. New frontiers in Alzheimer's disease genetics. Neuron. 2001 Oct 25;32(2):181-4. PubMed.

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  1. This news report does not mention that the serine protease at the centre of the urokinase-plasminogen activator system, namely plasmin, is selective for Aβ 42 and in cleaving Aβ 42 prevents its aggregation into β-pleated sheet structures (see Exley and Korchazhkina, 2001). It would seem that the "fog" has already begun to clear. It just went, apparently, unnoticed!

    View all comments by Chris Exley
  2. Aβ-degrading enzymes—many candidates, but few fit the bill

    This comment extends the news report filed directly from the meeting to provide a more detailed description of this emerging area. To date, a number of potential Aβ-degrading enzymes have been identified, including E24.11 (also known as neprilysin or NEP), insulin degrading enzyme (IDE), plasmin, matrix metalloproteinase 9, endothelial converting enzyme (ECE) and an elastase (or an elastase-like enzyme). More than 20 abstracts from 16 different groups presented data on of each of these activities (see 27.22, 56.12, 91.7, 94.2, 97.6, 98.15, 128.9, 192.11, 192.13, 322.19, 329.16, 350.4, 355.9, 428.3, 433.4, 583.11, 612.11 and 678.7).

    To date, neprilysin is the most extensively studied Aβ-degrading enzyme. It was first shown to possess this activity by Iwata et al., 2000, and its importance grew with the demonstration that degradation of both exogenous and endogenous Aβ is impaired in the brain of knockout mice in a gene dose-dependent manner (Iwata et al. 2001). At this meeting, Mark Kindy presented data extending these findings. He found that the amyloid burden (both Aβ40 and 42) in APP-transgenic mice increased after 4 months of infusion with either phosphoramidon (which inhibits neprilysin and ECE) or thiorphan (which does not inhibit ECE). Neprilysin knockout mice showed increased Aβ deposition, and neprilysin deficient neurons were more susceptible to Aβ toxicity in vitro.

    The potential importance of IDE in Aβ clearance was underscored by three poster presentations (127.3-.5), which reported genetic linkage to late-onset AD and a region on chromosome 10 that encompasses the IDE gene. Farris et al. (192.13) reported that IDE activity was decreased in lymphoblasts from an FAD kindred linked to chromosome 10. These authors also showed that unlike neprilysin, IDE appears to act on Aβ both intracellularly and at the cell surface, degrading exogenous Aβ added to the media of IDE-expressing cells while also degrading endogenous Aβ both before and after secretion.

    Two mammalian isoforms of ECE are known, ECE-1 on chromosome 1, and ECE-2 on chromosome 2. ECE-2 has an acidic pH optimum and is highly expressed in neural tissue, where it acts intracellularly. ECE-2 null mice are viable, indicating that ECE-2 is not necessary for the proteolysis of essential substrates. Nonetheless, they show increased levels of Aβ40 and 42, suggesting that ECE-2 is responsible for the turnover of at least a portion of cell-derived Aβ. ECE-1 knockout mice are embryonic lethal, indicating that ECE-1 is involved in the processing of essential substrates. Conversely, overexpressing ECE-1 in AβPP-expressing CHO cells increases clearance of Aβ.

    Carmela Abraham presented data based on inhibitor studies and N-terminal sequencing of Aβ-degrading activity, indicating that elastase 1 or an elastase-like enzyme was the principle Aβ-degrading enzyme in media conditioned by SKN-SH cells.

    There is no doubt that all of the above enzymes can degrade Aβ, but which one is the most important physiologically? The scientifically honest answer is: we don't know yet. Simple in vitro assays of Aβ degradation are of limited use; we need to assess the effects of knockout and overexpression of candidate proteases, as has been done for neprilysin. Also required is a detailed assessment of the primary structure and assembly forms of Aβ on which each protease acts. We already know that IDE degrades monomeric but not oligomeric or fibrillar Aβ, suggesting that IDE might represent the principle activity for degrading Aβ monomers whereas neprilysin might represent the major activity for removing its oligomeric forms. Other proteases may also contribute to Aβ clearance in a site- and age-specific manner.

    This information will only translate into therapy if suitable methods of upregulating activity are developed, and the pharmaceutical industry has had far more luck with inhibiting than with enhancing enzyme activity. Whatever the approach, investigators must carefully monitor the upregulation of enzymes, which are likely to have pleiotropic effects and therefore could cause serious side effects.

    View all comments by Dominic Walsh