Abstract
Alzheimer's disease (AD, OMIM: 104300), a progressive neurodegenerative disorder with no cure to date, is caused by the generation of amyloid-beta-42 (Aβ42) aggregates that trigger neuronal cell death by unknown mechanism(s). We have developed a transgenic Drosophila eye model where misexpression of human Aβ42 results in AD-like neuropathology in the neural retina. We have identified an apical-basal polarity gene crumbs (crb) as a genetic modifier of Aβ42-mediated-neuropathology. Misexpression of Aβ42 caused upregulation of Crb expression, whereas downregulation of Crb either by RNAi or null allele approach rescued the Aβ42-mediated-neurodegeneration. Co-expression of full length Crb with Aβ42 increased severity of Aβ42-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 Aβ42-mediated-neurodegeneration. We demonstrate a novel neuroprotective role of Crb in Aβ42-mediated-neurodegeneration.
Highlights
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no effective cure to date
AD neuropathology is associated with two types of abnormal protein deposition in the human brain viz.: (1) neurofibrillary tangles (NFTs) containing hyperphosphorylated forms of a microtubule associated protein Tau, and (2) the accumulation of the amyloid-beta (Ab42) peptide [1,2,3,4,5,6,7,8]
Using the Gal4/UAS system [21], we have developed an AD model with transgenic flies [3] where high levels of Ab42 are misexpressed in the differentiating photoreceptor neurons of the fly retina using a Glass Multiple Repeat driver [22] (GMRGal4.UAS-Ab42, hereafter GMR.Ab42)
Summary
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no effective cure to date. AD is characterized by the progressive loss of neurons in the hippocampus and cortex causing decline in cognitive and behavioral functions eventually leading to the death of the patient [1,2]. AD neuropathology is associated with two types of abnormal protein deposition in the human brain viz.: (1) neurofibrillary tangles (NFTs) containing hyperphosphorylated forms of a microtubule associated protein Tau, and (2) the accumulation of the amyloid-beta (Ab42) peptide [1,2,3,4,5,6,7,8]. Accumulation of Ab42 impairs basic cellular processes due to oxidative stress, misregulation of intracellular calcium, ER stress [10], and aberrant signaling through interaction with several receptors [3,5,6,8], which results in the death of neurons [7]. It is important to understand the mechanism underlying Ab42 mediated cell death and neurotoxicity
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