DYRK1A antagonists rescue degeneration and behavioural deficits of in vivo models based on amyloid-β, Tau and DYRK1A neurotoxicity

Alzheimer's disease (AD) involves pathological processing of amyloid precursor protein (APP) into amyloid-& beta; and microtubule associated protein Tau (MAPT) into hyperphosphorylated Tau tangles leading to neurodegeneration. Only 5% of AD cases are familial making it difficult to predict who will develop the disease thereby hindering our ability to treat the causes of the disease. A large population who almost certainly will, are those with Down syndrome (DS), who have a 90% lifetime incidence of AD. DS is caused by trisomy of chromosome 21 resulting in three copies of APP and other AD-associated genes, like dual specificity tyrosine-phosphorylation-regulated kinase 1A (DYRK1A) overexpression. This implies that DYRK1a inhibitors may have therapeutic potential for DS and AD, however It is not clear how overexpression of each of these genes contributes to the pathology of each disease as well as how effective a DYRK1A inhibitor would be at suppressing any of these. To address this knowledge gap, we used Drosophila models with human Tau, human amyloid-& beta; or fly DYRK1A (minibrain (mnb)) neuronal overexpression resulting in photoreceptor neuron degeneration, premature death, decreased locomotion, sleep and memory loss. DYRK1A small molecule Type 1 kinase inhibitors (DYR219 and DYR533) were effective at suppressing these disease relevant phenotypes confirming their therapeutic potential.

Automated summary

Alzheimer's disease involves the abnormal processing of APP and Tau proteins, leading to neurodegeneration. Only a small percentage of cases are familial, making prediction and treatment difficult. Down syndrome patients have a higher risk of developing AD due to genetic factors. Drosophila models with overexpression of DYRK1A showed neurodegeneration, and small molecule inhibitors of DYRK1A were effective in suppressing disease phenotypes.