Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism

Higaki, Jeffrey N.; Quon, Diana; Zhong, Ziyang; Cordell, Barbara

doi:10.1016/0896-6273(95)90322-4

Cited by 157 publications

(163 citation statements)

References 22 publications

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“…2; see also Ref. 25) is inconsistent with the level of available C99 being saturating for ␥-secretase processing and, instead, indicates that the availability of C99 is rate-limiting. A limiting role for C99 availability is further supported by the many reports that a double missense mutation in APP linked to familial Alzheimer's disease (the so-called Swedish mutation, see Ref.…”

Section: Discussionmentioning

confidence: 85%

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Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

Durkin¹,

Murthy²,

Husten³

et al. 1999

Journal of Biological Chemistry

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The Alzheimer's disease amyloid peptide A␤ has a heterogeneous COOH terminus, as variants 40 and 42 residues long are found in neuritic plaques and are secreted constitutively by cultured cells. The proteolytic activity that liberates the A␤ COOH terminus from the ␤-amyloid precursor protein is called ␥-secretase. It could be one protease with dual specificity or two distinct enzymes. By using enzyme-linked immunosorbent assays selective for A␤40 or A␤42, we have measured A␤ secretion by a HeLa cell line, and we have examined the dose responses for a panel of five structurally diverse ␥-secretase inhibitors. The inhibitors lowered A␤ and p3 secretion and increased levels of the COOH-terminal 99-residue ␤-amyloid precursor protein derivative that is the precursor for A␤ but did not alter secretion of ␤-amyloid precursor protein derivatives generated by other secretases, indicating that the inhibitors blocked the ␥-secretase processing step. The dose-dependent inhibition of A␤42 was unusual, as the compounds elevated A␤42 secretion at sub-inhibitory doses and then inhibited secretion at higher doses. A compound was identified that elevated A␤42 secretion at a low concentration without inhibiting A␤42 or A␤40 at high concentrations, demonstrating that these phenomena are separable pharmacologically. Using either of two methods, IC 50 values for inhibition of A␤42 and A␤40 were found to have the same rank-order and fall on a trend line with near-unit slope. These results favor the hypothesis that A␤ variants ending at residue 40 or 42 are generated by a single ␥-secretase.A hallmark feature of the neuropathology of Alzheimer's disease is the abundant deposition of amyloid into neuritic and diffuse plaques in the brain parenchyma. The predominant core constituent of amyloid plaques is a 40-to 42-residue amyloid peptide, A␤.1 A␤ is generated from the ␤-amyloid precursor protein (APP) by two sequential proteolytic cleavages. First, ␤-secretase activity liberates the NH 2 terminus of A␤, generating a 99-residue COOH-terminal APP fragment (C99). Second, ␥-secretase activity cleaves C99 to liberate the A␤ COOH terminus. APP is also processed in a nonamyloidogenic manner, being cleaved within the A␤ domain by an activity termed ␣-secretase. The terms ␣-, ␤-, and ␥-secretase are conceptual terms for proteases that are not yet definitively identified (reviewed in Refs. 1-3).The A␤ peptide is a constitutive secretory product of a variety of neuronal and non-neuronal cells, in which multiple NH 2 -and COOH-terminal cleavages generate several A␤ species. The most prevalent secreted forms of A␤ appear identical to neuritic plaque core amyloid A␤ and terminate either at residue 40 or 42 (4, 5). Although A␤40 variants are the predominant component of soluble A␤ extracted from brain and secreted by cultured cells, A␤42 forms are the predominant constituents of neuritic plaques (6 -9). In vitro, forms of A␤ that terminate at residue 42 form fibril faster than forms of A␤ that terminate at residue 40, by orders of magnitude (10). Mut...

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Section: Discussionmentioning

confidence: 85%

“…A␤40 and A␤42 are generated physiologically by ␥-secretase cleavage of C99, the 99 COOH-terminal residues of APP (5,25,28,29). We measured dose responses for inhibition of A␤40 and A␤42 secretion by the HeLa-pNAN8 cell line.…”

Section: Resultsmentioning

confidence: 99%

Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

Durkin¹,

Murthy²,

Husten³

et al. 1999

Journal of Biological Chemistry

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“…The degree of degeneration of neurons was related to the amounts of 14-and l5-kDa CT fragments of /IAPP. Higaki et al (1995) demonstrated that in Chinese hamster ovary cells overexpressing /IAPP 695, the A/I-bearing CT fragment accumulates with treatment with MDL 28170 (a calpain protease inhibitor) and that the degeneration of the accumulated fragment is inhibited by monensin, suggesting that an early endosomal compartment is involved in the processing of the CT fragment. Rab 1 B (the Ras-related GTP-binding protein) plays a key role in endoplasmic reticulum to Golgi transport of /IAPP in cultured 293 cells and that /IAPP must pass through a late Golgi compartment before entering either the asecretase or the amyloidogenic /I-secretase pathway (Dugan et al, 1995).…”

