Alzheimer Aβ neurotoxicity: Promotion by antichymotrypsin, ApoE4; inhibition by Aβ-related peptides

Ma, Joongsoo; Brewer, H. Bryan; Potter, Huntington

doi:10.1016/0197-4580(96)00112-1

Cited by 107 publications

(82 citation statements)

References 66 publications

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“…1E, lane b, shows the higher molecular weight inhibitory complex formed on incubation of ACT with chymotrypsin (band 1), whereas lane d shows that, when ACT is preincubated overnight with a 50-fold molar excess of A␤ prior to incubation with chymotrypsin, no ACT⅐chymotrypsin complex is formed and only intact (band 2) and cleaved ACT (band 3), along with the cleaved low molecular weight carboxyl-terminal peptide band, are observed. This is consistent with our observations (see below) and earlier ones of other investigators (27) that incubation of ACT with A␤ 1-42 results in loss of ACT inhibitor activity. It also confirms our earlier conclusion that the stabilization of intact ACT to denaturation after incubation with A␤ 1-42 is because of insertion of A␤ 1-42 into sA as a substitute for s4A, the reactive site loop strand.…”

Section: Resultssupporting

confidence: 83%

“…The blocking of ACT⅐A␤ 1-42 complex formation by A␤ 2-9 confirms the requirement for complex formation of binding of the amino terminus of A␤ . This experiment parallels the diminished neurotoxicity and A␤ 1-42 fibril formation of ACT⅐A␤ 1-42 observed in the presence of A␤ 2-9 (27), suggesting that the complex we have characterized here is relevant to the neurotoxic and fibrillogenic properties observed by others toward cells in cultures. Shorter incubation time (24 h) of A␤ with ACT is insufficient to produce SDS stable complexes (Fig.…”

Section: Resultssupporting

confidence: 52%

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Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Janciauskiene¹,

Rubin²,

Lukacs³

et al. 1998

Journal of Biological Chemistry

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The serpin ␣ 1 -antichymotrypsin is a major component of brain amyloid plaques in Alzheimer's disease. In vitro ␣ 1 -antichymotrypsin interacts with the Alzheimer's amyloid peptide A␤ 1-42 and stimulates both formation and disruption of neurotoxic A␤ 1-42 fibrils in a concentration-dependent manner. We have constructed a new hybrid model of the complex between A␤ 1-42 and ␣ 1 -antichymotrypsin in which both amino and carboxyl sequences of A␤ 1-42 insert into two different ␤-sheets of ␣ 1 -antichymotrypsin. We have tested this model and shown experimentally that full-length and amino-terminal segments of A␤ 1-42 bind to ␣ 1 -antichymotrypsin as predicted. We also show that A␤ 1-42 forms both intraand intermolecular SDS-stable complexes with ␣ 1 -antichymotrypsin and that the binding of A␤ 1-42 to ␣ 1 -antichymotrypsin abolishes the inhibitory activity of the latter and its ability to form stable complex with chymotrypsin. The existence of both inter-as well as intramolecular complexes of A␤ 1-42 explains the nonlinear concentration-dependent effects of ␣ 1 -antichymotrypsin on A␤ 1-42 fibril formation, which we have reinvestigated here over a broad range of A␤ 1-42 :␣ 1 -antichymotrypsin ratios. These data suggest a molecular basis for the distinction between amorphous and fibrillar A␤ 1-42 in vivo. The reciprocal effects of A␤ 1-42 and ␣ 1 -antichymotrypsin could play a role in the etiology of Alzheimer's disease.1 is a serpin serine proteinase inhibitor with specificity for cathepsin and chymotrypsin-like enzymes (1). Its physical properties (2), mechanism (3), and structure (4, 5) conform to the general model (6, 7) that has been established for serpins. These inhibitors present a flexible reactive site loop, which is cleaved at a susceptible residue by target proteinase (8, 9) to form a highly stable, covalent complex (10, 11). As in other serpins (12), the reactive site loop in the cleaved form of ACT is inserted into a preexisting, flexible ␤-sheet (sA) (4), and this cleaved form is stabilized to denaturation relative to the uncleaved native form (2). There is evidence (13, 14) consistent with proposals (10, 11) that insertion of the reactive site loop into sA is a prerequisite for stable proteinase-serpin complex formation. In further support of this, it has been shown that exogenous peptides of restricted sequence can insert into sA of the uncleaved serpin (15-17). These binary peptide⅐serpin complexes are similarly increased in stability to denaturation but have lost inhibitory activity, becoming substrates instead that do not form a stable complex with target proteinase.A possible link between ACT and Alzheimer's disease was established by the observation that ACT occurs in the senile plaques characteristic of this disease (18). Subsequently, it was shown in vitro that ACT can either stimulate formation of the neurotoxic fibrillar form of Alzheimer's peptide A␤ 1-42 (19, 20) or destabilize preformed A␤ 1-40 fibrils (21, 22), depending on the stoichiometry of ACT to A␤. Two models for the binding of A␤...

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Section: Resultssupporting

confidence: 83%

Section: Resultssupporting

confidence: 52%

Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Janciauskiene¹,

Rubin²,

Lukacs³

et al. 1998

Journal of Biological Chemistry

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“…The residues 12-28 of A␤ were identified as the binding site of apoE (37). It has been shown that using this small fragment of A␤ (A␤12-28) was able to competitively block the binding of full-length A␤ to apoE (30), suppressing fibril formation and enhancing the survival of cultured neurons (40). However, we found that A␤12-28 was not able to inhibit apoE-induced A␤ degradation by microglia (Fig.…”

Section: Facilitation Of A␤ Degradation Is a Common Feature Of Hdlcontrasting

confidence: 51%

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Lee

Tse

Smith

et al. 2012

Journal of Biological Chemistry

143

125

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Background: Intracellular A␤ degradation is enhanced in the presence of apoE. Results: Lowering cellular cholesterol levels facilitates intracellular trafficking of A␤ to lysosomes and enhances its degradation. Conversely, increasing cholesterol levels retards the delivery and inhibits degradation of A␤. Conclusion:The cholesterol efflux function of apoE mediates its ability to promote A␤ degradation. Significance: We demonstrate a direct role for cholesterol in AD.

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“…The neurotoxicity of A␤ has been reported to be increased by the presence of 1-antichymotrypsin or apoE4 [31] and decreased in the presence of various anti-inflammatory drugs [32,33].…”

Section: Microgliamentioning

confidence: 99%

Inflammation of the brain in Alzheimer's disease: implications for therapy

McGeer

1999

Journal of Leukocyte Biology

202

117

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We briefly describe the similarities and differences between a systemic and a local immune reaction and review the evidence that the latter occurs in Alzheimer's disease (AD) brains. The evidence comes mainly from studies on the complement system, microglia, and cytokines, all of which are important actors in the inflammatory process. The evidence is now overwhelming that the complement proteins and many of the mediators of inflammation are produced locally by brain cells. We will mention briefly the many epidemiological studies indicating that the use of anti-inflammatory drugs reduces the incidence and slows the progress of AD. Mention will also be made of some recent work on animal models of possible relevance to AD and inflammation. J. Leukoc. Biol. 65: 409-415; 1999.

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Alzheimer Aβ neurotoxicity: Promotion by antichymotrypsin, ApoE4; inhibition by Aβ-related peptides

Cited by 107 publications

References 66 publications

Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Alzheimer's Peptide Aβ1–42 Binds to Two β-Sheets of α1-Antichymotrypsin and Transforms It from Inhibitor to Substrate

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Inflammation of the brain in Alzheimer's disease: implications for therapy

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