Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice

Tucker, H. Michael; Simpson, J. A.; Kihiko-Ehmann, Muthoni; Younkin, Linda H.; McGillis, Joseph P.; Younkin, Steven G.; Degen, Jay L.; Estus, Steven

doi:10.1016/j.neulet.2004.07.011

Cited by 36 publications

(26 citation statements)

References 26 publications

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“…Plasmin, the active zymogen generated by tPA from plasminogen, cleaves both monomeric and aggregated forms of A␤ 40 and A␤ 42 at multiple sites (10,13), and the cleavage of A␤ by plasmin is protective against A␤ mediated cell death (12). Importantly, injection of A␤ into the brains of mice lacking either tPA or plasminogen confirmed that both these components are required for the effective clearance of A␤ from brain (22), although it should be noted that another study showed no effect of plasminogen deficiency on endogenous nonaggregated murine A␤ levels (27). Finally, aggregated forms of A␤ induce the expression of tPA in vitro and in vivo (13,15,16) and serve as cofactor for tPA-mediated plasminogen activation (10).…”

Section: Discussionmentioning

confidence: 96%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

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

130

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The amyloid hypothesis states that a variety of neurotoxic ␤-amyloid (A␤) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between A␤ production and clearance. Enzymes responsible for the degradation of A␤ are not well understood, and, thus far, it has not been possible to enhance A␤ catabolism by pharmacological manipulation. We provide evidence that A␤ catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain A␤ levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades A␤ oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain A␤. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain A␤ levels, restore long-term potentiation deficits in hippocampal slices from transgenic A␤-producing mice, and reverse cognitive deficits in these mice.Alzheimer ͉ plasminogen activator inhibitor ͉ tissue plasminogen activator A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the presence of intracellular neuronal tangles and extracellular parenchymal and vascular amyloid deposits containing ␤-amyloid peptide (A␤). A␤ is a 39-to 42-aa peptide derived from the proteolytic processing of the amyloid precursor protein (APP) (1). The ''amyloid hypothesis'' of AD postulates a central causal role for A␤ in AD pathogenesis and is supported by genetic and physiological evidence. All known early onset familial AD mutations result in enhanced levels of cytotoxic A␤ species, amyloid plaque deposition, and dementia. Furthermore, A␤ peptide is reported to be neurotoxic and synaptotoxic in vitro and in vivo, inhibiting long-term potentiation (LTP), a physiological correlate of memory (2). Based on these observations, a number of strategies to reduce brain A␤ levels are being pursued as therapeutic approaches to treat AD (3, 4).If the amyloid hypothesis of AD is correct and A␤ levels are pivotal to disease etiology, then the balance between A␤ production and catabolism is likely to be a key determinant of disease progression. It has been suggested that insufficient clearance of A␤ may account for elevated A␤ levels in the brain and the accumulation of pathogenic amyloid deposits in sporadic AD (5). A number of proteases have been implicated in the proteolytic clearance of A␤ from the CNS, including neprilysin, insulin-degrading enzyme, endothelin converting enzyme, and plasmin (3, 6-8). The relative contribution of these enzymes to A␤ catabolism remains unclear, but each protease may play a significant role in the degradation and clearance of A␤, resulting in a slowing of A␤ accumulation and aggregation and u...

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Section: Discussionmentioning

confidence: 96%

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Js¹,

Ta²,

Martone³

et al. 2008

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

130

View full text Add to dashboard Cite

show abstract

“…First, this approach will not necessarily identify all relevant proteases, particularly those that are operative only in a pathological context. Significant increases in brain A␤ levels have not been observed in mice lacking plasminogen, tPA, uPA, or CatB (23,41), yet evidence from other paradigms supports the involvement of each (7,23,42). Second, measurements of brain-wide A␤ levels fail to account for differential effects on distinct pools of A␤, some of which might be more pathogenic than others (4).…”

Section: Categories Of Investigationmentioning

confidence: 99%

The AβCs of Aβ-cleaving Proteases

Leissring

2008

Journal of Biological Chemistry

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The amyloid ␤-protein (A␤), which accumulates abnormally in Alzheimer disease (AD), is degraded by a diverse set of proteolytic enzymes. A␤-cleaving proteases, largely ignored until only recently, are now known to play a pivotal role in the regulation of cerebral A␤ levels and amyloid plaque formation in animal models, and accumulating evidence suggests that defective A␤ proteolysis may be operative in many AD cases. This review summarizes the growing body of evidence supporting the involvement of specific A␤-cleaving proteases in the etiology and potential treatment of AD. Recognition of the importance of A␤ degradation to the overall economy of A␤ has revised our thinking about the mechanistic basis of AD pathogenesis and identified a novel class of enzymes that may serve as both therapeutic targets and therapeutic agents.

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“…As with NEP, support for the physiological importance of IDE in regulating Aβ levels comes from the findings that genetic deletion of IDE in mice Miller et al, 2003) leads to elevated levels of cerebral Aβ, whereas transgenic over-expression of IDE causes a decrease in brain Aβ levels (Leissring et al, 2003). Unlike NEP and IDE, plasmin (EC 3.4.21.7) does not appear to contribute significantly to the normal catabolism of Aβ (Tucker et al, 2004), but rather seems to play a role in the diseased brain. Plasmin is a serine protease that is produced from its inactive precursor, plasminogen, by the action of tissue-type plasminogen activator (tPA), and mice lacking either tPA or plasminogen clear injected Aβ much less well than wild type mice (Melchor et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Aggregation and catabolism of disease-associated intra-Aβ mutations: reduced proteolysis of AβA21G by neprilysin

Betts

Leissring

Dolios

et al. 2008

Neurobiology of Disease

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Five point mutations within the amyloid β-protein (Aβ) sequence of the APP gene are associated with hereditary diseases which are similar or identical to Alzheimer's disease and encode: the A21G (Flemish), E22G (Arctic), E22K (Italian), E22Q (Dutch) and the D23N (Iowa) amino acid substitutions. Although a substantial body of data exists on the effects of these mutations on Aβ production, whether or not intra-Aβ mutations alter degradation and how this relates to their aggregation state remain unclear. Here we report that the E22G, E22Q and the D23N substitutions significantly increase fibril nucleation and extension, whereas the E22K substitution exhibits only an increased rate of extension and the A21G substitution actually causes a decrease in the extension rate. These substantial differences in aggregation together with our observation that aggregated wild type Aβ(1-40) was much less well degraded than monomeric wild type Aβ(1-40), prompted us to assess whether or not disease-associated intra-Aβ mutations alter proteolysis independent of their effects on aggregation. Neprilysin (NEP), insulin degrading enzyme (IDE) and plasmin play a major role in Aβ catabolism, therefore we compared the ability of these enzymes to degrade wild type and mutant monomeric Aβ peptides. Experiments investigating proteolysis revealed that all monomeric peptides are degraded similarly by IDE and plasmin, but that the Flemish peptide was degraded significantly more slowly by NEP than wild type Aβ or any of the other mutant peptides. This finding suggests that resistance to NEP-mediated proteolysis may underlie the pathogenicity associated with the A21G mutation.

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Plasmin deficiency does not alter endogenous murine amyloid beta levels in mice

Cited by 36 publications

References 26 publications

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

Enhanced clearance of Aβ in brain by sustaining the plasmin proteolysis cascade

The AβCs of Aβ-cleaving Proteases

Aggregation and catabolism of disease-associated intra-Aβ mutations: reduced proteolysis of AβA21G by neprilysin

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