Alzheimers Model Develops Early ADHD Syndrome

Alzheimer’s disease (AD) is a major healthcare problem, with over five million patients in the United States, and an annual economic impact of approximately $200 billion. With recent therapeutic trial failures and a rapidly increasing number of cases, improved approaches for high-throughput screening of large compound numbers are needed. To this end, simple models of AD, such as cellular models, invertebrate models, and transgenic mouse models, have been created. However, the invertebrate models described to date displaynumerous dissimilarities to human AD, such as expression of the relevant gene in muscle or eye rather than brain, and the hyper-expression of the gene, leading to generalized motor reflex deficits. In an effort to create a more relevant Drosophila AD model, we utilized the gene switch approach, inducibly expressing low levels of human amyloid-β precursor protein (hAβPP) and human β-site AβPP cleaving enzyme 1 (hBACE1). Surprisingly, this expression led to a phenotype highly reminiscent of attention deficit hyperactivity disorder (ADHD), with hyperactivity, male predominance, marked exacerbation by simple carbohydrates, reversible response to dextroamphetamine, and a “paradoxical response” to stimulants, all characteristics of human ADHD. This represents the first invertebrate model of ADHD faithfully reproducing these key features of ADHD.

We sought to create an invertebrate model of AD that more closely mimics the human disease in target tissue, mnemonic effects, and response to candidate therapeutics. To create such a Drosophila AD model, we used the RU-486-induced Elav-GeneSwitch driver to express low levels of hAβPPand hBACE1 in Drosophila. Previous studies have shown that over-expression of hAβPP and hBACE1 leads to severe motor reflex deficits. We therefore employed the Drosophila population activity monitors to measure spontaneous activity. Surprisingly, these flies were not found to be hypoactive compared to the uninduced controls, but rather were hyperactive, typically 50-100% more active than the control, uninduced Drosophila.