tyrosine kinase inhibition, given that a related compound lacking tyrosine kinase inhibitory activity, DV2-103, exerts similar effects on APP metabolism. In addition, DV2-103 accumulates at high concentrations in the rodent brain, where it rapidly lowers Aβ levels. This study suggests that long-term treatment with drugs that indirectly modulate BACE processing of APP but spare other BACE substrates and achieve therapeutic concentrations in the brain might be effective in preventing or delaying the onset of AD and could be safer than nonselective BACE inhibitor drugs.Alzheimer's disease | Gleevec | nonamyloidogenic | β-cleavage

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Section: Discussionmentioning

confidence: 96%

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Netzer

Bettayeb

Sinha

et al. 2017

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

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“…Indeed, these positions are conserved among physiological substrates (36). An example is APP, which is cleaved by Mβ at the β-secretase site (M 671 -D 672 ; APP residue numbers as subindices according to UniProt P05067) in vivo and in vitro to generate amyloidogenic Aβ42 and Aβ41 peptides (14,15). This process entails that upon Michaelis-complex formation, APP segment D 672 AEFRHDSGYE 682 occupies substrate positions P 1 ′-P 11 ′.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, human meprin β (Mβ) was found to specifically process APP in vivo, which may contribute to Alzheimer's disease (14,15). It was also reported to activate cell-anchored α-secretase ADAM-10 and to be widely expressed in brain, intestine, kidney, and skin (14,(16)(17)(18).…”

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confidence: 99%

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

Arolas

Broder²,

Jefferson³

et al. 2012

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

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Ectodomain shedding at the cell surface is a major mechanism to regulate the extracellular and circulatory concentration or the activities of signaling proteins at the plasma membrane. Human meprin β is a 145-kDa disulfide-linked homodimeric multidomain type-I membrane metallopeptidase that sheds membrane-bound cytokines and growth factors, thereby contributing to inflammatory diseases, angiogenesis, and tumor progression. In addition, it cleaves amyloid precursor protein (APP) at the β-secretase site, giving rise to amyloidogenic peptides. We have solved the X-ray crystal structure of a major fragment of the meprin β ectoprotein, the first of a multidomain oligomeric transmembrane sheddase, and of its zymogen. The meprin β dimer displays a compact shape, whose catalytic domain undergoes major rearrangement upon activation, and reveals an exosite and a sugar-rich channel, both of which possibly engage in substrate binding. A plausible structure-derived working mechanism suggests that substrates such as APP are shed close to the plasma membrane surface following an "N-like" chain trace. P hysiological processes in the extracellular milieu and the circulation require finely tuned concentrations of signal molecules such as cytokines, growth factors, receptors, adhesion molecules, and peptidases. Many of these proteins are synthesized as type-I membrane protein variants or precursors consisting of a glycosylated N-terminal ectoprotein, a transmembrane helix, and a Cterminal cytosolic tail. Their localization at the cell surface restricts their field of action to autocrine or juxtacrine processes. However, to act at a distance in paracrine, synaptic, or endocrine events, they have to be released from the plasma membrane into the extracellular space as soluble factors through "protein ectodomain shedding" (1, 2). This entails limited proteolysis and is a major posttranslational regulation mechanism that affects 2-4% of the proteins on the cell surface, occurs at or near the plasma membrane (3), and apparently follows a common release mechanism (2). It may also proteolytically inactivate proteins to terminate their function on the cell surface (4). Peptidases engaged in such processing are "sheddases" and the most studied transmembrane sheddases are members of the adamalysin/ADAMs (4, 5) and matrix-metalloproteinase (MMP) (6) families within the metzincin clan of metallopeptidases (MPs) (7-9). These include ADAM

