Refining the kokanee salmon model of vertebrate brain aging and Alzheimer's Disease: progress in cloning the presenilin-1 gene.
Over 85 point mutations in the presenilin genes, PS1 and PS2, are
known to cause early onset Alzheimer's Disease with 100%
penetrance. PS1 is believed to function as the "gamma
secretase" that cleaves amyloid precursor protein to yield
beta-Amyloid (A [beta]) peptides. Cerebral A [beta] peptides aggregate
into extracellular deposits called plaques, the presence of which is
used to diagnose AD. Although most animals used in AD research
don't naturally produce A [beta] plaques, kokanee salmon both
naturally and invariably produce A [beta] plaques during migration and
spawning. We sequenced 374 nucleotides of a putative kokanee PS1 that is
74% identical to transmembrane regions 2-5 of human PS1. The salmon PS1
partial sequence does not bear any of the published sequence variations
that are known to cause AD in humans. Complete sequencing of kokanee
salmon PS1 will allow comparison of salmon and human PS1 sequences and
in-vitro biochemical activity, and also permit characterization by
in-situ hybridization of salmon PS1 mRNA expression during spontaneous A
[beta] plaque formation and accelerated neurodegeneration. We hope that
these studies will lead to the development and use of a novel
nontransgenic model of A [beta] plaque formation and accelerated
neurodegeneration with implications for human brain aging and AD.
Steven L. Hobbs *, Pei-San Tsai, David O. Norris * EPO Biology,
University of Colorado, Boulder.
* Denotes membership in the Colorado-Wyoming Academy of Science.