The Link Lab

Project Summary

Our laboratory uses the simple nematode worm Caenorhabditis elegans to study the basic biology of human amyloid diseases, including Alzheimer's Disease (AD). The key assumptions here are that some of the molecular and cellular events underlying amyloid disease pathology are likely to occur even in a simple metazoan such as C. elegans, and the experimental advantages of this model system will simplify understanding these events. Our general approach is to : 1) construct transgenic C. elegans animals expressing human amyloidic proteins, 2) determine the resulting physiological effects, and 3) seek to determine the molecular basis of these effects.

Most of our work has employed transgenic animals that contain a chimeric unc-54/beta 1-42 minigene that leads to muscle-specific expression of the human beta-amyloid peptide. Expression of this peptide leads to amyloid deposits similar to those observed in the human brain. Animals expressing the beta-amyloid peptide are unhealthy and show a progressive paralysis.

To investigate the relationships between the primary sequence of the beta peptide, the formation of beta-amyloid deposits, and cellular toxicity, we have generated a series of transgenic worms expressing single amino acid variants of the beta peptide, as well as a novel single chain dimer construct. As we have recently reported the met35cys and single chain dimer variants show a sitdramatic reduction in thioflavin S-reactive (amyloid) deposits, despite expressing appropriate levels of the human peptide.

Our current work is focusing on the characterization of mutations that suppress the paralysis observed in amyloid worms, and examining the effect of amyloid expression on global gene expression using DNA microarray analysis.

These studies employ a new transgenic strain with temperature-inducible muscle-specific expression of the beta 1-42 minigene.  Induction of the beta peptide in this strain leads to paralysis and arrest.  Control transgenic animals which do not express the beta peptide show wild type movement.  Please note "paralysis and arrest" and "wild type movement" are movies and may take a few minutes to download.

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