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“…1D) (26). Furthermore, cells expressing meprin ␤ produced significant amounts of A␤2-X even in the presence of a BACE1 inhibitor, whereas meprin ␤ inhibition significantly reduced its production (26). Further work has suggested that unlike BACE1, meprin ␤ cleaves APP at the cell surface and may directly compete with ADAM10 in vivo, as indicated by increased sAPP␣ in the soluble fractions derived from meprin ␤ knock-out mice brains (27).…”

Section: -Secretasementioning

confidence: 99%

“…In addition, a concomitant reduction in markers of gliosis, increases in neuronal (Fig. 1D) (26). Furthermore, cells expressing meprin ␤ produced significant amounts of A␤2-X even in the presence of a BACE1 inhibitor, whereas meprin ␤ inhibition significantly reduced its production (26).…”

Section: -Secretasementioning

confidence: 99%

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

Andrew

Kellett

Wang

et al. 2016

Journal of Biological Chemistry

150

122

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Proteolysis of the amyloid precursor protein (APP) liberates various fragments including the proposed initiator of Alzheimer disease-associated dysfunctions, amyloid-␤. However, recent evidence suggests that the accepted view of APP proteolysis by the canonical ␣-, ␤-, and ␥-secretases is simplistic, with the discovery of a number of novel APP secretases (including ␦-and -secretases, alternative ␤-secretases) and additional metabolites, some of which may also cause synaptic dysfunction. Furthermore, various proteins have been identified that interact with APP and modulate its cleavage by the secretases. Here, we give an overview of the increasingly complex picture of APP proteolysis.Currently over 46 million people worldwide are living with dementia (see the Alzheimer's Disease International website) with Alzheimer disease (AD) 3 representing the most common form of dementia. In AD, the amyloid cascade hypothesis posits that amyloid-␤ (A␤), produced through the sequential proteolytic cleavage of the amyloid precursor protein (APP) by the ␤-and ␥-secretases, is a key molecule in initiating and propagating disease pathology including neurofibrillary tangle formation, neuronal cell loss, aberrant synaptic activity, and brain atrophy that lead to the clinically recognized symptoms of dementia (1). However, identification of the A␤ peptide 25 years ago has not yet led to the advent of a viable therapeutic strategy that can slow or halt the progression of AD. Recent studies have revealed new complexities in the proteolytic processing of APP, including the identification of novel secretases which generate APP metabolites that accumulate in the brains of AD patients and may contribute to the synaptic dysfunction observed in the disease. In addition, numerous proteins are being identified that interact with APP, modulating its proteolysis and A␤ production. These new APP secretases and metabolites, along with the APP interactors, may present novel therapeutic targets that are independent of direct modulation of the canonical secretases and that will need to be considered when evaluating the results from current A␤-directed therapies. In this Minireview, we summarize the recent developments in APP proteolysis focusing on the novel secretases, APP interactors, and APP metabolites that are impacting on our understanding of both APP biology and the neurodegenerative disease process. The Canonical ␣-, ␤-, and ␥-Secretases and APP FragmentsThe generally accepted model of APP proteolysis is that APP is processed by one of two distinct proteolytic pathways (Fig. 1A). In the amyloidogenic pathway, ␤-secretase, the ␤-site APP-cleaving enzyme 1 (BACE1), cleaves APP within the ectodomain and liberates a soluble proteolytic fragment, termed soluble APP␤ (sAPP␤), primarily in the endosomal system from the transmembrane APP holoprotein (2). The remaining C-terminal membrane-bound APP fragment, CTF␤, is subsequently cleaved by the presenilin (PS)-containing ␥-secretase multisubunit complex to liberate the A␤ peptide and the APP intrace...

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The Metalloprotease Meprin β Generates Amino Terminal-truncated Amyloid β Peptide Species

Cited by 119 publications

References 38 publications

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Gleevec shifts APP processing from a β-cleavage to a nonamyloidogenic cleavage

Structural basis for the sheddase function of human meprin β metalloproteinase at the plasma membrane

A Greek Tragedy: The Growing Complexity of Alzheimer Amyloid Precursor Protein Proteolysis

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