Section: Channel (Pore)-forming Activities and Neurotoxicity Of Ct Frmentioning

confidence: 99%

An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

Suh

1997

Journal of Neurochemistry

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Amyloid~3protein (A/3), 39-43 amino acids long, is the principal constituent of the extracellular amybid deposits in brain that are characteristic of Alzheimer's disease (AD). Several lines of evidence indicate that A~3 may play an important role in the pathogenesis of AD. However, there are several discrepancies between the production of A/3 and the development of the disease. Thus, A/may not be the sole active fragment of~3-amybid precursor protein (~3APP) in the neurotoxicity associated with AD. Consequently, the possible effects of other cleaved products of /3APP need to be explored. The recent concentration on other potentially amyloidogenic products of /IAPP has produced interesting candidates, the most promising of which are the amyloidogenic carboxyl-terminal (CT) fragments of~3APP. This review discusses a possible etiological role of CT fragments of /3APP in AD. Key Words: Amyloid precursor proteinCarboxyl-terminal peptide-Amyloid /3 protein -Etiological role-Alzheimer's disease. J. Neurochem. 68, 1781Neurochem. 68, -1791Neurochem. 68, (1997.Alzheimer' s disease (AD) is characterized by amybid deposits in senile plaques, in neurofibrillary tangles, and on the walls of cerebral blood vessels and dystrophic neurites, gliosis, and loss of neuronal synapses. various evidence indicates that amyloid~3pro-tein (A/3), which is a principal constituent of senile plaques (Glenner and Wong, 1984), may play an important role in the pathogenesis of AD (for review, see Selkoe, 1994;Checler, 1995). The A/I is composed of 39-43 amino acids and proteolytically derived from larger /3-amyloid precursor protein (/3APP) isoforms of 695, 714, 751, and 770 amino acids (Kang et al., 1987). Several mutations of /IAPP around the A/I domain have been discovered in certain types of earlyonset familial AD (FAD) (for review, see Tanzi et al., 1993), supporting its causal role in the pathogenesis of AD.To date, at least three processing pathways have been described: the nonamyloidogenic secretory pathway (a-secretase), which releases soluble ectodomain and prevents A/I formation (Esch et al., 1990); the endosomal-lysosomal pathway, in which some cell surface /IAPPs are reinternalized (Haass et al., 1 992a,b) and cleaved around at the N-terminus of the A/I sequence by /3-secretase to produce A/3-bearing amyloidogenic breakdown products of various sizes (14-22 kDa) Golde et al., 1992; Haass et al., 1992a,b;Shoji et al., 1992;Tamaoka et al., 1992) and subsequently possibly cleaved by 'ysecretase to release soluble 4-kDa A/I (Koo and Squazzo, 1994); and the 4-kDa A/I-producing pathway (/3-and y-secretases), involving coated pit-mediated endocytosis, which may be independent of the constitutive secretory pathway (Koo and Squazzo, 1994).Classically, A/I is the marker for AD, and it has been linked to the accompanying neurodegeneration (see, e.g., Sisodia et al., 1990). Several lines of evidence suggest that the overexpression of /3APP and the subsequent production of A/I could be linked to the genesis of AD (for review, see ...

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“…There is little information published about other potential specific inhibitors of ␤-secretase. Several studies have shown that peptide aldehyde protease inhibitors affect the secretion of A␤ peptides (12)(13)(14). Of these peptide aldehydes, MG132 was one of the most potent inhibitors of A␤ peptide secretion (15).…”

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confidence: 99%

The Protease Inhibitor, MG132, Blocks Maturation of the Amyloid Precursor Protein Swedish Mutant Preventing Cleavage by β-Secretase

Steinhilb¹,

Turner²,

Gaut³

2001

Journal of Biological Chemistry

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Amyloid (A␤) peptides found aggregated into plaques in Alzheimer's disease are derived from the sequential cleavage of the amyloid precursor protein (APP) first by ␤-and then by ␥-secretases. Peptide aldehydes, which inhibit cysteine proteases and proteasomes, reportedly block A␤ peptide secretion by interfering with ␥-secretase cleavage. Using a novel, specific, and sensitive enzyme-linked immunosorbent assay for the ␤-secretasecleaved fragment of the Swedish mutant of APP (APPSw), we determined that the peptide aldehyde, MG132, prevented ␤-secretase cleavage. This block in ␤-secretase cleavage was not observed with clasto-lactacystin ␤-lactone and thus, cannot be attributed to proteasomal inhibition. MG132 inhibition of ␤-secretase cleavage was compared with the serine protease inhibitor, 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF). AEBSF inhibition of ␤-secretase cleavage was immediate and did not affect ␣-secretase cleavage. With MG132, inhibition was delayed and it decreased secretion of ␣-cleaved APPSw as well. Furthermore, MG132 treatment impaired maturation of full-length APPSw. Both inhibited intracellular formation of the ␤-cleaved product. These results suggest that peptide aldehydes such as MG132 have multiple effects on the maturation and processing of APP. We conclude that the MG132-induced decrease in ␤-secretase cleavage of APPSw is due to a block in maturation. This is sufficient to explain the previously reported peptide aldehyde-induced decrease in A␤ peptide secretion.

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Inhibition of β-amyloid formation identifies proteolytic precursors and subcellular site of catabolism

Cited by 157 publications

References 22 publications

Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

Rank-Order of Potencies for Inhibition of the Secretion of Aβ40 and Aβ42 Suggests That Both Are Generated by a Single γ-Secretase

An Etiological Role of Amyloidogenic Carboxyl‐Terminal Fragments of the β‐Amyloid Precursor Protein in Alzheimer's Disease

The Protease Inhibitor, MG132, Blocks Maturation of the Amyloid Precursor Protein Swedish Mutant Preventing Cleavage by β-Secretase

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