Alzheimer’s disease (AD) affects an estimated 27 million people worldwide. AD patients exhibit early memory loss, followed by a gradual decline in cognitive functioning, and ultimately death. There is no cure, and the drugs that are currently in use treat the symptoms without slowing progression. Accumulation of amyloid beta (Aβ) peptide oligomers, the principal component of the characteristic senile plaques, in the brain is crucial for AD development, and drugs targeting the secretase enzymes that regulate the conversion of amyloid precursor protein (APP) into Aβ peptides are under clinical investigation. However, there is still a pressing need for further fundamental research, and for more and better drugs directed against both known and novel targets.
Mouse models have been used to study AD pathogenesis, but are of limited use for high-throughput drug development and testing, as disease onset is slow. Transgenic Drosophila and C. elegans can also recapitulate several aspects of AD histopathology, particularly the formation of Aβ plaques, but these invertebrates may not be the most appropriate models for understanding human neurological diseases, owing to their distant evolutionary relationship to humans. The closest invertebrate relative of humans is the ascidian, or sea squirt, and recent technological advances make it a feasible model organism.
The authors use the ascidian Ciona intestinalis to study AD pathogenesis, specifically human APP processing and Aβ plaque formation. Unlike other invertebrate models, ascidians contain all AD-relevant genes including a putative β-secretase (BACE) homolog, and a transgenically expressed human APP is processed in the ascidian in a manner similar to vertebrates. In ascidians, the expression of an altered form of human APP containing mutations that are analogous to those found in early-onset inherited forms of AD causes aggressive plaque formation in less than 24 hours, as compared with weeks in other animal models. Transgenic ascidian tadpoles expressing the human Aβ peptide also develop plaques extremely rapidly, and attach poorly to a solid surface, suggesting AD-like neuronal dysfunction. Importantly, reducing Aβ aggregation either by using the anti-amyloid drug 3-APS or by expressing an Aβ-CFP fusion protein improves larval attachment and reduces plaque numbers.
Implications and future directions
This study suggests that the ascidian is a suitable model system to rapidly examine AD pathogenesis, and that it could be a technically feasible and cost-effective method for conducting high-throughput in vivo drug screening for anti-amyloid therapeutics. Future work should determine the specific behavior(s) affected as a result of Aβ expression, such as larval light and gravity responses, and whether transgenic ascidians exhibit other aspects of the complex pathology of AD, including tau pathogenicity and the mechanisms of neurodegeneration.