Marine tunicate tadpoles developed brain plaques within 24 hours of APP administration, as reported in Disease Models & Mechanisms.
San Diego State University researchers have discovered a potentially valuable model for Alzheimer disease (AD) research and drug testing in the form of the sea squirt Ciona intestinalis.
The team reports on their studies with the marine tunicates in a paper titled “Ascidians: an invertebrate chordate model to study Alzheimer’s disease pathogenesis,” which appears in Disease Models & Mechanisms.
The fact that vertebrate models can take months or years to generate AD plaques is one reason why researchers are increasingly turning to the use of invertebrate model systems, particularly Drosophila and C. elegans, for research and drug screening, explain lead authors, Mike Virata, Ph.D., and Bob Zeller, Ph.D. However, because these nonchordates have a distant evolutionary relationship to vertebrates, research findings can be difficult to extrapolate to humans. The lack of BACE exhibiting β-secretase activity in both flies and worms has complicated efforts to examine amyloid precursor protein (APP) processing in these systems, they point out.
In contrast, sea squirts are possibly the closest invertebrate relatives to humans, Drs. Virata and Zeller claim. The animals not only share about 80% of their genetic make-up with humans, but in their immature forms as tadpoles, they also resemble vertebrates. In addition, bioinformatics analysis indicate that the sea squirt genome contains orthologs of all Alzheimer-relevant genes.
The latest findings suggest that the sea squirt may represent the first invertebrate model of AD capable of correctly processing APP to generate the plaques characteristic of the disease. When the researchers administered APP to sea squirt tadpoles, the animals rapidly formed amyloid beta containing plaques in their brains within just 24 hours. Treating the plaques with an experimental antiplaque drug subsequently reversed both plaque formation and the accompanying behavioral defects demonstrated by the tadpoles.
“Our results suggest that the ascidian will be a useful, rapid, invertebrate chordate model system to study the early stages of Alzheimer’s disease,” the scientists state. “Through its use, we believe that fundamental questions regarding the molecular mechanisms coordinating AD and its pathogenesis will be answered. Furthermore, owing to its small size and experimental tractability, the ascidian may permit cost-effective and rapid screening of candidate therapeutic compounds for AD early in the drug development process.”