Novel Neuroprotective Function of Apical-Basal Polarity Gene Crumbs in Amyloid Beta 42

Alzheimer's disease (AD, OMIM: 104300), a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (A[beta]42) aggregates that trigger neuronal cell death by unknown mechanism(s). We have developed a transgenic Drosophila eye model where misexpression of human A[beta]42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb) as a genetic modifier of A[beta]42-mediated-neuropathology. Misexpression of A[beta]42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the A[beta]42-mediated-neurodegeneration. Co-expression of full length Crb with A[beta]42 increased severity of A[beta]42-mediated-neurodegeneration, due to three fold induction of cell death in comparison to the wild type. Higher Crb levels affect axonal targeting from the retina to the brain. The structure function analysis identified intracellular domain of Crb to be required for A[beta]42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in A[beta]42-mediated-neurodegeneration.